The Psychedelic Renaissance - 3rd Edition
Excerpt from Chapter 9: A sneak preview of some of Chapter 9, on the latest developments in the world of psychedelic research. Enjoy!
CHAPTER 9
The Psychedelic Renaissance Part Two: Contemporary Research
Evidence-based practice!
When do we want it?
After peer review!
— Banner held by anonymous protester at a 2011 Occupy March
So Many New Developments!
The landscape has changed considerably since the last edition of this book. Not only are there now far more university-based academic teams studying psychedelics, but as described in the previous chapter, we now also have a load of private psychedelic pharmaceutical companies and biotech enterprises part of the game. And because this psychedelic research and development universe is so dynamic, it would be impossible to document all of the ongoing activities in a static print book like this.
Thankfully we also now have a great many internet-based platforms for gathering general information about current psychedelic research. One such resource is the Psychedelic Educators Network, provided by Psychedelic Alpha1. It contains a quite extraordinary amount of up-to-date information on all aspects of psychedelic research, industry developments, educational opportunities and commentary. Take a look at it. Another source for academic developments is provided by the UC Berkley Center for the Science of Psychedelics, which is an enormous database of latest published research articles2.
But before launching into the latest developments, a few brief words about why this current period of history is a psychedelic renaissance, and how it all came to an end until it began again in the 1990s.
When Did the Psychedelic Renaissance Begin?
The truth is psychedelic research never stopped entirely, but after LSD was made illegal – in the USA and most other places by the end of the 1960s - it certainly drastically reduced in volume and ceased being mainstream by the end of the 1960s. After this point, it was difficult to obtain a licence to research or work clinically with psychedelic drugs. Sandoz also stopped distributing its product and recalled all remaining stocks from people who had stockpiled Delysid, although, by then, many other places were synthesizing the drug. Czechoslovakia had a particularly good record for LSD manufacture. While these restrictions significantly reduced psychedelic research, not everyone gave up. Behind the Iron Curtain, beyond the restrictions of the Western World’s struggle with the developing drug culture, LSD research continued — especially in Czechoslovakia up until 1974 in Sadska under Dr Milan Hausner3. leaving a rich legacy of psychedelic interest throughout that country4.
In the UK, any psychiatrists who still had supplies of LSD could continue prescribing it if they wished; and this carried on into the 1970s, with the last recorded dose being given to a patient in private practice in 1976. The next time a classical psychedelic was legally given to anyone in the UK was 33 years later, when in 2009 David Nutt injected me with psilocybin5.
MDMA emerged in the late seventies and was used legally by a small handful of therapists right up to 1985. When it was banned, there followed a further 25 years of persistent campaigning to get the next MDMA human clinical research published.
Superficially the 1970s and ’80s do look a bit like the Dark Ages for psychedelic research. There was certainly a big comedown from the exuberance enjoyed in the fifties and sixties, but not all the lights were out. In 1971 Nixon launched The War on Drugs (though of course legislation to limit the range of legally sanctioned states of consciousness had actually been in place since the beginning of the century). Throughout the world psychedelics found themselves targeted by politicians. There were still some medical voices prepared to stand up for psychedelic research, but once LSD was banned most doctors were not happy to work outside the law. There were simply not enough medics prepared to stand up to the anti-psychedelic stance forced upon the profession by paranoid governments6.
In the 1970s it became a fashionable topic in psychiatric research to propose biological mechanisms for schizophrenia. The psychoanalytical and ‘schizophrenogenic mother’ theories of the 1950s were being rapidly eroded as the profession learned more about genetics and neurobiology7. With the prevailing social attack on psychedelics in the early 1970s, there was a flurry of research proposing links between drugs and schizophrenia and LSD was one of the first candidates in their sights. Despite the lack of similarities between the psychedelic state and schizophrenia that had been adequately dismissed by the psychedelic researchers of the 1960s, the suggestion that LSD could cause schizophrenia became hotly debated8. Whilst it is arguable that a person with pre-existing psychosis ought best to avoid psychedelics for fear of precipitating an acute episode, there were, at the time, many important objections against the suggestion that LSD causes schizophrenia, including the phenomenological distinctions and the lack of epidemiological correlations9. The overall rates of schizophrenia did not increase during the wide scale use of LSD nor decline as the drug became less popular in subsequent decades. Schizophrenia has remained at a reasonably steady rate throughout the world, for generations, with a lifetime prevalence of around 1%. And as the 1970s progressed and more research emerged it became clear that other drugs, not the psychedelics, were more likely candidates as a primary cause for schizophrenia10. Most studies found higher associations between schizophrenia and the use of potent dopamine agonists such as cocaine and amphetamine, as opposed to the use of hallucinogens.
However, LSD and her cousins remained under the spotlight as drugs that cause harm. And throughout the 1970s, LSD became difficult to get hold of for legal medical uses. By then it did look as if it was all over for LSD as a mainstream treatment for mental illness. What a long, strange trip it had been.
So, although psychedelic research never completely went away, in the last 20 years we have seen an unprecedented growth of psychedelic interest within the mainstream, which is what this current renaissance is all about.
How to Get a Drug to Market
For those not familiar with how a research team gets a drug approved as a clinical medicine, I will gave a brief description. It is frustrating when I hear pseudoscientists arguing against what they see as the corporatisation of psychedelics, with unexperienced arguments about accessibility to medicines, when they clearly don’t understand the fundamentals about the infrastructure of the pharmacology business. It is a subject that one needs to understand if one is to comment on the current developments in the psychedelic industry11.
However, whilst anecdotal reports of personal drug experiences are, a) often rather dull, and b) not considered ‘science’, there is nevertheless a wealth of information to learn about how people outside of science use psychedelics for personal growth and development12. Many clinical treatments in medicine first arise out of accidental anecdotal experience. Many others arise because a pharmaceutical company has specifically designed a new molecule with a target in mind. When a new chemical emerges in this way, there are pre-clinical studies that must be carried out to test whether the chemical is safe to be given to humans. In vitro (which means literally “in glass”) involves adding concentrations of the chemical to isolated slices of biological material (heart, lungs, kidneys, brain, etc.) outside of a living organism, to determine the drug’s toxicity tissues. The new chemical will also be tested in living animal models, which provides further information about safety and toxicity. This process of animal testing is highly controversial for many people outside the field of pharmacology and understandably often arouses a strong emotional response — especially amongst many in the psychedelic community. Nevertheless, it is doubtful LSD would have ever made it out of Hofmann’s lab without such studies. (Whether someone else might have discovered LSD had Hofmann not, remains an interesting question).
The next part of the process of drug development is known as ‘Phase 1 studies’ in which the drug is tested on healthy human volunteers; that is, people without the specific disorder the drug is intended to treat. The purpose of such tests is to gather information about appropriate safe doses and subjective effects of the new drug. Volunteers, often students at the university where the research is being carried out, are usually paid for their services. I have taken part in lots of such trials, though never paid, because I find them interesting. Once this part is over, one can begin the Phase 2 studies. These involve small-scale clinical trials in which the drug is given to handfuls of patients with the specific disorder one is testing.
Clinical studies must be rigorously designed to reduce as many aspects of bias as possible. The gold standard for drug development is the double-blind placebo controlled randomised study, in which identically matched subjects are randomly assigned into a control group or an experimental group. Then experimental group gets the active drug and the control gets the placebo drug (they look identical). Neither the subjects (single blind) nor the examiners (double blind) know which group has been given which drug, to try and avoid any expectancy effects or observer bias. In this way one hopes to demonstrate that any differences seen in outcomes between the two groups can be put down entirely to the physiological action of the drug and not due to any influences from either the test subjects or the experimenters. Phase 2 studies can be divided into phase 2a and phase 2b. In phase 2a, the drug is transparently given (‘open label’). Both the examiners and the subjects know what drug is being given. The phase 2a study will provide data about safety and dose response but cannot provide efficacy data (whether the drug effects actually work). A phase 2b, however, is blinded, which can provide data about efficacy, and is essentially a ‘mini phase 3’ approach. Sometimes phase 2a studies morph into a phase 3, as the best protocol for conducting the study emerges. Between 10 to 40 people is usual in a phase 2b study, depending on how much funding the team has to provide results that would meet statistical analysis.
After Phase 2 comes Phase 3, in which the established best treatment regime with the new drug is rolled out to larger, multicentre groups for wide-scale testing on clinical patients. In this way, many hundreds of patients will receive treatment under a standardised protocol to ensure uniform results. Then, with all the phase 3 data collated, analysed and written-up, one submits to the data for approval by a regulatory agency (in the States it is the FDA, in the UK it is EMA and MHRA). If it gets approved by the regulatory agency, at this point, your new molecule has become an official medicine (with a capital M). From here the newly licensed and approved drug may then go out to market, but under a restricted license. Thousands of patients will get to use it in an open-label fashion (that is, they know what they are taking, rather than blindly) and their doctors will closely monitor their process and document any adverse effects to the drug company.
The timescale and costs of the process described above are extremely variable. It can take between 5 and 20 years to get a drug to market in this way. Today the average cost of getting a brand-new drug to market is around £75 million.
How This Research Method Relates to Psychedelic Drugs
As we have discussed in the previous chapter, the interesting thing about the psychedelic drugs is that we have literally tens of millions of cases of anecdotal uses of the drugs LSD, psilocybin, MDMA, ketamine, ibogaine, ayahuasca, cannabis and others over many decades — largely with safe and positive therapeutic effects.
This is great, but because these non-clinical, recreational or ceremonial uses have been occurring outside of the official clinical environment, such cases are not enough for the regulatory authorities to immediately support these drugs becoming licensed medicines. And although people have been consuming psychedelic drugs for millennia and their toxicity profiles are low, we still must carry out all the pre-clinical studies described above, as if they were brand new, just invented novel molecules. Only once the drugs are deemed safe for human consumption using the standardized tests, can the psychedelic drugs become Medicines.
One might have thought that the costs and timescales for getting psychedelic drugs to market ought to be quicker than for a genuinely brand new invented chemical with no documented human use, like Prozac or Viagra, but this is not the case. Although we may already know from anecdotal use psychedelics are relatively safe, this does not count as sufficient data for regulatory authorities, who are not the least bit interested in the drugs’ thousands of years of recreational use. Furthermore, because the psychedelic drugs are all controlled or illegal drugs, one must have government approval to work with them, which means jumping through many legal and political loopholes and even putting up with unwanted media intrusions into one’s research. The sum of the unbelievably harsh regulatory processes applied to this kind of research makes the process prohibitively lengthy and costly — as we have seen with MAPS’s extremely costly and lengthy journey to see MDMA licensed as a treatment for PTSD.
Looking at the Contemporary Research for the Drugs
As a departure from previous editions of this book, I have decided to categorise the current research topics by functional or psychiatric indication – rather than by compound. This also makes sense in the context of how many new, novel compounds have arisen in recent years, with a focus on diagnostic targeting, rather than the molecules themselves.
This (very long!) chapter will explore the latest psychedelic research on the following topics:
1. Psychedelic research to inform neuroscientific research into neuroflexibility and neuroplasticity
2. Psychedelic research to treat neurodegenerative, neurodevelopmental and neurological disorders
3. Psychedelic research to treat post traumatic stress disorder (PTSD)
4. Psychedelic research to treat depressive disorders
5. Psychedelic research to treat anxiety disorders
6. Psychedelic research to treat addiction disorders
7. Psychedelic research to treat eating disorders
8. Psychedelic research to manage personality disorders
9. Psychedelic research associated with neurodiversity and autism spectrum disorders
10. Psychedelic research informing neuroscience
11. Contemporary microdosing research
1. Psychedelics to Inform Research into Neuroflexibility and Neuroplasticity
Neuroflexibility – or neuroplasticity – is an incredibly sexy subject in psychedelics today. It has received a lot of research activity – and not only within the psychedelics field, but in neuroscience and psychiatry in general13. It refers to the concept that brains are ‘plastic’ and will shift, change, develop, bend and adapt according to dynamic changes and influences, to move towards an alteration in functioning. In its simplest terms, it makes perfect sense in a cause-and-effect way. Over time our brains (via the growth of dendrites and neurons) will dynamically change in the number and configuration of connections between different parts of the brain, according to the conditions that are imposed upon them.
Trauma, Stuckness and their Developmental Roots
This is, essentially, what all learning and child development is all about. Over many years of exposing a child’s brain to a harmful environment (e.g. maltreatment), the brain develops to try and adjust to this exposure (e.g. excessive fear responses as a means of survival adaption), which in turn leads to negative narratives about oneself and the world, and, eventually, we see Complex-PTSD emerging. This is an example of a negative neuroadaptive response, which leads to a poor outcome. In some ways, brains are lazy and flawed. They tend to ‘do what they are used to’. From a child development perspective, (which as a child psychiatrist by training I am bound to take), the development is overseen by a remarkable process called attachment. Attachment is the beautiful reciprocal game played between a pre-verbal infant and their primary care giver, usually (but not exclusively) their mother. The child’s brain develops in tune with the signals the care giver gives them. If the child is fortunate enough to be loved, cared for, played with and praised, the child will grow up with self-narrative beliefs that they are worthy, smart, lovable and able. But if that child is hurt, humiliated, abused or maltreated, they will develop negative beliefs about themselves, and they will see the world as dangerous and unsafe.
I see this as an unfortunate design flaw in the human brain. Wouldn’t it be great if a child, say at 16 years old, was able to say to themselves: “OK, so I was hurt and abused by my parents – whom I am supposed to trust – but they were wrong about me. In fact, I am a smart, able and worthy person, and I will choose to disregard the noxious lessons they have given me!” Sadly, that doesn’t happen. The flaw is that our brains appear to trust our attachment experience as right. That maltreated child will go into adult life believing they are useless, stupid, guilty and to blame for their problems. And this is because one’s attachment relationship becomes the blueprint by which we measure our future versions of ourselves and the world around us.
The broad word used in psychology to describe this process is ‘trauma’, and it is arguably the root cause of most lifelong mental health problems in those individuals who are genetically susceptible; whatever the diagnosis14. Whether one looks at depression, anxiety, addictions or PTSD, one consistently sees that trauma – especially childhood trauma – often underpins their life experience. Sometimes in psychiatry we might talk about ‘Big T’ trauma versus ‘little t’ trauma, where Big T refers to issues such as sexual and physical abuse – the kind of abuse that hits the social services radar for children - and little t being emotional abuse and neglect, where the child is not subjected to physical or sexual harm, but through repeated experiences of humiliation, denigration and neglect they are nevertheless no less abused. I always say, ‘Don’t take your eye off the ball when it comes to emotional abuse’. Repeatedly telling a developing child that are stupid, useless, ugly and unloved can have a devastating effect on their sense of self and psychological development.
I am useless
I am a failure
I am unloved
I am unlovable
People cannot be trusted
World is a dangerous place
I am unsafe
It’s my fault
I deserve to feel like this
This leads to:
Depression
Anxiety
PTSD
Eating Disorders
Addictions
And the other big problem with brain development governed by attachment, is that once those narratives are present, they tend to become fixed and rigid. If a child has been exposed to negative stimuli for 16 years, it will take a lot more than a psychotherapist or friend saying, “No! You aren’t useless. You are fine! Pull your socks up and think positively!” And nor will a ton of Prozac have any effect on those fixed narratives.
It is the fixedness, the rigidity and stuckness of this situation that results in so many mental disorders becoming lifelong, chronic and difficult to treat – or what we might call treatment-resistant. Sometimes one can work for years with a patient, trying all the available SSRIs, sleeping tablets and mood stabilisers on the market, and putting the patient through decades of psychotherapy, and they are still left believing the negative narratives about themselves that they heard in their first five years of life. It is incredibly sad. Psychiatry can be a desperate and lonely place in which to work sometimes. No matter how much we try to shift our patients’ negative beliefs about themselves, they remain stuck – and unwell with depression, anxiety, PTSD or addictions. So, how do we disrupt this stuckness?
Disrupting the Stuckness with Psychedelic Neural Flexibility
This is where psychedelics come in. There have been emerging evidence over recent decades that psychedelics– for a few brief hours - ‘shake the snow globe’ – a great term coined by my mate Robin Carhart-Harris, in such a way as to increase connectivity and put the brain into a temporary neuroplastic / neuroflexibility state, to such a degree that it has not enjoyed since infancy15. Under psychedelics, there is a rapid proliferation of new dendritic connections, akin to a very fast period of learning, which has been extensively studied in recent years16,17. And in this ‘plastic’ state, the patient is able – for the first time in decades of mental illness – to tackle their rigid negative narratives. For a few privileged hours under LSD or psilocybin, ‘anything is possible’, and when this is translated to a patient who has been dogged by stuck, rigid narratives, which underpin their unremitting mental illness, this sudden moment of flexibility gives them a chance to re-appraise their emotional belief in themselves. And when combined with focused psychotherapy, the plastic changes can be remoulded and maintained. The clinical application of this physiological change in brain state is clear18,19.
Picture HERE:
Psychedelic neuroflexibility and plasticity. Picture taken from the excellent paper by Ly et al (2023)17
In his seminal series of papers on this subject, over the course of ten years, Carhart-Harris and his team at Imperial College London, in collaboration with the Beckley Foundation, and under the auspices of Professor David Nutt, have used multimodal imaging, with functional Magnetic resonance imaging (fMRI) in combination with Magnetoencephalography (MEG), to demonstrate the changes in brain activity that occur in healthy subjects when under the influence of three classic psychedelic drugs – psilocybin20, LSD21 and N.N.-DMT22. It is impossible to ignore the importance of this series of neuroscientific work. Not only has Robin’s work demonstrated that all three of those classic psychedelic drugs have a similar mode of action in the human brain, but the findings have opened the way for a better understanding of how normal consciousness works. And this then opens the way to developing new clinical applications for psychedelics.
Picture HERE:
This picture showing increased network connectivity between multiple brain regions on psilocybin, compared to placebo, has become a famous and often reproduced site in popular psychedelic literature. It first appeared in the Journal of the Royal Society23.
Psilocybin
The early results of this work, initially with LSD, was published in the distinguished Proceedings of the National Academy of Sciences (PNAS) journal and were tremendously well received. A glitzy press launch at the Royal Society in London in April 2016 was attended by psychedelic pioneers of old and new and caught the media’s attention. Using LSD as a tool alongside multi-modal imaging techniques to investigate the neural correlates of consciousness, the study has advanced the understanding of neuroscience by decades. Results showed that LSD increases connectivity between multiple neural networks in the brain and modulates the brain’s default mode by reducing blood flow to the posterior cingulate cortex and medial prefrontal cortex. Activity and connectivity between the occipital cortex (the visual centre) and other parts of the brain is greatly increased21. As Robin describes it:
"Normally our brain consists of independent networks that perform separate specialised functions, such as vision, movement and hearing - as well as more complex things like attention. However, under LSD the separateness of these networks breaks down and instead you see a more integrated or unified brain.
"Our results suggest that this effect underlies the profound altered state of consciousness that people often describe during an LSD experience. It is also related to what people sometimes call 'ego-dissolution', which means the normal sense of self is broken down and replaced by a sense of reconnection with themselves, others and the natural world. This experience is sometimes framed in a religious or spiritual way - and seems to be associated with improvements in well-being after the drug's effects have subsided.”
The Entropic Brain
Another popular meme that has come out of Robin Carhart-Harris’s work and the concept of flexibility is that of the entropic brain theory24. Entropy is the physical process whereby systems that are highly organised, when left to their own devices, the natural order of the universe is that they move towards a less ordered, less complex and more chaotic state. A good example is a cup of coffee. To create that cup of coffee one needs to put a lot of energy into that closed system, to warm the water. At that point the coffee cup is ‘highly organised’. All the heat from that energy put in is closed in that cup. But once made, if you then just leave the cup of coffee on a table, it will slowly cool down. The energy that was encapsulated in the water will gradually diffuse into the atmosphere. The system would become ‘less organised’, with the energy spread out beyond the cup. Incidentally, no energy is ever lost. Rather, as the coffee becomes cooler, the room becomes (very slightly) warmer.
The idea is that we can think of the rigid, stuck brain state as being in a low state of entropy. It is too ordered, too tidy. This is analogous to certain pathological mental states such as depression (too many negative thoughts, not enough room for other versions of self) or anxiety (too many fearful thoughts and ruminations on singular worries, with no room for alternative explanations – OCD is a good example), and addictions (a singular pursuit of an addictive substance – with no space for considering alternative strategies to manage one’s emotions). This stuck state is ‘too organised’, and results in rigid and narrow thinking: “I must have my alcohol/heroin/nicotine…I cannot accept any other scenario.”
When on psychedelics, or when dreaming, or inside the brain of infants however, the brain is in a greater state of ‘chaos’. It is less fixed and rigid. Psychedelic drugs induce neuroplasticity and neuroflexibility, and the brain suddenly becomes rewired, with multiple new connections and pathways appearing that were previously not present. Now, it might sound on the surface to be an unpleasant experience to have one’s brain in a state of chaos for a few hours. And indeed, it can be difficult and challenging at times, which is why we provide so much support for patients undergoing psychedelic therapy. But from a clinical point of view, those few hours in which the brain is ‘chaotic’ and less rigidly organised into maladaptive and stuck patterns of thinking is ‘the holy grail’ opportunity for psychotherapy.
The pictures below illustrate the concept. The bedroom on the left is highly organised and tidy. Everything is neatly put away and in its place. It requires a fair amount of energy to get the bedroom into this state (like putting energy into that cup of coffee). But if I just live in that tidy bedroom, after a while it will naturally move towards the bedroom on the right. Less organised and more chaotic.
Now, as mentioned, no one wants to live in a messy bedroom all the time. Just as no one wants to be on LSD on magic mushrooms all the time, it would be very irritating to always be in a state of chaos. But if one’s problem is that one has too much organisation and rigidity in one’s brain, then a few hours spent in the chaotic, malleable, open-minded psychedelic state – when combined with careful support and focused psychotherapy, then the many new possibilities of thinking can lead to new ways of looking at one’s life.
Picture HERE:
Rigid/ narrow thinking, ruminations, depression, addictions and anxiety.
“I am useless and worthless. Nothing can change my mind about this.”
As seen in dream states, infantile consciousness and when on psychedelic drugs.
“Wow, I can be anything I want! Maybe I’m not as useless and worthless as I thought?”
MESSY BEDROOM
High state of entropy:
Highly chaotic
TIDY BEDROOM
Low state of entropy:
Highly organised
For me, it has been an immense personal and academic pleasure to have been involved with a number of these Imperial College-Beckley studies alongside Robin Carhart-Harris, Amanda Feilding, David Nutt, Leor Roseman, Mendel Kaelen, Mark Bolstridge, David Eritzoe, James Rucker, Tim Williams and so many other people in the Imperial College London Centre for Psychedelic Research team between 2010 and 2020 when that series of studies were being conducted. We could never imagine that what started with that humble moment when David Nutt injected me with IV psilocybin and Robin slid me under that wooden mock MRI scanner in a lowly clinic room in Bristol’s Royal Infirmary, to demonstrate the safety of psilocybin humans, that so much world-changing science would have emerged in the work that followed25,26.
Picture HERE:
The Imperial College London LSD Pilot Study crew in Cardiff in 2015. With Neiloufar Family, Robin Carhart-Harris, Mendel Kaelen and Mark Bolstridge. A selfie at the end of a day’s dosing from one of their intravenous LSD volunteer test subjects.
Picture HERE:
The Imperial College Psilocybin fMRI Team, Cardiff, UK, 2014. Drinking non-alcoholic fizz out of plastic cups after discharging the final participant. Robin Carhart-Harris, Luke Williams and Tim Williams.
Flexibility-Inducing Psychedelics as Transdiagnostic Treatments
Sticking with the theme of neuroflexibility, there is now increasing scientific evidence emerging that all the psychedelics – whether they be psilocybin and LSD27,28, N.N.-DMT29, 5-MeO-DMT30, MDMA31,32,33,34, or ketamine35,36 appear to have similar neuroflexibility effects on the brain37,38,39. And, having stated earlier that most chronic, difficult to treat, psychiatric diseases – whether they be depression, anxiety, PTSD or addictions – have their developmental roots in early childhood, what we see now emerging is that psychedelic drugs – through their neurobiological actions to induce neuroflexibility – when combined with psychotherapy, all do the same thing for pretty much all, psychiatric disorders. That is, psychedelic psychotherapy – with any psychedelic drug – can be considered truly transdiagnostic40. This is a fascinating finding of the last ten years. Basically, as a clinician, you could use either psilocybin, MDMA, ketamine, or 5-MeO-DMT on just about any diagnosis – and it is likely to be effective at relieving that patient’s symptoms.
But is it the essential combination of the drug’s effects, coupled with focused psychotherapy, that makes the treatments so effective. The drug can be seen as a ‘primer’, to set the brain up in a highly flexible, plastic state, and then ‘hitting the patient’ at that point with focused, bespoke psychotherapy, results in the ability to tackle old narratives and form new, lasting versions of themselves. And then, finally, after decades of unshifting mental illness, the patient can reboot, defrag, rebuild and reappraise their psychological problems.
Psilocybin
Ketamine
MDMA
Creates Neuroplasticity
Biologically opens window of opportunity.
Patient can imagine new possibilities and can tackle their rigid narratives. This allows for lasting psychological change
Add BESPOKE FOCUSED PSYCHOTHERAPY here
Picture HERE:
Perhaps the most important picture in this whole book to summarise how psychedelics work to treat intractable mental disorders!
How do we work in that window of opportunity?
So, once primed with an acutely administered psychedelic drug (of any kind), it is then the skill of the psychotherapist to work within that psychedelic state, that window of opportunity, that ‘messed up bedroom’, to help the patient to access, challenge and resolve those emotional aspects of themselves that have hitherto been stuck, but are now loosened and ripe for reappraisal. The drug has caused a loosening of the ego, provides access to the unconscious, where repressed memories can be worked through in real time in a non-directive fashion.
Not all the psychotherapeutic work takes place during the drug session. And all psychedelic therapy courses are always a mixture of drug and non-drug sessions. Some drugs allow for real-time psychotherapy during the drug experience; MDMA is particularly good for this, as the ‘switched off’ amygdala means the patient can explore past forbidden or painful memories that they would usually avoid. With ketamine-assisted therapy on the other hand, the patient is usually completely ‘knocked off’ in a deep dissociative state, and very little, if any talk therapy takes place during the acute fully-dissociated drug experience. This makes the importance of the next day, non-drug session so valuable.
I have had the experience of patients the day after a KAP drug session coming into the clinic and saying things like, “I used to think I was useless and a failure….But now, weirdly, after yesterday’s ketamine session, I’m not so sure that’s true…Maybe there are other versions of myself that I hadn’t considered before?…” It’s remarkable, and highly satisfying as a therapist to literally see before you a new brain in a new plastic and flexible state.
2. Psychedelics to Treat Neurodegenerative, Neuro Developmental and Neurological Conditions
Following on from the concept of neuroflexibility, it would be appropriate next to focus on disorders that are characterised by brain states in which there is a notable lack of connectivity, or even a lack of available brain tissue itself to allow normal functioning.
One of the cornerstones about brain damage that I was taught at medical school, is that once we lose central nervous tissue – whether that be from a stroke (which kills off areas of brain when the blood flow to that region is impaired), degenerative conditions such as Parkinsons Disease, Alzheimer’s Disease, or acute damage to the brain or spinal cord due to a severe injury –such as breaking one’s neck and being paralysed thereafter - the lesson I learned was that ‘brain doesn’t grow back’.
And a useful analogy was used, describing neurons as trees in a forest. We are born with a certain number of trees. In adolescence we undergo a pruning process, whereby we lose some neurons and many of the dendritic connections between them, networks are formed and become fixed, and we are ‘stuck’ with that configuration thereafter. We can always grow new connections between trees (analogous to branches and roots), but we can never grow any more trees again. Meaning, when we lose trees (through stroke, brain damage or degeneration diseases like Alzheimer’s), the changes are pretty much irreversible.
So, you can see why there is so much excitement about psychedelics’ potential for new brain growth through acute flexibility that leads to lasting brain changes. Perhaps with psychedelics we can now challenge that narrative that ‘brain tissue never grows again’?
Alzheimer’s Dementia and Cognitive Functioning
Alzheimer’s Dementia is a devastating illness, in which sufferers experience a slow, gradual decline in cognitive functioning as their brain is eroded by the appearance of amyloid plaques and neurofibrillary tangles in the central nervous tissue. Patients experience confusion, disorientation, have difficulty planning or making decisions, problems with speech and language, problems moving around without assistance or performing self-care tasks. Often their personality changes, they may become aggressive, demanding and suspicious of others, or they may become disinhibited and labile, and sometimes they may experience hallucinations (seeing or hearing things that are not there) and delusions (believing things that are untrue). And they frequently experience low mood and anxiety41.
Crucially, the disease is progressive. That is, it only goes in one direction: from good to worse. There are no known cures. The best the medical profession has is a bunch of drugs that may slow the progression a slight amount in some people who respond positively to the treatments. And with an aging population, the prevalence of Alzheimer’s disease is rising. This makes the dementia treatment market a lucrative opportunity for any pharma company that can come up an effective and safe new treatment.
Albert Hofmann lived until 102 years old. And it has long been suggested anecdotally that classic psychedelics such as psilocybin and LSD can lengthen life, with the issue being enthusiastically embraced by contemporary longevity industries 42 and research groups43,44,45,46. Several new start-up psychedelic pharma companies are focusing their efforts on researching Alzheimer’s disease.
One such company is Silo Pharma, who are targeting Alzheimer’s with their NCE drug SPC-14, that utilizes ketamine as one part of the formulation47. Another company is Eleusis, who has carried out preclinical research into LSD as a medicine to alter the course of Alzheimer’s disease48. And Johns Hopkins University are currently running a major study exploring the role of psilocybin in improving cognitive functioning in people with Alzheimer’s49. Another prospective interventional study – for which I was study doctor in 2015 on one of the experimental days and prescribed the drug to participants - looked at the safety and tolerability of LSD in an elderly population50. That was one of the early studies carried out by Eleusis, testing different doses, from 5 to 25 mcg, of LSD in a group of older people.
Picture HERE:
The Eleusis Corporation LSD Research Team, London, 2015.
David Luke, Leor Roseman, Russell Shernoff, Guillerme Livera, Neiloufar Family and Maria Pap.
Another recent study by Kettner et al (2024) worth mentioning here is a prospective observational cohort study that measured mental health outcomes in older people who had used psychedelics including psilocybin and ayahuasca at ceremonial retreat centres51. And an interesting study by Fonseca et al (2024) looked at the long-term health outcomes - focusing on cognitive functioning and memory – amongst regular users of ayahusaca52. This area of research is bound to continue to grow as the population ages and more people seek safe and effective treatments for Alzheimer’s disease.
Other Neurological and Pain-Related Conditions
Psychedelics are being researched as possible candidates for other neurological conditions, some of which are increasingly being understood to be autoimmune diseases, and research with psychedelics is informing this direction of scientific exploration53. Parkinson’s Disease, another hugely debilitating progressive neurological condition is being targeted by Silo Pharma and conducted at the Clinical & Translational Science Institute (CTSI) at the University of California, San Francisco (UCSF)54, and at the University of Calgary in another study55. And in Europe the European Union has recently fully funded a study of psychedelics, awarding more than €6.5 million through the EU’s Horizon Europe program. Psilocybin studies will be explored on patients with four progressive diseases: chronic obstructive pulmonary disease, multiple sclerosis, amyotrophic lateral sclerosis and atypical Parkinson’s disease56.
Chronic pain has received a lot of research attention from the psychedelic community. Especially pain associated with severe headaches, migraines and cluster headaches. It has long been known anecdotally that the classical psychedelic drugs LSD and psilocybin, when used recreationally, have a positive analgesic effect at treating the severe pain associated with cluster headaches. This incredibly disabling condition has sometimes been referred to as ‘suicide headaches’ because the intensity of pain has been known to drive some sufferers to kill themselves.
Yet frequently, when people take small, sub-psychedelic doses of LSD or magic mushrooms, not only does their headache disappear during the intoxication, but also for many weeks or even months afterwards. The mechanism for how this works is not fully understood but it probably relates to the classical psychedelics’ role as central vasoregulators. The anaesthetist Eric Kast discovered these analgesic effects of LSD in the 1960s. He carried out studies with the drug and found it to be more effective and better tolerated than traditional opiate-based analgesics57.
In modern times, the idea to study cluster headache sufferers arose when, in 2004, the internet-based support group Clusterbusters approached MAPS and asked them to evaluate the large numbers of anecdotal reports that the website was getting about the usefulness of recreational classical psychedelics for relieving cluster headache pain. A subsequent case review paper was published by the late Andrew Sewell, alongside John Halpern and Harrison Pope in 200658.
Together with Matthias Kurst, Michael Bernateck and Torsten Passie at Medizinische Hoschule Hannover in Germany, John Halpern has also been in the process of developing a non-psychedelic analogue (2-Bromo-LSD, or ‘BOL’) to be used as an alternative to the hallucinogenic effects of LSD. They subsequently carried results of their internet survey of 53 patients with cluster headaches59,60.
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Torsten Passie. Veteran psychedelic researcher whose experience continues to inspire. Here seen at the ICPR conference in Amsterdam in 2016, with Dave Luke and Björn.
The implications for this work could be far-reaching and stretch well beyond psychiatry. Because it seems that the drugs exert their analgesic effects at such low doses and without the need for specialised psychedelic psychotherapy, this kind of psychopharmacology research could radically rewrite the textbooks as far as standard analgesia for general medicine goes.
More recent studies continue to look at psilocybin as a treatment for cluster headaches and other chronic pain conditions61,62. In the light of an increasing public awareness of the potential for psychedelics to relive chronic pain, some members of the public have made the (in my opinion perfectly acceptable) decision to not wait for slow governments to push such research forward, and decided to flout the drug laws and turn to recreational use of psilocybin mushrooms and LSD to self-medicate for their pain relief63. An interesting survey carried out by The Beckley Foundation and Kim Kuypers’ team at Maastricht University has shown that psychedelic users benefit from psychedelic use to manage pain in conditions such as fibromyalgia, arthritis, migraine, tension-type headache and sciatica64.
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Eating ice cream with Kim Kuypers at a conference in Helsinki in 2018. Kim’s team have looked at how psychedelics might be beneficial for many different types of neurological disorders.
Fibromyalgia is a condition characterized by widespread chronic pain that is highly prevalent, poorly understood and inadequately managed by traditional medicine. The Imperial College London / Beckley Foundation psychedelic research group are currently conducting a study looking at the condition using psilocybin65, as is Peter Hendrick’s team at the University of Alabama, USA66. And the commercial psychedelic company Tryp Therapeutics, in conjunction with the University of Michigan, USA, have recently started dosing in their phase 2a clinical trial using psilocybin in the treatment of fibromyalgia67. As usual, these hard to treat common psychiatric / neurological disorders seem like ideal target for research groups and new companies eager to challenge traditional medicine. And what better way to catch up with the latest developments in psychedelic pain medicine than checking out the new publication by Joanne Kempner, who provides an excellent history of Clusterbusters and psychedelic pain relief in her book Psychedelic Outlaws: The Movement Revolutionizing Modern Medicine68.
Before leaving this section, we look briefly at concussion and Traumatic Brain Injury (TBI), which has attracted some attention in the psychedelic research community in recent times. Concussion and TBIs frequently occur with PTSD, and together they can cause a suite of symptoms, including depression, anxiety, irritability, fatigue, impulsivity, headaches, insomnia, nightmares, and poor concentration, attention and processing speed. The disorder is especially associated with combat-related issues, as TBI can occur in soldiers who are exposed to repeated blasts from firing artillery. Repetitive sub-concussive head injury is a known risk factor for neurodegenerative disease, including dementias. New York psychiatrist, Julie Holland, a seasoned psychedelic doctor and researcher has carried out an excellent review of the subject69.
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With Eric Vermetten at a conference in Oslo. With his joint experience of working within the military and also trained to use MDMA and psilocybin, Eric is well placed to spearhead the delivery of psychedelic therapies to combat veterans with PTSD and TBI.
Eric Vermetten, who is a psychiatrist with a career in military medicine has always been a firm supporter of psychedelic medicine. He and colleagues have published a good review on concussion and TMI and the use of psychedelics to manage this complex disorder70. There has also been a particular focus on the use ibogaine as a treatment for TBI71,72.
3. Psychedelics to Treat Post Traumatic Stress Disorder (PTSD)
Most contemporary research with MDMA has centred on its role as an adjunct to trauma-focused psychotherapy for PTSD. I have described in preceding chapters why MDMA is so perfectly suited for this kind of work. It is almost as if the drug were designed with this purpose in mind (though that is not actually the case). Having experienced first-hand the massive difficulties in helping stuck patients with repressed and intrusive memories of severe psychological trauma, my colleagues and I are absolutely committed to putting ourselves behind MDMA research.
The Multidisciplinary Association for Psychedelic Studies (MAPS) lead the way in global MDMA-for-PTSD studies. The first study (now referred to as their ‘flagship’ study) was carried out by Michael Mithoefer et al, and published in 201073.
In this initial study Michael Mithoefer, together with his co-therapist wife, the enigmatic Annie Mithoefer, provided MDMA-assisted psychotherapy for 20 patients with chronic PTSD, refractory to both psychotherapy and psychopharmacology. 12 patients received inactive placebo and eight received two or three sessions of MDMA (initial dose of 125mg, followed two hours later by a further booster of 62.5mg). Both groups received a course of preparatory and follow-up non-drug psychotherapy. Using the Clinician-Administered PTSD Scale (CAPS) as a primary outcome measure, Mithoefer demonstrated that at two and twelve-month follow-up 83% of the experimental group no longer met the criteria for PTSD, compared to just 25% of the patients in the placebo group. He also looked at neurocognitive and neurophysiological measures and showed that there were no drug-related serious adverse events, adverse neurocognitive effects or clinically significant blood pressure increases.
The Mithoefers’ study set a high benchmark for others to follow. Since the publication of this initial study in 2010, the Mithoefers immediately began collecting long-term follow-up (LTFU) data. And in 2013 they published the results of the LTFU study — having tracked the cohort of successfully treated patients with severe PTSD for up to four years after the initial single course of MDMA-assisted psychotherapy. The results showed that rates of remission were maintained; without having any further doses of MDMA since the original study, over 80% of the original cohort remain free from the diagnosis of PTSD74.
When the positive results of the flagship pilot study were released in 2010 there were initially some critical responses; with some commentators finding fault with the impossibility of maintaining the blind control. Other critics attributed the positive results to the fact that the Mithoefers themselves were so inspirational and positive that such strongly significant results could never be reproducible in further studies. However, as we can see below, the MAPS armoury of positive MDMA-PTSD results now extends far beyond the magical reach of just Michael and Annie; a mantle I am certain they are happy to hand on to others in the field.
Further MAPS phase 2 studies Exploring MDMA Therapy for PTSD
Following the success of the early pilot study, (labelled MP-1 by MAPS), MAPS went on to carry out five further randomized, double-blind phase 2 studies at multiple sites around the world, including USA (MP-8, MP-12), Canada (MP-4), Switzerland (MP-2), and Israel (MP-9). Data were collected from April 2004 to March 2017. These phase 2 studies will be briefly described below.
MP-2:
As the world persisted seamlessly into 2013, and the pseudo-scientific elements of the psychedelic community came to terms with the realization that the ending of the Mayan calendar had no demonstrable effect on the planet, PTSD continued to be high on the agenda for psychedelic research. That year Peter Oehen published the results of his MAPS-sponsored Swiss MDMA MP-2 Psychotherapy study for treatment-resistant PTSD.
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Few psychedelic therapists in recent times have had the experiential opportunities of (legal) therapy that Peter Oehen and his close colleagues received as part of the Swiss Psycholytic Society open training between 1988-1993. They have all gone on to do great things. Here is Peter in San Francisco in 2013, celebrating the publication of MP-2.
The objective of Peter’s study was to determine whether three eight-hour long sessions of MDMA-assisted therapy, scheduled three to five weeks apart, could be safely administered to participants with PTSD, and whether combining a fully therapeutic dose of MDMA with therapy, when compared with a low (“active placebo”) dose of MDMA, would reduce PTSD symptoms. Together with co-therapist, Verena Widmer, Oehen’s was a smaller study than Mithoefer’s and although there was a definite trend in the direction of MDMA therapy being superior to placebo, at first sight the statistics failed to demonstrate a significant reduction in CAPS for the experimental subjects75. However, Henri Chabrol of Toulouse University looked at the data again using effect size as a measure. Chabrol concluded that Oehen had been overly conservative, and the results were indicative of MDMA psychotherapy providing substantial improvements for treatment resistant PTSD76.
MP-4:
This was a Canadian-based randomized, double-blind, placebo-controlled evaluation study of 12 patients with chronic, treatment-resistant PTSD using MDMA-assisted therapy. Six participants started treatment, but this study was terminated early by the sponsor due to “insufficient rate of accurate and incomplete data collection”77. There were also serious safeguarding concerns that occurred during MP-4, which have subsequently had profound effects on MAPS’s integrity and future. These issues will be discussed later in the book.
MP-8:
Following the success of his pilot study, Mithoefer went on to study the role of MDMA-assisted psychotherapy specifically for treating military veterans, firefighters and police officers (“first responders”) with service-related PTSD. This is a very important topic and was a shrewd move on the part of the Mithoefers and MAPS. The non-evidence based politically biased wars in Iraq, Afghanistan, Syria and Yemen were taking their toll on the US and UK military personnel and nations at large. Governments are spending billions in disability payments for tens of thousands of sufferers of post-combat PTSD returning from warzones. It has become a medical, financial and political problem of growing proportions. The military is desperate for a way out, but the current treatments for PTSD are less than perfect and too many veterans are going untreated.
Some commentators within the psychedelic community object strongly to psychedelic researchers working with the military; citing that there ought to be no part for psychedelic research aimed at treating veterans of America’s arrogant wars. But, thankfully, Doblin and Mithoefer — neither of them supporters of war themselves — do not see things this way. Rather, they accept that if the military is going to continue to do what it is doing, then someone must be there to pick up the casualties. And if MDMA can offer a ray of hope to such hapless sufferers then that is all well and good. As a pacifist and a clinician I share their point of view.
MP-8 was a Phase 2 randomized, triple-blind study examined the safety and efficacy of MDMA-assisted therapy in 24 veterans, firefighters, and police officers with service-related PTSD. The study was to explore three different doses of MDMA to determine if they would successfully blind subjects, therapists, and the independent rater, to dose received. PTSD symptoms were significantly reduced at the 12-month follow-up compared with baseline after all groups had full-dose MDMA78.
MP-9:
This phase 2 study took place in Be’er Ya’aqov, Israel, with Prof. Moshe Kotler as clinical investigator. The study demonstrated a successful outcome, with change in CAPS-4 from baseline to primary endpoint significantly higher in the full MDMA dose group, compared to -9.0 (SD: 15.62) for participants in the low dose (active placebo) group. No serious adverse events occurred and MDMA was well-tolerated by participants79.
MP-12:
This double-blind, placebo-controlled, Phase 2 pilot study in 28 participants was conducted in Boulder, Colorado, USA, run by principal investigator Marcela Ot'alora. Participants in the study were U.S. veterans with PTSD, from Iraq, Afghanistan, or Vietnam, along with survivors of childhood sexual abuse, assault, and other types of traumas. The study was a great success. Marcela found that one month after their second Experimental Session of MDMA-assisted therapy, 42.9% of participants in the active-dose (100 mg and 125 mg) MDMA groups did not qualify for a diagnosis of PTSD, compared to 33.3% of participants in the low-dose MDMA (40 mg active placebo) control group. 12 months after the third active-dose Experimental Session, 76% of participants no longer had PTSD80.
MPVA-1:
In 2020 MAPS published the results of a pilot open-label study exploring the safety, tolerability, and efficacy of cognitive behavioural conjoint therapy (CBCT) integrated with MDMA-assisted therapy for the treatment of chronic PTSD. Taking place in Charleston, South Carolina, in which Michael Mithoefer worked with Candice Monson and Julie Holland, in a departure from Mithoefer’s previous study design, this study delivered therapy for six pairs of participants consisting of one person diagnosed with PTSD, and another who does not have a PTSD diagnosis but who is experiencing problems associated with their partner’s PTSD. This study opened a whole new paradigm for MDMA research. The authors concluded that, “MDMA holds promise as a facilitator of CBCT to achieve more robust and broad effects on individual and relational functioning in those with PTSD and their partners.”81
MAPS Summarise MDMA-PTSD phase 2 data and Prepare for Phase 3
Mithoefer wrote an interesting review paper in 2019, in which he summarised the pooled data from all of these phase 2 studies82. Again, using CAPS as the primary outcome measure. The outcomes were excellent, showing that after two blinded active doses of MDMA with combined psychotherapy, versus psychotherapy with placebo doses, more participants in the active dose group (54.2%) no longer met PTSD diagnostic criteria compared to the control group (22.6%). Analysis of the data also showed that offering a further 3rd MDMA session would likely provide even better benefit.
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Outcome of pooled phase 2 MDMA-PTSD studies, showing positive effect size of MDMA therapy over placebo, with even better results when a 3rd session is added. This pooled data from 6 phase 2 studies paved the way for the design of MAPS’s phase 3 program.
In Michael Mithoefer’s review paper he reflected on potential limitations of the studies – especially considering the risk of functional blinding (patients and/or therapists guessing whether the patient is in the full therapeutic MDMA arm of the study, or in the placebo group) and whether this could affect results or be better managed in future phase 3 study designs. Mithoefer stated:
“To reduce bias, blinded independent raters who were not present during therapy sessions administered the CAPS-IV. However, participants and therapists often, but not always, accurately guessed dose assignment)—a recognized limitation in clinical trials of all drugs with perceivable effects and in all psychotherapy studies where there is no possibility of effective blinding.”
And Michael made this interesting statement:
“Low doses (25 mg, 30 mg, 40 mg) produce some changes in subjective effects that could presumably enhance blinding as an active placebo but would be inadequate for a therapeutic response…. The FDA, after reviewing all available data in 2016, granted Breakthrough Therapy Designation in 2017 and approved.”
There is a reason why I am labouring this point (and underlining the above phrase) about MAPS’s attempts to reduce functional unblinding – and what the FDA thought about the issue back in 2019 – will become clearer to the reader when we get on to exploring what happened when MAPS finally took their data to the FDA advisory committee meeting on 4th June 2024. They got a unexpected and bruising outcome, which we will come to presently.
And in another unfortunate turn of events for MAPS and MDMA clinical science, in August 2024 the editors of the journal retracted Mithoefer’s 2019 review article, after they were informed of protocol violations amounting to unethical conduct at the MP4 study site by researchers associated with this project83. This issue will also be discussed in greater detail below.
MDMA/PTSD U.S. Relapse Study
Not knowing of the challenges and objections that were to come four years later in respect of these studies, MAPS went on to carry out a long-term follow-up (LTFU) study of participants who had taken part in the phase 2 studies. The idea was to explore whether the positive effects of the treatment can be maintained for up to 12-months after the studies, even for those people that relapsed. The results were positive. The number of participants who no longer met PTSD criteria increased from treatment exit (56.0%) to LTFU (67.0%). Most participants reported benefits, including improved relationships and well-being, and a minority reported harms from study participation84.
This study marked an important precedent. So far MDMA clinical research has been burdened by the need to show that MDMA therapy acts like a one-off magic bullet. By why should that be the case? After all, the current traditional treatments for PTSD involve taking daily SSRI drugs and carrying out multiple courses of trauma-focused psychotherapy. Who says, therefore, that in order to be considered efficacious, MDMA-therapy must work the first time if it is to be deemed a success? MAPS plan a similar LTFU of the cohort of patients who participated in the subsequent phase 3 studies (MPLONG)85.
MAPS Expanded Access Program for MDMA-PTSD
Following the success of the phase 2 program, in January 2019, MAPS approached the U.S. Food and Drug Administration (FDA) to apply for expanded access status. Expanded access is a program that allows patients to receive an investigational treatment not yet approved by the FDA for treatment outside of a clinical trial. The rationale of the expanded access program is to treat more patients with MDMA-assisted therapy, and to generate real world evidence (RWE), that will further the data pool in using MDMA therapy to treat PTSD. After some back-and-forth between MAPS and the FDA, the expanded access program (labelled EAMP1 by MAPS) was granted in December 201986. Everything seemed to be going swimmingly. The MAPS Public Benefit Corporation (MPBC) had been running since 2015, and funds were coming in to push ahead with phase 3 – the final stage of development before MAPS could submit their massive data pool to the FDA and eventually see MDMA therapy for PTSD become a licensed treatment in the USA.
MAPS Phase 3 Studies
With the resounding achievements of multiple phase 2 studies under their belt, MAPS – in line with the guidelines for any new drug development – progressed onto phase 3 trials. The first MAPS phase 3 trials (MAPP1) took place at fifteen study sites across the United States, Canada, and Israel, and involved manualized therapy with MDMA (n=46) or with placebo (n=44). In the first experimental session, participants received an initial dose of 80 mg followed by a supplemental half-dose of 40 mg, 1.5 to 2.5 hours later. In the second and third experimental sessions, participants received an initial dose of 120 mg followed by a supplemental half-dose of 60 mg. Each experimental session was followed by three 90-minute integrative sessions spaced one week apart in order to allow participants to incorporate their experiences. Results of MAPP1 were published in 2021, and were good, showing that MDMA-assisted therapy in people with severe PTSD benefitted from three sessions of MDMA-assisted therapy, which significantly reduced PTSD symptoms and functional impairment, compared to placebo87.
There then came the second, confirmatory Phase 3 trial of MDMA-assisted therapy for posttraumatic stress disorder, MAPP2, which were published in Nature Medicine in 202388.
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Speakers on the International MDMA Research symposium, at Psychedelic Science, Oakland, USA, 2013. Representing ongoing projects from Canada, Israel, USA, Australia and the UK. Featuring: Jim Grigsby, Martin Williams, Andrew Feldmar and Marcela Ot'alora.
MAPS Submits Data to FDA for final approval of MDMA-PTSD
In December 2023, MAPS Public Benefit Corporation formally submitted their New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA), which included data from MAPP1 and MAPP2 phase 3 trials, as well as their earlier phase 2 trials.
In June 2024, representatives from MAPS (now their newly formed company, Lykos Therapeutics) were invited to attend the FDA’s Psychopharmacologic Drugs Advisory Committee Meeting (PDACM)89. Lykos had a specific focus on seeing MDMA-PTSD therapy rolled out as a licensed medicine. MDMA had now been given a new name: midomafetamine, (which in my opinion is a strange and overly tongue-twisting choice for licensed MDMA). This FDA committee, the PDACM, does not give the final word on whether a new drug application will be accepted by the FDA itself. But history has shown that the FDA tend to go with the recommendations (or not) of the PDACM. What happened next surprised and saddened everyone.
The PDACM committee, by a vote of 9 to 2 against, did not recommend approval of midomafetamine moving ahead as a licensed medicine for treating PTSD. It was a shocking outcome for all of those who have been involved in the development of MDMA therapy for PTSD over the decades. MAPS had had years to prepare for this meeting, and they had thought they had ticked all the boxes requested by the FDA throughout their rigorous phase 2 and 3 programmes.
So where did it go wrong at the FDA meeting in June 2024? There have been numerous commentaries across the media since the meeting, with people trying to answer this question.
Broadly speaking, the FDA’s PDACM for MDMA primarily rejected Lykos’s claim of both efficacy and safety of midomafetamine. Efficacy was rejected on the grounds that functional unblinding and participants’ subjective experience of euphoria renders the outcomes of phase 3 studies defunct, despite the strong effect size. And secondarily, the committee expressed concern regarding safety aspects of MDMA, mainly focused on the risk of addiction.
Closer Examination of the FDA’s PDACM’s decision on MDMA in 2024: By comparing it with the FDA’s approval of Spravato in 2019
Like many other commentators at the time, in June 2024, David Nutt and I were astounded by the PDACM’s outcome, and David asked me to prepare a document comparing Jensen’s 2019 application to the FDA of their new Esketamine product, Spravato, with Lykos’s application for midomafetamine in 2024. What Nutt and I were looking for was whether there had been an irrational bias against MDMA by the FDA, which they did not exert when reviewing the submission for Esketamine’s approval. In particular, I was looking at whether issues of euphoria, functional unblinding and addiction were brought up in 2019 by the PDACM in respect to Esketamine, as they were for MDMA.
At the FDA ACM meeting for Spravato – held on 12th Feb 2019 – Esketamine (Spravato) was approved by the committee with a vote of 14 to 3 in favour90. But were the issues of euphoria, functional unblinding and addiction brought up by the FDA with Jensen’s submission?
Firstly, the issue of euphoria: Was euphoria mentioned in 2019 as a problem in respect of Spravato? The simple answer: No. Not once is the word euphoria mentioned in the Spravato-ACM documentation. There is only one mention of the subjective effects of Spravato as being ‘not unpleasant’, by lay member of the Esketamine panel, a 69-year-old patient who participated in three Esketamine trials, at Adams Clinical in Watertown, Massachusetts. This is what she said:
“When I went to get my first dose of Esketamine, I was a little nervous as I was every time I tried a new medication. The experience was certainly unique, but not unpleasant. Esketamine is easily administered and as its effects diminish, you return to normal with no side effects.”
Interestingly, the issue of ‘euphoria’ is mentioned in the subsequent approval meeting minutes for Spravato (on 5th March 2019), in the section about ‘Benefit-and-Risk-Dimensions’, in respect of this contributing to a potential abuse risk. The mention is as follows:
“Abuse Potential: Esketamine has similar drug-liking characteristics
(i.e., euphoria and dissociation) to ketamine, a known drug of abuse.
This effect was confirmed in a phase 1 abuse potential study (Study
1015); subjects on esketamine endorsed similar drug-liking scores to
IV ketamine and higher than placebo.”
However, it appears that the approval committee were sufficiently reassured by the subsequent Risk Evaluation Mitigation Strategy (REMS) put in place by the applicant to address this potential risk:
“This application will be approved with a Risk Evaluation Mitigation Strategy (REMS) … The REMS goals are intended to mitigate the risks of sedation, dissociation, and abuse and misuse…..”
My opinion on the issue of euphoria in respect of MDMA, but not ketamine, would be that I am not surprised. It makes sense that the issue of euphoria is more pertinent when looking at MDMA compared to ketamine. The subjective experience of ketamine is many things – weird, strange, other worldly, dark and peculiar. But it is rarely euphoric. Some more esoteric commentators (e.g. John Lilly and Karl Jansen) would talk about ketamine in a psychospiritual and blissful manner, but for the most part, ketamine is not a euphoric drug. So, in my opinion, the FDA PDACM were correct in exploring the issue of euphoria for MDMA, and not so much for ketamine.
Secondly, the issue of functional unblinding: Did the Spravato PDACM focus on blinding issues in February 2019? The answer is YES. The specific issue of the committee’s concerns about functional unblinding in the Esketamine trials was mentioned five times in the meeting’s minutes. However, the applicants (Jensen) satisfactorily reassured the committee on several occasions that the issue of functional unblinding, which was acknowledged as a potential factor, was nevertheless addressed in the trials and not considered to be sufficiently relevant to render efficacy claims impaired. It appears that the main justification for making this claim was that the degree of subjective dissociation under Esketamine was not sufficient (or sustained enough) to consider that functional unblinding had occurred. It appears that this justification from the applicant was enough for the Spravato PDACM to not be bothered about the risk of functional unblinding impairing the claim of efficacy. Indeed, when the issue of functional unblinding was mentioned again in the final approval meeting documentation (of 4th March 2019), this is all that was mentioned in that document:
“The primary clinical review team was concerned that unblinding (i.e., patients familiar with dissociative effects of Esketamine would know if they were randomized to placebo) may have biased the study in favour of finding a treatment effect. The team conducted a number of exploratory analyses in an attempt to quantify the influence of unblinding. However, they were unable to determine conclusively whether unblinding swayed the study results.”
In my opinion, that statement above is somewhat strange. It acknowledges that functional unblinding occurred in the Spravato trials, and it even acknowledges that the applicants cannot conclusively determine whether this might have swayed efficacy results. But the Spravato-PDACM approves anyway. (Unlike they did for the midomafetamine application in 2024). Why did this issue not matter for Esketamine (Spravato), but it did for MDMA?
Turning now to how the issue of functional unblinding was approached by MAPS in their submission. As described earlier, both Mithoefer (in his 2019 review of the MAPS phase 2 studies) and Mitchell in the write-ups of the phase 3 data in 2021 and 2023, went to considerable efforts to address the issue of functional blinding, to try and alert the FDA to the issue. And crucially, they subsequently received support from the FDA to go ahead both with their expanded access program, and design their phase 3 studies accordingly, with the blinding issue addressed sufficiently. Yet, when it came to MDMA-PDACM in 2024, it was this issue that was given as one of the reasons to reject the submission.
And finally, in respect of the MDMA-PDACM stating that MDMA carried significant addiction potential – this is where I really get on my soap box! In the 12th February 2019 Spravato-PDACM, the word ‘addiction’ is only used once, in relation to the REMS policy to be put in place. The word ‘dependence’ in relation to ketamine is not mentioned at any point. This is surprising, as (recreational) ketamine addiction is a well-recognised clinical syndrome91. Both use and addiction to (recreational, racemic) ketamine has increased year-on-year since records started in 2007, up to the last UK’s Office for National Statistics dataset in 202392. So, it’s not surprising that the February 2019 Spravato-PDACM does mention ‘abuse’ and ‘misuse’ - on 23 occasions in fact. But mostly these allusions are in respect of describing Jensen’s REMS policy to mitigate against the risk. The FDA commentary on Spravato addiction risk concludes:
“The agency believes that limiting Esketamine administration to a medically supervised healthcare setting decreases the likelihood of potential serious adverse outcomes from sedation and dissociation and decreases the likelihood that the medication will be misused or abused.”
Another point of interest in the Feb 2019 and March 2019 Spravato-PDACM meetings regarding addiction risk, centres around the difference between racemic ketamine and Esketamine, with the emphasis that the latter is less addictive. This looks like an attempt by Jansen to separate Esketamine from recreational racemic ketamine abuse and addiction. And it looks like FDA bought it. Please note here, I am not being ‘down’ on ketamine when I am undertaking this exercise of comparing two FDA PDACM approaches. I’m just trying to explore whether MDMA got a fair trial!
In conclusion regarding ketamine versus MDMA addiction risks - basically, in my opinion, the FDA liked that Esketamine is a ‘new’ product, and ‘not the same as recreational ketamine’. Whereas Lykos’ MDMA, midomafetamine, is the same as ‘street’ MDMA. And they didn’t like that.
Turning to how abuse, misuse, addiction and dependence to MDMA were discussed with the midomafetamine submission, it is clear from the committee’s minutes that one reason they considered MDMA more of an addiction risk was simply that it was considered ‘pleasant’ by many of the MAPS trials participants. They state at one point:
“….midomafetamine not only appears to produce similar subjective effects to other psychostimulants but also possess what some authors referred to as “empathogenic” effects such as happiness and openness. This is relevant given that empathogenic effects are desirable and may contribute to its abuse potential.”
In my opinion, there are two main problems here. One is that, it seems, midomafetamine is being criticised simply because it was well tolerated by participants. This is a misnomer in my opinion. What’s wrong with a treatment being tolerable – or even (dare I say it?) pleasant? If it still works, I don’t see a problem with patients considering the treatment to be both beneficial and pleasant. By way of an example, if a patient undergoes CBT, or Art Therapy or something unusual like Equine Therapy – and they state that they enjoyed it and found it pleasant – does that mean such treatments are not to be considered efficacious? Do medical interventions have to be subjectively noxious in order to be considered useful?!
The second issue that appears to have been hugely overlooked – or ignored by the FDA – is that despite recreational MDMA being a popularly used drug (third only to cannabis and powder cocaine), the addiction potential for MDMA is staggeringly low. It seems that the FDA are conflating high prevalence of use with addiction. That is an error. Many things have high prevalence (socks, coffee, golf and horse riding…), it doesn’t make them addictive.
In a new paper that I have recently written with Steve O’Brien - long term collaborator and former manager of the Awakn clinic and BIMA research assistant - we showed, recreational MDMA use has a low risk of addiction, with a minuscule number of people seeking drug services support for primary MDMA addiction or abuse93. The massive pool of data from MAPS studies showing no addiction risk has occurred across all of its clinical studies with MDMA (and around 2000+ clinical research administrations in the last 20 years).
MDMA is not addictive. It is simply the fact that the MDMA experience is ‘pleasant’ that makes it a target for FDA’s concerns. So, what we have here is that ketamine, which has a known high risk of addiction potential is considered safe by the FDA. But MDMA, with its very low risk of addiction potential, is not.
So, what happened after the FDA-MDMA-PDACM failed to support the efforts made by MAPS in their application of midomafetamine?
After the FDA’s PDACM committee rejected MDMA-PTSD in June 2024, two months later the FDA then made its own decision. And sadly (but not unexpectedly), in August 2024, the FDA rejected the submission by Lykos for midomafetamine therapy for PTSD. This led to significant soul-searching and questioning for many people involved in MAPS’s long, long project. There were changes made at MAPS and Lykos. Rick Doblin resigned from the Lykos board of directors, and several staff were let go from MAPS. As part of the changes, David Hough, previously Vice President of Research and Development at J&J Innovative Medicine (a Johnson & Johnson company) was brought on board by Lykos to lead and oversee the clinical development program and FDA engagement regarding the resubmission of midomafetamine94.
The aftermath of this situation is still playing out, and no one is sure of what the future holds for clinical MDMA and the MAPS company / Lykos themselves. I am informed nevertheless that Rick has not given up, and his determination to see MDMA approved as a medicine for PTSD is a strong as ever. After all, this is certainly not the first challenge Rick has had over the years!95
In my opinion, another reason FDA had such a problem with the MDMA application, is because of the psychotherapy component of the MAPS application. The FDA have never been comfortable with the concept of ‘MDMA Psychotherapy’. They have repeatedly asked MAPS to provide them with data about whether patients with PTSD had relief of symptoms when given MDMA alone, with no psychotherapy, but this is a study that MAPS (or anyone else) has done. (I remember Rick asked me to do such a study many years ago, but it never happened).
It could be that there may be too much emphasis in MAPS materials about the psychospiritual element of the subjective effects of MDMA. Perhaps some of the language used in the MAPS Therapy Manual, is far too ‘hippyish’ at times?
For example (my bold type):
From MAPS Manual96:
“It is important for the therapists to be prepared for the possibility that, during experimental sessions, the participant may have transpersonal experiences that might transcend conventional Western concepts of consciousness and its relationship to the physical body. Such “transpersonal” experiences that are common during MDMA-assisted therapeutic sessions extend beyond biographical memory and may include unusual sensations in the body, as well as perinatal and/or spiritual experiences. There may be perceptions that are felt to extend well beyond the usual sense of self, such as feelings of oneness in which the participant experiences an openness and enhanced connection to his or her own humanity and to the surrounding environment.”
How is a body like the FDA going to react to words such as ‘transpersonal …. perinatal experiences… enhanced connection to humanity’? The answer: Very badly. So, perhaps this language played a part. At the time of writing this, MDMA therapy has hit a bit of a brick wall. We shall have to wait to see what happens next. One way or the other – Rick Doblin deserves a Nobel prize for his dogged determination in the face of 40 years of irrational authoritarian objection to MDMA – simply because it is ‘pleasant’.
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With Rick outside the aptly named Renaissance Hotel in one or other of those Nordic or European countries where we have worked together over the years. Rick Doblin is not giving up. He will see MDMA become a medicine!
MDMA Studies Terminated Early
Before we move on from MAPS’s monumental efforts to see MDMA become a licensed medicine for treating PTSD, it is worth mentioning a few studies that never quite made it. Given the complexities of MDMA research in today’s political climate, not all of those proposed have managed to get off the ground. The following studies illustrate the difficulties involved in clinical research with psychedelic compounds. The hurdles can sometimes feel insurmountable, and the scale of problems faced are testament to the sheer determination of those researchers who initiate such work.
The Spanish MDMA for PTSD study was run by José Carlos Bouso in Madrid. It started in 1999, then, in 2002, after treating just six of 29 planned patients, the permission was revoked, and the study was shut down because of political pressure. But they did publish data on the six participants who underwent the study before it was terminated97. Bouso and his team found that low doses of MDMA (between 50 and 75 mg) were both psychologically and physiologically safe for all the subjects.
An MDMA study run by John Halpern at Harvard University planned to explore the role for MDMA-assisted therapy to treat Anxiety Secondary to Advanced Stage Cancer. It began recruiting soon after its approval in 2004 and planned to treat twelve subjects. But only one subject completed the study and after the second subject dropped out the study was closed due to enrolment challenges.
Another MAPS-sponsored MDMA study that was initially planned, but has sadly floundered since 2011, is the one in Jordan. A team lead by Nasser Shuriquie from Amman continue to await Jordanian approval to begin their project.
Another (partially) MAPS-sponsored MDMA-PTSD study that has still not yet managed to make it off the ground is one in the UK, the Cardiff MDMA/PTSD Study. After first meeting Michael Mithoefer at the ENCP conference in Vienna in 2007, I started talking to MAPS about a wish to develop a UK-based MDMA study. We brainstormed several different ideas, then I met Jonathan Bisson in 2009 when I was invited with Mithoefer and Charlie Grob to convene a panel on psychedelic therapy for the Royal College of Psychiatrists annual conference in Liverpool. Bisson, who is ex-services himself, is the lead of a large clinical research facility at Cardiff University, which specialises in cases of post-combat trauma. He sees hundreds of new cases every year and is an open-minded doctor with a passionate desire to try anything that could reliably work to improve the treatment rates for PTSD.
With David Nutt on board, we looked for financial backers, including MAPS, the Beckley Foundation and Anton Bilton of the Tyringham Research Institute. Working with young psychiatrist (then in training), Matthew Hoskins, assisted by co-therapist Chrissie Turner-Wilson, the plan was to give patients with treatment-resistant PTSD either MDMA or placebo, and perform fMRI on them as we get them to recall their trauma histories. The plan was to combine MDMA versus / placebo with neuroimaging to demonstrate associated with reduced amygdala and boosted pre-frontal cortex responses under MDMA, in patient with PTSD. We explored carrying out the sessions at the newly built CUBRIC-2 imaging centre in Cardiff, to be sponsored by Cardiff University. This study would have added valuable data towards the raft of clinical studies underway; demonstrating the physiological substrate for MDMA-assisted psychotherapy’s effects.
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In a Cardiff pub with Matt Hoskins and Chrissie Wilson, on the day that Michael Mithoefer came to town to assist on the setting up of the Cardiff MDMA Project.
The idea was that this would not be a therapeutic study (we were not planning on providing any formal psychotherapy for the participants), but rather were hoping to demonstrate that even a single dose of MDMA, delivered in a facilitative setting by trained MDMA therapists, could have a positive effect on the participants’ PTSD symptoms. Indeed, this ‘MDMA-lite’ approach could even herald a new model for global MDMA therapy in the future. Demonstrating the clinical deliverability of MDMA in a standard NHS clinic, is, we feel, an essential component of MDMA research if we are to convince the regulatory authorities that it is not only experienced and inspirational experts like Mithoefer and Oehen that can make this sort of therapy effective.
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Mat Hoskins, psychiatrist from Cardiff University with a keen eye on the evitable role MDMA will play in the future of his profession. Here displaying our poster of our Cardiff plans at an event at Imperial College London to mark the press launch of Robin Carhart-Harris’ LSD study results in 2016.
We got as far as presenting a poster on our plans, but unfortunately due to regulatory difficulties and disputes between the local NHS trust and the university sponsor around insurance issues, the Cardiff study never got underway. Nevertheless, getting to know Matt, Jon and Chrissie was a great pleasure, and they have all continued to advance the field of MDMA science
Other PTSD Research with Other Psychedelics
Whilst undoubtedly MDMA seems to be the front runner of psychedelics being explored for treating PTSD, there is plenty of evidence that other compounds could also be of use. After all, as described earlier, all of the psychedelic drugs appear to be broad-spectrum, non-specific amplifiers of psychotherapy – whether they be MDMA, psilocybin, ketamine, LSD or ayahuasca. All of these compounds, in combination with guided psychotherapy, allow patients to address typically repressed traumatic issues and break the chain of rigidity that keeps them stuck in their illness.
Research demonstrates that psilocybin promotes fear extinction, suggesting a similar biological effect as MDMA. This makes psilocybin a potential candidate as a treatment for PTSD98,99. To date there has not yet been a completed and published study of psilocybin therapy to treat PTSD in humans. But several are on the way, including one under the auspices of Ohio State University and John Hopkins University, with their protocol published online100. Another study, run by Ross M Allison, of NW Therapies Trauma Unit, in collaboration with the World Health Organisation will look at regular micro-doses of psilocybin the treatment of PTSD and other trauma-related disorders101. Dr Stephen Ross, the Associate Director of the NYU Langone Center for Psychedelic Medicine, and the Director of the NYU Psychedelic Medicine Research Training Program at New York University made his psychedelic research name in studying psilocybin for anxiety related to end-stage cancer102, which we will explore in more detail later in this chapter. Stephen’s NYU team have also begun exploring psilocybin’s potential role for treating PTSD.
Ketamine, which is well known as an agent that increases neuroplasticity and therefore an excellent candidate for allowing a stuck patient to address old problems in a new light, is also a form candidate for PTSD therapies, with a few small pilot studies published in the mid-20-teens104,105, with a raft of more recent research106,107,108,109, and some useful meta-analyses of ketamine’s potential role for PTSD in recent years110,111.
The most memorable quotation to describe about ketamine’s remarkable neuroflexibility effects comes from my friend and past colleague Mendel Kaelen, who has also been quoted by Michael Pollan in his book, How to Change Your Mind, as follows:
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“Mendel Kaelen, a Dutch postdoc in the Imperial lab, proposes a more extended snow metaphor: “Think of the brain as a hill covered in snow, and thoughts as sleds gliding down that hill. As one sled after another goes down the hill, a small number of main trails will appear in the snow. And every time a new sled goes down, it will be drawn into the preexisting trails, almost like a magnet.” Those main trails represent the most well-travelled neural connections in your brain, many of them passing through the default mode network. “In time, it becomes more and more difficult to glide down the hill on any other path or in a different direction. “Think of psychedelics as temporarily flattening the snow. The deeply worn trails disappear, and suddenly the sled can go in other directions, exploring new landscapes and, literally, creating new pathways.” When the snow is freshest, the mind is most impressionable, and the slightest nudge—whether from a song or an intention or a therapist’s suggestion—can powerfully influence its future course.”112
Very beautiful words. Thanks Mendel. Ketamine, and indeed all psychedelics in combination with focused psychotherapy, most certainly have a Psychedelic Future in the treatment of PTSD113.
4. Psychedelics to Treat Depression
Globally, an estimated 5% of adults - approximately 280 million people in the world have depression. Depression is about 50% more common among women than among men. Depression is a major cause of suicide, and globally more than 700,000 people kill themselves every year. Alongside MDMA for PTSD, the next closest psychedelic contender for a new approval as a medicine is psilocybin as a treatment for depression. While MDMA continues its post-phase 3 flirtation with the FDA for hopeful approval in 2024/2025, psilocybin for depression is just a few years behind. Phase 3 studies are now underway, so expect another 3 to 5 years before we see it being submitted to the FDA.
Psilocybin as an Antidepressant
Before reviewing the (very many) contemporary studies exploring psilocybin therapy for depression, let’s look briefly at some of the neuroscience that brought us here.
When Robin Carhart-Harris and his Beckley-Imperial (then Bristol) University crew started their studies using fMRI to explore the neurophysiological basis of psilocybin back in 2009, by injecting me with the stuff, no one knew exactly what they would find. It was a chance finding that psilocybin appeared to reduce neural activity in the anterior cingulate cortex (ACC) and the medial pre-frontal cortex (mPFC). It was known, however, that the ACC and the mPFC are areas that are over-active in depressed patients. This pointed the way to a new study exploring whether there may be a role for the drug as an antidepressant. Findings from their initial, open-label pilot study — in which 12 patients were given two doses of psilocybin 7 days apart — were published in the Lancet in 2016 and supported the feasibility and safety of the proposed larger-scale double-blind placebo-controlled study, with preliminary efficacy data suggesting an antidepressant effect114.
Robin went on to carry out a 6-month follow-up study, which showed sustained benefits from the intervention115, and also published neuroimaging data, demonstrating the neurobiological mechanism behind how psilocybin can be beneficial for depression116. And many other international teams have provided further valuable data to the science behind how psilocybin in combination with therapy can treat depression117, including from placebo-controlled trials118,119, 120. Neuroplasticity and increased global integration remain at the heart of our understanding about psilocybin works clinically121,122. Stephen’s Ross’s NYU team have contributed to this research with their studies looking at depression (as well as anxiety) symptoms in patients with end-stage cancer treated with psilocybin therapy123.
Since then, there have been a number of randomised placebo-controlled trials, which have been helpfully reviewed in a metanalysis in the BMJ in 2024124. The review by Metaxa in 2024 included nine studies, and shows that when combined together, a clear benefit of psilocybin therapy for depression is seen:
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Forest Plot of psilocybin-for-depression metanalysis by Athina-Marina Metaxa in 2024
The research organisation leading the way in the race to see psilocybin therapy approved as a medicine for depression, is Compass Pathways. Their phase 2 double blind trials published by Goodwin et al in 2022125 and 2023126 are the culmination of a massive multisite international effort by Compass Pathways, conducted at 22 sites in 10 countries across Europe (Czech Republic, Denmark, Germany, Ireland, the Netherlands, Portugal, Spain and the United Kingdom) and North America (Canada and the United States) between 2019 and 2021. Dr James Rucker, the lead for Compass’s phase 2b study at Kings College London summarised the work done so far:
"These findings are a positive step in the right direction. Our task now is to investigate psilocybin for treatment-resistant depression in larger trials with more participants, comparing it both to placebo and to established treatments."127
So, once psilocybin therapy had been shown to be so effective at treating depression, the next question that arose was: OK, but how does it compare to other treatments currently available? This question led Robin’s team to carry out the world’s first ever psychedelic versus traditional treatment study. They compared psilocybin against a commonly used SSRI antidepressant, escitalopram in a double blind trial128. The outcome of the psilocybin-versus-escitalopram trial were not as awesome as had been hoped for or expected. The trial did not show a significant difference in antidepressant effects between psilocybin and escitalopram. However, psilocybin was better tolerated and certainly acted faster than the SSRI at reducing depression symptoms. This trial sparked a lot of debate in the psychedelic research community, and the study team re-visited the results using a Bayesian analysis to provide a more informative examination of the results. The conclusions of this re-examination were that psilocybin, “did indeed outperform escitalopram in this trial, but not to an extent that was clinically meaningful, and that psilocybin is almost certainly non-inferior to escitalopram.”129 More such head-to-head comparison trials are required on psilocybin’s long road towards approval for depression.
Unlike MDMA therapy, which has usually involved taking several – up to three – doses of MDMA alongside non-drug therapy sessions, clinical research with psilocybin for depression has been aiming towards the efficiency of using just single doses of drug-assisted therapy. This has been the typical dosing regimen for the Compass (Goodwin) trials, and also for other contemporary studies130,131. One might ask whether the move towards single dosing protocols are an attempt to increase efficiency – and therefore profitability - on the part of new companies stepping forward to deliver psilocybin-depression therapies in the future. Or one might support protocols that are less clinically invasive for patients, as long as they demonstrate sufficient efficacy. Long-term positive results are an important part of designing new clinical treatments, if we are going to meaningfully tackle the huge clinical burden of global depression. And some research appears to favour two psilocybin sessions over one, for better, longer-lasting results. One such study run by Alan Davies at Johns Hopkins University showed favourable results with two sessions of psilocybin, combined with psychotjerapy132. And a follow-up study showed that positive results were sustained at 12-months133.
Ketamine as an Antidepressant
Psilocybin is certainly not the only drug being researched as an adjunct to psychotherapy for treating depression. Ketamine, as we have discussed earlier, is not only extensively researched as an antidepressant, but also given that it is the only licensed existing psychedelic drug in most countries, is widely used all over the world as a rapid acting antidepressant (RAAD), and its use has transformed the management of treatment resistant depression, improving the lives of hundreds of thousands of patients worldwide134.
It all started in the mid-2000s, when a simple case series involving just two patients who coincidentally showed reductions in pre-existing depressive symptoms when being given injections of ketamine for a different condition (Complex Regional Pain Syndrome)135. In another study, which was randomised, double blind and placebo controlled, a single injection of ketamine significantly improved symptoms in depressed patients who had been taken off all their usual antidepressant medication for up to a week. The effect size was large, and the ketamine treatment was well tolerated136. This study by Zarate opened up an interesting new line of research in treating depression. Most licensed antidepressants work by raising levels of the monoamines (particularly serotonin and noradrenaline), but ketamine, which exerts its effects by glutamate inhibition — perhaps via increased activity at AMPA receptors — is getting a lot of psychiatrists talking right now. The concept that depression could be managed by a monthly or fortnightly injection, rather than having to take daily antidepressant tablets, is revolutionary. It is not unlike dialysis for the brain. Furthermore, because — unlike LSD, psilocybin, MDMA and most other psychedelic drugs — ketamine was already a licensed drug (albeit not for psychiatric depression or other psychiatric disorders, but rather as an anaesthetic) doctors can prescribe it ‘off label’ with far greater ease and far fewer regulatory hurdles than those required for the other psychedelics. This means series of case studies can be built up over time to test its relative safety and efficacy.
A significant amount of research came out of the UK, from Rupert McShane, a consultant psychiatrist in Oxford. In his initial open-label study, which was carried out on patients with severe depression attending the ECT clinic in Oxford 137, he showed that ketamine infusions could be given safely to patients attending an NHS clinic. The effects on depression were moderately good, with 29% of patients responding to the treatment and in half of the sample, depression remitted completely. Patients did not experience any memory loss because of being given ketamine. Whilst these results, on face value, do not look particularly spectacular, one must bear in mind that these are severely depressed patients (who in many cases would otherwise be getting ECT). So, the remittance rates are not too bad at all. Rupert has been running a successful NHS-based ketamine treatment service (with RAAD infusions, not KAP) for many years in Oxford, and he was supportive of the Awakn team in setting up our first clinic in Bristol, kindly having me and our nurses and therapists spend a day with his team in the Oxford ketamine clinic in 2020. It was fun to go back to the old hospital where I had trained many years earlier.
As ketamine RAAD treatments became more widespread, we started to see some useful meta-analyses of published studies into ketamine for depression138. The review acknowledged that the “clinical evidence demonstrates rapid improvements in mood and suicidal thinking in most participants”, but rightly pointed out that thus far, “study numbers have generally been small, and many trials are unblinded and methodologically weak”. The review went on to state that some studies suggest ketamine might also augment electroconvulsive therapy. The review reflected that one of the problems with ketamine is that the antidepressant effects are, “relatively temporary, disappearing after days to weeks”. Nevertheless, the review concludes that the research is highlighting some: “exciting data providing new insights into neurobiological models of depression, and potentially opening up a new class of antidepressants.”
As time went on, we saw further studies emerging, not on patients with severe unipolar depression, but on patients with bipolar depression. Early results showed ketamine can improve mood and reduce and suicidality in this group139,140. It seems that there is still a long way to go before we will see ketamine challenging the long-held position that SSRIs have in mainstream psychiatry for treating affective disorders. But the rapid international growth of ketamine infusion clinics continues globally. One day maybe, one day, SSRIs will become a thing of the past. But don’t hold your breath.
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“Whoever stole my antidepressants, I hope you’re happy”
Bristol is the home of the legendary graffiti artist, Banksy, and his work is seen all over the city. This picture is from 2024, which I spotted on a cycle ride through the city one afternoon. I doubt very much this text was him, but the image in lower left-hand corner looks like it could be … Whatever. SSRIs are now synonymous with everyday culture.
As explored in previous chapters, there is a significant difference between using ketamine in combination with psychotherapy (KAP), which broadens its range of potential psychiatric indications above and beyond just depression, or using it on its own, without guided psychotherapy for RAAD. However, even when used just as RAAD ketamine infusion therapies are useful. The antidepressant effect works quickly – much faster than the 4 to 6 weeks it takes to start feeling the effects of SSRI medications. This makes it a useful tool for fighting severe depression, where rapid response is required141. The rapid rise of ketamine science, since the discovery of its rapid-acting antidepressant actions, has furthermore advanced the wider exploration of its mechanisms and added fuel to the fire of the understanding of neuroplasticity and neuroflexibility. Excitement around ketamine has therefore been a big driver for this broader field of scientific work142, informing scientists more about the neurobiological mechanisms behind depression, and how these understanding could be applied to the development of new drugs for broader indications beyond depression143. Just as psilocybin has informed non-psychedelic neuroscience, so has ketamine informed the non-psychedelic world of psychopharmacology. This demonstrates the importance of psychedelics as tools for science, as well as being marvellous healing medicines and popular party drugs.
Given the widespread use of ketamine as an RAAD, with the growth of ‘ketamine clinics’ all over the world – there are estimated to be over 2000 in North America and Europe – I will not attempt to describe them all here! There are now such vast datasets around the world –that suffice to say, the results for RAAD use of ketamine are extremely favourable. Several large metanalyses have robustly demonstrated the RAAD ketamine therapy (without psychotherapy, remember) is beneficial, and superior to traditional treatments with SSRIs and CBT144,145,146. Because so many thousands of patients have now been treated with RAAD ketamine, it is possible to analyse huge Real World Data sets, which adds further evidence to the picture147. With such large datasets, researchers can look in detail at ketamine’s RAAD effects for specific areas of depressive disorder, such as its beneficial effects in reducing sucidality148,149. Or large data pools that allows RAAD ketamine infusions to be reliably compared against electroconvulsive therapy (ECT) as a treatment for severe deporession150,151,152. There remains some debate in the field about whether ketamine is superior to, or could even supersede, ECT as a treatment for severe depression153. But what is clear is that (from outside the profession of psychiatry – those who know, know), ECT has always been rather unpopular in the public imagination.
Moving from RAAD ketamine to KAP ketamine treatments, in recent years we have seen more and more clinics and therapeutic teams exploring the combination of ketamine administrations with a course of regular sessions of guided psychotherapy; not just considering the drug experience itself to be ‘an irritating side effect that must be endured in order to get the antidepressant effect’', but rather, a useful and beneficial mental state that could have meaning and can be interpreted and worked with in and around by the patient and therapist top provide lasting meaningful changes154. With so many clinics now operating, there is a wide range of different techniques and styles, different psychological models being employed and different routes of administration or number of ketamine sessions offered in KAP courses. Attempts have been made to provide review and metanalysis of the many KAP services, which support favourable outcomes155,156. The popular press and media are full of success stories of how ‘ketamine psychotherapy saved my life’157, and much attention has turned towards KAP. I hope that this will encourage some of the purveyors of RAAD infusions towards a more psychotherapeutic model for administration of the drug. But not all of the current RAAD providers are convinced of the benefits of KAP158. In more recent years, ketamine therapy has also been emerging out of the clinic, with the development of sublingual doses of ketamine, for patients to use at home. Studies assessing take-home ketamine treatment protocols have been favoiurable159,160. And whilst take-home ketamine is certainly worth considering as a more convenient method of administration for users – it does away not only with psychotherapists, but also with clinics themselves! – it is arguable that such treatment methods might not possibly provide the vulnerable patient with the level of support that they would get from a full course of face-to-face psychotherapy whilst undergoing clinical-based KAP. Certainly, the rapid proliferation of ketamine-based products and availability of take-home formulations, has sparked some degree of concerns about safety and efficacy by such widescale unmonitored use161. Ketamine’s fantastic availability has meant all sorts of novel approaches are being explored, including ketamine group therapies162, couples therapy163, and even including specifically directed towards people who have experienced Covid-19-related burnout164. Yes, now the ket has been let out of the bag….it seems to be everywhere.
Ketamine Isomers
Before we move on from ketamine, it is important to discuss that ketamine (like many molecules and drugs) comes in two different isometric forms. This is highly relevant to the psychedelic renaissance, as there have been some important clinical developments in respect of these two different isomers of ketamine. Ketamine displays ‘stereoisomerism’, due to the chirality (‘handedness’) of the C-2 carbon of the cyclohexanone ring.
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The right-handed (R) and left-handed (S) forms of ketamine are non-superimposable mirror images. Specific enantiomer structure determines receptor affinity, pharmacological activity, tissue uptake and metabolism.
S-(+)-ketamine has been shown to have a higher affinity for NMDA receptors compared to equivalent doses of R-ketamine and racemic ketamine. Therefore, lower doses needed to elicit similar effects, with lower incidence of side effects such as drowsiness, lethargy, agitation and disturbed memory. And S-ketamine has been found to have a higher clearance and potency than R-ketamine165,166. Whereas, R-(-)-ketamine has been shown to have a lower NMDA receptor affinity than the S-isomer. At present, R-ketamine has not yet been developed as a clinical drug. However, rodent studies show R-enantiomer induces synaptogenesis and longer-lasting antidepressant effects when compared to the S-version167,168. And R-ketamine has been shown to cause fewer side effects such as dizziness, dissociation and sensory deficits169. Important to note that when ketamine is used all over the world – in anaesthesia, in ketamine infusion clinics for RAAD, and in clinics providing KAP – they are almost always using racemic ketamine – not one of these pure S- or R-isomers of ketamine. Racemic ketamine consists of equal quantities (50:50) of R- and S-enantiomers. It is marketed all over the world as an anaesthetic agent for diagnostic and surgical procedures, and it is usually administered by intravenous or intramuscular injection. And above all – it is extremely cheap, as it is a generic drug.
A major step in the psychedelic renaissance in recent years has seen the development and licensing of Esketamine – the pure S-isomer – as a treatment for depression. We touched on this development, by pharma company Jensen, earlier when discussing MDMA’s torturous route to market.
A brief timeline of Jensen’s Esketamine (Spravato) approval process is as follows:
· Jan and April 2018 – Two Phase 2 data studies published170
· May 2018 – Phase 3, and Phase 3 long-term FU data published171
· Sept 2018 – Jensen submits Esketamine nasal spray (Spravato) to the FDA
· 12th Feb 2019 – FDA Advisory Committee meets and recommends approval of Spravato for TRD.
· 5th March 2019 – FDA approves Spravato for TRD
· 3rd August 2020 – FDA approves Spravato for dep + acute suicidal ideation and behaviour
The implications of having Esketamine approved as a licensed medicine to treat treatment-resistant depression (TRD) are vast. Whilst racemic ketamine has been around for donkeys years as an anaesthetic – and more recently in an off-label fashion as an RAAD, by Jensen getting formal approval for Esketamine as a new medicine, this means the drug can become a NICE recommended treatment, and can therefore be funded by insurance companies and approved by the National Institute for Health and Clinical Excellence (NICE), for use on the NHS (theoretically). However, because Spravato is a new, non-generic patented drug, it is extremely expensive, costing up to £800 per administration (by nasal spray). This contrasts wildly with the cost of generic racemic ketamine. In the psychedelic medical clinic where I worked delivering KAP, we used racemic ketamine, which cost just £10 a bottle, which could treat up to ten patients. Nevertheless, Jensen did a clever thing in getting ketamine in the S-isomer form onto the market. Interestingly, emerging research is showing that S-ketamine – whilst a lot more expensive than good old racemic ketamine – is not necessarily any better than the racemic form172. This situation is a good example of the nuances of contemporary drug development. Sometimes new drug developments are as much about financial success as they are patient satisfaction.
It is worth mentioning again that alongside research of existing psychedelics, many psychedelic start-up companies are pursuing new chemical entities (NCEs), for which they own the Intellectual property (IP) or patent on new molecules for treating depression. Examples include Atai’s VLS-01, which is being explored in a Phase 2 study in treatment-resistant depression (TRD), Cybin’s CYB003 (Deuterated Tryptamine) for Major Depressive Disorder (MDD), GH Research’s products, GH001, GH002 an GH003, various formulations of mebufotenin in inhalation, intravenous and intranasal forms for treatment resistant depression, and bipolar 2 disorder. Beckley Psytech is developing its own novel intranasal formulation of 5-MeO-DMT (BPL-003) for depression. And the Alexander Shulgin Research Institute (ASRI) is developing their novel molecule, called XOB, which they hope could revolutionize the treatment of bipolar disorder173. So, it looks like creative pharmacology of psychedelics is here to stay. I am certain that Sasha would be proud to know that his legacy is being continued.
What About MDMA as an Antidepressant?
Before we leave this section on contemporary psychedelic drug developments for the treatment of depression, interestingly, MDMA has not played a particularly large role as a potential antidepressant. MDMA has a very clear effect on raising mood and improving feelings of wellbeing. After all, that is why 750,000 people every weekend in the UK take the drug recreationally. But what happens when depressed people take MDMA174? Because of the gap in our knowledge about therapeutic applications for MDMA, this question cannot yet be answered with confidence. The theoretical potential of using MDMA as a potent serotonin-enhancer to treat depression has been postulated by Riedlinger and Montagne in a chapter in Julie Holland’s Ecstasy book175. But there is very little empirical clinical information regarding the effects of MDMA on depressed patients. There exist numerous anecdotal reports of the expected transient rise in mood during recreational use of MDMA by depressed people, but for a significant minority this is followed by a subsequent depressed mood and other associated unpleasant psychological and physiological ‘hangover’ effects. Because of these negative effects, there is little evidence — anecdotal or otherwise — of depressed people carrying out long-term self-medication with MDMA.
The existence of a hangover associated with MDMA is well documented by recreational users of Ecstasy. Among Ecstasy users, this hangover effect (sometimes called the ‘mid-week blues’ or ‘Suicide Tuesday’), may last for between one and seven days, exacerbated by the adverse environmental circumstances in which recreational Ecstasy is often consumed (i.e., at night with consequent sleep deprivation, missing meals, excessive physical exertion (dancing to techno) and often being taken with other psychoactive drugs, including alcohol). No one has ever explored the MDMA mid-week blues in detail with a prospective controlled clinical study, despite it being such a prevalent narrative amongst ravers.
But in our Bristol-Imperial-MDMA-Alcoholism (BIMA) study, we assessed mood, sleep disturbance and suicidal measures for seven days post-MDMA in 12 patients. Contrary to those anecdotal reports of come downs and post-ecstasy affect drops 3-days after taking recreational ecstasy reported by ravers, we found that there were no acute come downs as the drug wore off, and no low moods in the days following clinical MDMA. Indeed, our patients described a sustained 7-day improved mood – an afterglow effect176.
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Using the Profile of Moods Sates measure, we showed that there was no mood / affect drop for 7-days after taking clinical MDMA. This contrasts with anecdotal reports of come downs and low moods after taking recreational ecstasy. From: Sessa B, Aday JS, O'Brien S, Curran HV, Measham F, Higbed L, Nutt DJ. (2021) Debunking the myth of 'Blue Mondays': No evidence of affect drop after taking clinical MDMA. J Psychopharmacol
The paper was written from a multidisciplinary perspective, by experts from the scientific MDMA community, clinicians, and from a drug policy perspective, and tallied with the prevalent understanding that the adverse effects of ecstasy are more likely to be lack of sleep, excessive physical activity (dancing), poor fluid and heat balance and impure source of drugs taken, rather than directly related to MDMA itself. But not everyone liked our paper ‘Debunking the Myth of Blue Mondays’. The authors of one paper misunderstood our point, thinking we were ignoring the fact that blue Mondays occur at all177. We were not; indeed the phenomenon is clearly widespread amogst recreational ectssy users. Rather, we were proposing that the effect is not necceserilly a pharmacological effect of MDMA, but rather due to confounding factors. We felt therefore our paper represented an important step in tackling the dreadful stigma that exists against MDMA, and especially the frequent tendency for some commentators to conflate recreational ecstasy use with clinical MDMA. Certainly, a better study would be one that rigorously tests MDMA versus placebo in subjects who are variously exposed to lack of sleep versus being allowed to sleep, being allowed food versus being starved, after vigorous exercise versus relaxation, with cannabis and other drugs versus no other concomitant drugs; thereby mimicking all the various ‘raving’ experiences. Then we might get a better idea as to whether the mid-week post-MDMA blues truly exist or not. Sounds like a great study — but one fraught with ethical considerations.
There is certainly a place, however, for a trial that examines the possible role for MDMA in treating depression. Recreationally, and in the current MDMA-assisted psychotherapy studies, subjects tend to use doses of 120mg plus. But it is not known what effect the drug may have if taken at much smaller dosages (say 10–25mg) for longer periods of time. Taken repeatedly at these lower doses, could sub-threshold MDMA microdosing have a gradual, beneficial effect on mood? One might expect the drug to have similar effects to the SSRI drugs, but because one need not wait for serotonin levels to build up slowly through inhibiting re-uptake of the neurotransmitter, one might propose the mood-enhancing effects of low-dose MDMA might be noticed much quicker than with an SSRI drug. And perhaps, if taken in such low doses, there might not be such a dramatic rebound serotonin depletion causing a significant hangover effect. The possibility of using MDMA to lift mood early and rapidly, and then transfer to an SSRI or other antidepressant to continue longer term might be considered. Be on the lookout to see if this sort of research emerges to explore whether MDMA could be developed as an antidepressant. Some researchers, including my mate Dan Titheradge in Bristol, has started to explore the possibility of MDMA as an antideopressant178, and studies are in the pipeline now179.
MDMA as an Alternative to ECT
One area where MDMA’s rapid onset of action may be of use clinically is in circumstances where mood elevation is required quickly for emergency reasons and there is no time to wait for up to six weeks for the antidepressant effects of traditional drugs. In these situations, the current treatment is electro-convulsive therapy (ECT). In this scenario, could MDMA be used instead of ECT180,181?
ECT, like psychedelic therapy, is one of those great areas of psychiatry where there exist many erroneous preconceptions in the public that have the net result of withholding an effective, safe, cheap and relatively unobtrusive treatment from those patients who might otherwise benefit from it. The general public’s understanding of ECT is appallingly bad. This is the case, at least, in the Western world. It is of note that in many non-Western countries they queue up for ECT, which they do not consider to be nearly as barbaric as we do in the West (perhaps because the 1976 film One Flew Over the Cuckoo’s Nest was not seen so prolifically). Indeed, in India the general public consider the practice of taking daily doses of drugs as treatments for depression — as we are so prone to do here — to be far more invasive and unsavoury than a few quick and effective doses of electricity. So, the idea that ECT is a bad thing can be seen as a cultural construct. This illustrates well that our opinions about psychiatric treatments are often based not on any particular evidence, but on where we live and what sort of propaganda we have been exposed to. All though I am sure some people within the profession of psychiatry would disagree with me, the vast majority of those with experience of working with severe mental illness will generally opt to choose ECT for resistant depression, as evidenced by a survey in which the majority of Indian psychiatrists themselves said it would be their first choice if they had severe depression182.
In the West, we reserve ECT only for the most severe cases, those in which other treatments have failed or in which we need a rapid serotonin rush to kick-start someone out of the depths of severe — often catatonic — depression in which, by refusing food, the sufferer risks death by starvation. I have always been interested to know what would happen if you gave a high dose (say 150mg) of MDMA to a severely depressed catatonic patient. Who knows? My guess is that it would rapidly bounce them out of their catatonic state. If so, it could be lifesaving. Another study to look out for in coming years. Furthermore, because ECT is generally seen as such an unsavoury thing in the West then I believe a study that could be billed as ‘the nail in the coffin for ECT’ might get easily approved and supported.
5. Psychedelics to Treat Anxiety Disorders
Anxiety is a hugely prevalent global health problem, which is often misdiagnosed, underdiagnosed and difficult to treat. Strictly speaking, PTSD is classified as an anxiety disorder in the psychiatric categorisation manuals, DSM and ICD, but I have given PTSD its own section in this chapter earlier, because of the sheer volume of psychedelic research and treatments aimed at PTSD. In this next section we will explore other anxiety-related disorders such as obsessive compulsive disorder and anxiety associated with end-stage cancer, as a lot of psychedelic work has been done in these conditions183.
Psilocybin for OCD
Obsessive-compulsive disorder is a seriously disabling condition in approximately 0.5% of the population. First-line treatments are with cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs). But there is a high treatment resistance and psychiatrists are increasingly looking for innovative options. One of the earliest psychedelic research studies in the early days of the last 25 of the psychedelic renaissance has been conducted on OCD. It has long been known anecdotally that many sufferers with OCD frequently show a spontaneous remission of symptoms, sometimes lasting several weeks, when they take LSD or magic mushrooms. When MAPS sponsored this double-blind placebo-controlled pilot study by Francisco Moreno at the University of Arizona in 2006, it became the first piece of clinical psilocybin research since 1970. Moreno looked at nine patients with severe OCD, which had not responded to traditional treatments. Psilocybin was shown to substantially reduce OCD symptoms in several of the patients, one for several weeks after the treatment184.
Since then, OCD research with psilocybin has accelerated rapidly, and it is now a central area of focus for contemporary psychedelic centres. A useful retrospective online survey exploring the use of serotonergic psychedelics (such as LSD and psilocybin) amongst OCD sufferers showed that patients benefit from their (non-prescribed) psychedelic use to reduce their OCD symptoms185. Several contemporary publications have demonstrated robust improvements in the symptoms of OCD after just a single dose of psilocybin, in combination with psychotherapy186,187. And more studies are on the way, with one at Yale University188, and plans for another study from the Imperial College London psychedelic group189.
Ketamine for OCD
One of the drawbacks of using SSRIs to treat obsessive symptoms is the delays involved in waiting for the positive effects of SSRIs to start working, which can take up to 8 to 12 weeks before the anti-obsessive effects begin. A single case study published in 2011 showed that a ketamine infusion rapidly reduced obsessive symptoms in a patient190. And whilst a subsequent open-label study failed to demonstrate significant improvements in OCD with ketamine191 a small randomized cross-over study published in 2013 showed that 50% of patients with OCD responded positively to the drug192. Even with no adjunctive psychotherapy it is now well-recognised that a single dose of ketamine can rapidly reduce obsessive thoughts193. A useful review of recent research looking into ketamine therapies as a treatment for OCD examined nine recent studies in 2021 and concluded that the rapid anti-obsession effects of ketamine have a role to play in the acute treatment of OCD. However, treatments must be continued in a maintenance therapy fashion, which may limit it’s use194. A further review published in 2022 found similar results, and both reviews stated the need for larger double-blind randomized controlled trials to explore ketamine’s potential role for OCD195. Combining ketamine administration with specifically guided psychotherapies could certainly improve results196.
LSD for Other Anxiety Disorders
The classic psychedelic LSD has in general played a far smaller role in modern research than its natural cousin, psilocybin. At the time of writing the 3rd edition of this book there had been only a small handful of completed clinical studies of LSD psychotherapy. This is despite an extensive history of LSD psychotherapy and many thousands of papers written during the 1950s and ’60s describing its use — from Sandison, Grof, Leary, Osmond, Hoffer, Fadiman, Stolaroff and countless others.
There are several reasons why LSD has not been studied more extensively during the latest psychedelic renaissance, some of which are psychopharmacological but most of which are political. Many contemporary studies in which the researchers wanted to use a ‘classic’ psychedelic have opted for psilocybin rather than LSD. This may be because psilocybin is slightly easier to use than LSD; it is shorter acting, less cumbersome for a clinical study involving many patients and repeated sessions with the drug, and the high itself is generally a little less intense and perceptually distorting (though many would challenge this). But the main reason why researchers have opted for psilocybin is simply that LSD has such a widespread negative reputation in the eyes of the media, politicians, ethics boards and parents everywhere, which has a detrimental effect on obtaining a research license and funding. Many lay people, while perhaps familiar with magic mushrooms, have not heard of the drug psilocybin, which makes it an altogether easier proposition to use for a study in which researchers are keen to avoid unwanted media intrusions.
Basically, then, after sixty years since the dreaded ‘psychedelic sixties’ came to an end, those three little letters L.S.D. are still enough to strike fear into people’s hearts and make research very difficult indeed.
Peter Gasser’s LSD Study
Because of the reasons described above — and in homage to Albert Hofmann — when the Swiss psychotherapist Peter Gasser designed his clinical trial of psychedelic-drug assisted psychotherapy for the treatment of anxiety associated with end-stage cancer, he was determined not to take the easy route and choose psilocybin. He insisted on using LSD. Gasser was keen to get his study off the ground during Hoffman’s lifetime, which he achieved. Hofmann died in 2008 after a lifetime dedicated to psychedelic research during which he saw his creation, LSD, initially hailed as a ‘wonder drug’ in the 1950s, turn into a ‘problem child’ in the 1960s, and then almost entirely disappear in modern medicine.
Gasser was granted permission to carry out his study in December 2007, prompting Hofmann to say: ‘My wish has come true. I didn’t think I’d live to find out that LSD had finally taken its place in medicine’.
Peter carried out a double-blind, randomized, active placebo-controlled pilot study to examine the safety and efficacy of LSD-assisted psychotherapy in 12 patients with anxiety associated with life-threatening diseases197. Treatment included drug-free psychotherapy sessions supplemented by two LSD-assisted psychotherapy sessions 2 to 3 weeks apart. The participants received either 200μg of LSD or 20μg of LSD, a sub-threshold dose in most people, as a control group. At the 2-month follow-up, anxiety was found to be reduced with no acute or chronic adverse effects persisting beyond 1 day after treatment or treatment-related serious adverse events.
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Peter Gasser kindly sent me an (empty!) LSD capsule container that he used in his landmark study – in a swap with some of my own MDMA bottles from our BIMA study. He also sent an LSD bottle (empty!) from some more recent trials. What a gent!
Gasser then carried out a second, follow-up, qualitative study at 12 months, and showed that reductions in anxiety were sustained198. The implications of Gasser’s early studies were enormous; not only in demonstrating the clinical efficacy of LSD as a potential treatment for anxiety, but also in terms of the political hurdles that had to be surmounted to see the project reach fruition. Albert would have been extremely proud. And even more proud to see how LSD has been studied even more in recent years.
The company MindMed are exploring the use of LSD tartrate (their product labelled MM120) to treat Generalised Anxiety Disorder (GAD) a hugely prevalent and disabling condition that affects many sufferers worldwide199. The initial MindMed MM120 phase 2b clinical study was a dose-finding response trial. Patients with GAD were given LSD at doses of 25µg, 50µg, 100µg or 200µg. It was found that a single 100µg dose was very effective at relieving the symptoms of GAD, while having only relatively minor side-effects200. After MindMed posted its positive preliminary results in 2024, the FDA granted Breakthrough Therapy Status to LSD as a treatment for GAD, which paves the way for further studies201. A useful review of LSD’s capacity for the management of anxiety disorders published in 2023 brings together all the current evidence in this field of study202.
Psilocybin to Treat Anxiety Associated with End-stage Cancer
When Charles Grob, Professor of Child and Adolescent Psychiatry at the Harbor-UCLA Medical Center, Torrance, California, initially planned his psychedelic study to treat anxiety associate with end-stage cancer patient, he started out with the proposal to use MDMA as the active agent. But this was at a time when the public discourse against MDMA was particularly harsh, and Grob switched to psilocybin because of the apparently insurmountable regulatory problems associated at that time with MDMA research.
There is a rich history of using psychedelics to assist patients with the existential issues associated with dying, with much of the work in this field being done by Stanislav Grof and Joan Halifax in the 1960s. Charlie Grob’s study became the first psychedelic treatment with terminally ill patients since the early 1970s. All the patients in the study had end-stage cancer and were experiencing unremitting anxiety. Using a double-blind placebo-controlled method, Grob demonstrated that psilocybin-assisted psychotherapy reduced psycho-spiritual anxiety, depression, and physical pain for these patients203.
I wrote a brief introductory review article about psychedelic therapies in palliative care way back in 2008204. And since then, the role of psilocybin therapy in the field has grown enormously, with a much better and more up-to-date review article published in 2023205. Another of the (modern era) early psilocybin clinical studies for sufferers of end-stage cancer was carried out by Roland Griffiths’ team at Johns Hopkins University. In this study 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety participated in a randomized, double-blind, cross-over trial, which investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin. Results were impressive, with the authors stating:
“High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety.”206
Griffith’s team also showed that psilocybin relieves the pain associated with cancer as well as improving quality of life and helping patients to overcome the anxiety and existential crises associated with their diagnosis of cancer. That same year (2016) also saw publication of Stephen Ross’s study exploring psilocybin therapy for relieving the anxiety associated with end-stage cancer, with similarly positive results after a single dose of psilocybin with accompanying psychotherapy207, with results sustained at long-term follow-up208, and an interesting publication of four participants’ experiences of undergoing the trial209. Other teams Further larger scale studies are now underway210. Oncology experts around the world are increasingly looking towards psychedelics as having the potential to transform how medicine can improve the lives of people suffering with cancer211,212, which must be tremendously exciting to see for those early researchers of psychedelics in palliative care in the 1960s and 1970s.
6. Psychedelics to Treat Addictions
There is something about having had the psychedelic experience that lends itself perfectly to a subsequent desire to shed addictive behaviours. The psychedelic drugs themselves (with the exception of ketamine) have a low risk of addiction213,214,215,216. After glimpsing the numinous, one has little craving for repeating it any time soon, and one gains an instant recognition of the folly of chasing after thrills. Other, far more harmful substances, such as alcohol and opiates seem inferior and superfluous by comparison with the mind-blowing experience of ego dissolution and being bathed in the white light of ultimate knowledge. Whether one looks at the lower rates of alcoholism and cannabis use amongst indigenous peyote users217, ibogaine, ayahuasca or psilocybin users, or the pattern of reduced substance use amongst western users of psychedelics218, it is clear that psychedelics have a very important place in the history of treating or reducing the prevalence of addictions. These naturalistic anthropological observations – together with the well-recognised fact that current contemporary treatment protocols for addictions with modern psychiatry219 - makes psychedelic therapies an excellent target for modern addiction psychiatry research220,221. In this section we will explore addiction and dependence disorders according to substance, and briefly review the current state of psychedelic research for each condition.
A) Psychedelics for Alcohol Use Disorder (AUD):
MDMA for AUD
From 2017 to 2020, I was proud to be chief investigator, alongside my then supervisor, David Nutt, research associate Claire Durant, co-therapist Laurie Higbed, research assistant Steve O’Brien, study doctor Chloe Sakal, and consultant psychiatrist Tim Williams in a ground-breaking UK study, the world’s first addiction study to explore the use of MDMA therapy to treat alcohol addiction – or alcohol use disorder (AUD).
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The original Bristol-Imperial MDMA-Alcoholism (BIMA) Study Team, Bristol 2015.
Left to right: Claire Durant, Ben Sessa, David Nutt, Tim Williams and Laurie Higbed.
The physical, mental and societal problems associated with alcohol misuse are pervasive and on the increase. The UK has a peculiarly harmful relationship with alcohol. Over half of adults in the UK drink above the maximum recommended weekly limits and a quarter are labelled as problem drinkers.
The burden of alcohol abuse in Britain in horrendous, with 8,000 deaths each year, one person in twelve dependent on alcohol, 20% of suicides and 65% of suicide attempts related to alcoholism, up to 1.3 million children adversely affected by family drinking, around 35% of accident and emergency attendance and ambulance costs alcohol related, and drink driving responsible for 17% of all road deaths222.
In psychiatry, we have a large range of traditional treatments available to manage alcoholism, including many different pharmacological approaches and a raft of psychotherapies of varying efficacies. The current treatments for alcohol dependence are not great. A meta-analysis conducted ten years ago looked at 361 controlled studies and ranked treatment modalities223. Top of the list was the ‘brief intervention approach’, followed by ‘motivational enhancement’ and two different pharmacotherapies: GABA agonist treatment (e.g., acamprosate) and opiate antagonists (e.g., naltrexone). Those approaches that attempted to simply educate or shock fared the least effective at reducing rates of alcoholism.
So how good are acamprosate and naltrexone for treating alcoholism? A meta- analysis of 20 controlled trials involving 4,000 patients treated with acamprosate showed that at 12 months, abstinence rates were 27% for acamprosate compared to 13% for placebo, so basically not that great224. And a meta-analysis of 24 trials for naltrexone treatment only found significantly improved abstinence rates for the first 12 weeks and no differences between placebo and naltrexone at 12 months225. When acamprosate and naltrexone are combined, results are slightly better, with up to 73% abstinence after a 12-weeks treatment period compared to just 20% on placebo. But this rate of improvement had dropped to 66% at three-month follow-up and by 12 months combined treatment was no better than naltrexone alone226.
None of these current treatments are particularly effective at providing a lasting treatment for alcohol dependence. Indeed, rates of relapse three-years post-treatment for alcohol dependence approach 90%. After 100 years of modern psychiatry this is not good enough. Successive UK governments have a transparently sinister relationship with the UK drinks industry, which I liken to our equivalent of the US’s National Rifle Association, in which money and power trump evidence-based data and influence political decision-making. Governments ignore the calls for legislation to increase the price of alcohol and reduce its availability (which are the two most effective evidence-based to reduce the harms of alcohol use) and we have seen in recent years a proliferation of availability and normalization of heavy alcohol consumption.
With this in mind, we recognised that alcoholism was therefore an area of medicine that is well in need of an innovative approach. Whilst the use of classic psychedelics – LSD in the 1950s, 1960s and 1970s, and psilocybin in modern times – had been well studied, no one had at that time considered using MDMA therapy as an agent for treating alcohol use disorder. But we were unsure whether MDMA Therapy for alcoholism would even work?227 It does, after all, not provide the same level of ‘spiritual / mystical’ experience of the classical psychedelics. And all the other addictions studies with the classical compounds have emphasised that it is the depth of the induced subjective spiritual effects of the experience that best predicts maintained abstinence from substance use. But there is a slight subjective spiritual / mystical experience associated with MDMA use. True, it is less pronounced; with around 17% of MDMA first-time users reporting spiritual effects compared to around 80–90% of classical users228,229. However, MDMA’s capacity to ‘make yourself present in the moment’, which is a core concept of mindfulness; and, crucially, the MDMA experience is generally more easily tolerated than the classical psychedelics, with less perceptually disturbing effects compared to LSD and psilocybin. Not all patients are able to tolerate the classical psychedelic experience, or even the idea of a treatment involving these experiences, and compliance is a critical part of addiction therapy. Therefore, MDMA therapy could offer, we anticipated, an alternative opportunity for enhanced psychotherapy for many patients.
Our Bristol-based study, sponsored by Imperial College London, delivered an eight-week course of MDMA-Assisted therapy in a safe setting, after thorough screening of suitable patients, scrutiny of physiological measures and intensive integrative follow-up. We called it BIMA: The Bristol Imperial MDMA for Alcoholism study. Using an open-label design, with strict inclusion and exclusion criteria, we examined whether 14 patients who have been medically detoxed off alcohol can use two sessions of MDMA-assisted Therapy to access, explore and resolve ingrained negative psychological dynamics that maintain addictive behaviours — most of which are underpinned by long-standing psychological trauma. The hope was that MDMA therapy could provide an important opportunity for patients with alcohol dependence to maintain abstinence and recovery.
Running that study was a pleasure and a challenge from beginning to end. For me personally it was a terrific opportunity to experience the trials and tribulations of carrying out a complex human psychopharmacology clinical trial, using a maligned and controversial substance (MDMA), with all the hurdles that such a thing requires, whilst also working with a population of patients whom I respect and admire, and a stellar clinical and research team. Pretty much everything that could go wrong, did go wrong during the five years of the BIMA project. But we overcame all the challenges and produced some splendid results.
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The final BIMA clinical team in 2018, when we were eventually ready to get going with the clinical part of the trial. Michael and Annie Mithoefer, Rick Doblin and Ilsa Jerome at MAPS were incredibly supportive. Michael came to visit us in Bristol just as we were starting the dosing sessions.
Here he is pictured alongside Laurie Higbed, Tim Williams, Chloe Sakal, Steve O’Brien and David Nutt. A historic and exciting moment in the field of MDMA clinical science in the UK.
The first difficulty we had was getting the clinical grade (GMP) MDMA to dose with. MAPS were supportive in providing the compound at a low price. At that time, there were very few companies capable of or willing to provide GMP MDMA. (That is not the case today; with dozens of chemists producing commercial GMP MDMA all over the world). The chemists chosen – based in Newcastle, UK – struggled to get the purity of the MDMA batch up to the 99.98% purity required by the MHRA. And what started as a 1kg batch was gradually wasted down to just 190g, after multiple re-crystallisations were required to reach the purity we needed. This resulted in a long delay before we could start dosing.
In order to not waste the time of the clinical team we had assembled to run BIMA, we decided to run a different study whilst waiting for the chemists to come good with the drug. Because BIMA was designed as an open label study – a necessary first-step when exploring a new drug with a new condition (no one had ever explored MDMA for alcoholism before), we had no placebo control group. All the patients got MDMA. But we could run a demographically identical observation study, using a similar population of patients with AUD. This would give us a chance to become familiar with the processes involved in recruiting, screening and assessing patients with AUD in the local area, using the same raft of rating scales we would eventually use in the MDMA study. And it would give us a helpful ‘treatment as usual’ comparison group, against which we could compare our open-label MDMA study group.
The subsequent study we performed was called the ‘Outcomes Study’, and it provided – as expected - predictably poor outcomes for people in Bristol undergoing medical detoxes and treatments for AUD. In the paper abstract we described the sad situation for patients being treated for AUD with traditional medical inputs:
“This paper presents the results of an observational study that followed a group of 12 patients from the start of their community detox for 9 months, collecting information about outcomes. In respect of drinking behaviour, results post-alcohol detoxifications were poor. Three months post detox, 8 out of the 12 participants had relapsed to drinking. Six participants had a second, and one participant had a third detox within the 9-month follow up period. Given the burden of alcohol use disorder (AUD) on the population of Bristol, this study is an important step on the journey of developing new and innovative treatments for this population. And in the context of the current Covid 19 pandemic, attention to the issue of best management of AUD has become even more pertinent.”230
Knowing now how to recruit, screen and assess our population of AUD patients, we set about delivering the 8-week course of MDMA therapy. Fourteen patients with AUD completed their community-based alcohol detoxification courses and then received an eight-week course of recovery-based therapy. After screening for eligibility and baseline rating scale assessments, patients underwent two non-drug preparatory psychotherapy sessions, then on weeks 3 and 6 of the 8-week course, received MDMA-assisted therapy.
The MDMA dose used at each session was 125mg followed after 2-hours by a half-dose again (62.5mg) to prolong the opportunity for psychotherapy. Psychological support was provided before, during and after each session. Safety and tolerability were assessed alongside psychological and physiological outcome measures. Alcohol use behaviour, mental well-being and functioning data were collected for nine months after alcohol detoxification. It was a complex program, requiring the invaluable support of trainee psychiatrists in Bristol to provide overnight sitting for patients after their two MDMA sessions. The day after each drug session there was a vital non-drug session. There were then further non-drug sessions, and then evaluation visits at 3-months, 6-months and 9-months after the end of the course. We published a brief case series report before the main paper came out231.
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Planning the study, developing patient journey timelines, receiving the medicine for the pharmacy the first time and preparing the room for MDMA sessions in the early days of BIMA. With clinical psychologist / co-therapist Laurie Higbed and study psychiatrist, Dr Chloe Sakal. These were very exciting times!
The results of the BIMA study were impressive. MDMA treatment was well tolerated by all participants. No unexpected adverse events were observed. Psychosocial functioning improved across the cohort. And regarding alcohol use, at nine months post detox, the average units of alcohol consumption by participants was 18.7 units per week compared to 130.6 units per week before the detox232. This compared favourably to the previous observational study ('Outcomes') with a similar population of people with AUD233. Whilst the Outcomes group were not a randomised arm of the same cohort – so cannot be considered a proper control group – comparing the two studies against one another provides a valuable illustration of how MDMA therapy appears to outperform traditional treatments for patients with AUD post-detox.
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The top line is the OUTCOMES STUDY: At 9-months, 75% of patients had returned to drinking over 14 units of alcohol/week (one of the definitions of AUD) post-detox.
Compared to:
The lower line, the BIMA STUDY, with only 21% still fulfilling the criteria for AUD by drinking over 14 units of alcohol/week at 9-months post-detox. We were very proud of this result!
After the original paper, we published several other papers using original research data from the BIMA study, including ‘Debunking the Myth of Blue Mondays’ (described earlier) demonstrating no evidence of come downs or affect drop for a week after taking clinical MDMA234. And Steve O’Brien used original data from the BIMA study to provide evidence of a lack of addiction risk with clinical MDMA in his 2024 paper The Safety Profile of MDMA in Psychotherapeutic Practice: A Systematic Review of Addiction Potential235. A further study, currently under peer review, first authored by Hannah Thurgur at Nutt’s Drug Science unit, will be publishing results of the secondary outcome measures not published in the original paper, suggesting reductions in alcohol craving and improvements in sleep and aspects of psychosocial functioning at 3 months follow-up compared to baseline.236.
To date, no one else has carried out any other studies exploring MDMA therapy for AUD. The next step for BIMA would be a placebo-controlled MDMA-AUD study. We started making plans for such a study, writing the protocol and designing the trial, but at present there is no home (specifically a funding stream) for such a piece of work. I truly hope this happens somewhere at some point.
Psilocybin for AUD
As described at length in previous chapters, classic psychedelics – and especially Osmond’s work with LSD in the early days – have a premier place in the history of psychedelic research for addictions. And since Teri Krebs’ and Pal Johanson’s important 2012 meta-analysis that demonstrated the efficacy of those early Osmond LSD studies as viable treatments for alcoholism, psychiatry has been waiting for someone to recreate a modern psychedelic study with alcoholics237. And, as mentioned, in modern times LSD has somewhat (but not completely) fallen out of favour, primarily for ease-of-study-approval reasons. So, it is psilocybin that has risen up as a popularly studied agent for psychedelic drug-assisted psychotherapy research for AUD238.
It was New Mexico psychiatrist Michael Bogenshutz who having first written an influential paper reviewing the history and potential mechanisms of classical psychedelics as treatments for addictions239 then went to on to do the first alcohol-psilocybin study in modern times study, published in 2015. Bogenshutz carried out a single-group proof-of-concept study on 10 volunteers with alcohol dependence. They received two doses of oral psilocybin (0.3 mg/kg and 0.4 mg/kg — approximately 21–28 mg) separated by 4 weeks in combination with 12 weeks of outpatient psychosocial treatment including preparation, debriefing, and motivational enhancement therapy.
Results showed abstinence increased significantly following psilocybin administration (p < 0.05). The gains were largely maintained at follow-up to 36 weeks. There were no significant treatment-related adverse events. And, like all the other addictions studies, the intensity of positive, especially spiritual, effects in the first psilocybin session predicted decreases in craving and increases in abstinence240.
Bogenshutz then went on to do a double-blind randomized clinical trial with 93 participants. Results showed the percentage of heavy drinking days during 32 weeks of follow-up was significantly lower in the psilocybin group than in the control group (using diphenhydramine), published in 2022241. Looking at the same cohort of participants used in the RCT, his team then went on to publish results of an fMRI neuroimaging study, which showed that across both alcohol and emotional cues, psilocybin increased activity in the medial and lateral prefrontal cortex (PFC) and left caudate, and decreased activity in the insular, motor, temporal, parietal, and occipital cortices, and cerebellum, suggesting enhanced goal-directed action, improved emotional regulation, and diminished craving, which proposes a robust neurobiological mechanism for how psilocybin-assisted therapy can be useful in treating AUD242.
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Michael Bogenshutz has been behind most of the current psilocybin-alcoholism research globally, and he was also terrifically supportive in helping us set-up our Bristol MDMA addiction study. We owe him a great debt of gratitude.
And further studies have proposed the psychological mechanisms behind the positive changes seen with psilocybin therapy for AUD, with the authors stating that, “results support the assertion that psilocybin increases the malleability of self-related processing, and diminishes shame-based and self-critical thought patterns while improving affect regulation and reducing alcohol cravings” 243. Since then, other centres have started investigating psilocybin for AUD, with one large study planned in Belgium244 and another at the University of Calgary in the pipeline245.
Other Classic Psychedelics for Treating AUD
Turning to contemporary ayahuasca research, it is worth noting that much has already been said in earlier chapters about the history, pharmacology and established research with this amazonian compound. But I will describe now a few of the most contemporary studies in respect to the field of alcohol addiction studies.
It has well been recognised that indigenous and ceremonial users of ayahuasca – even before western medicine discovered the brew – have benefitted from the anti-addiction qualities of the ayahuasca psychedelic experience246. A modern study of today’s contemporary ceremonial ayahuasca users from across ten regions of Brazil showed a reduced consumption of alcohol and tobacco in that population247. A recent online survey of ayahuasca users showed improved well-being and reduced consumption of alcohol in that cohort248. And in 2024 a large cross-sectional survey demonstrated the associations between ayahuasca consumption in naturalistic settings and a reduction in alcohol and other drug use249. Even outside of naturalistic settings, a single dose of ayahuasca has been shown to be associated with reduced alcohol use in college students, in a small study published in 2024250. And the internet is awash with anecdotal reports of salvation from alcoholism after people’s personal experiences with ayahuasca. From everyday people251,252, big sports celebrities253 and even reports on Trip Advisor!254
As described in a previous chapter, the increasing emergence of psychedelic retreats frequently target addictions as one of the conditions they treat, with ayahuasca being a popular approach. Many renowned centres are dedicated to treating substance misuse problems. An open-label observational study investigated the safety and long-term effectiveness of ayahuasca treatment for individuals suffering from addiction and dependence. Combining Western psychotherapeutic techniques with South American shamanic healing practices, participants on a retreat in British Columbia, Canada received four days of group counselling consisting of psychosomatic techniques coupled with group sharing and dialogue and two expert-led ayahuasca ceremonies. Participants showed reductions in their use of cannabis, alcohol and tobacco, with statistically significant reductions in cocaine use. There were also improvements in measures of hopefulness, empowerment, mindfulness and two measures of quality of life that were sustained at six-month follow-up255.
And numerous scholars have been at looking at the anthropological and social aspects of ayahuasca in non-Western cultures, how this relates to the stability of those populations and how it is increasingly emerging as a tool for self-exploration and healing in the West. For an excellent extensive review of many of the earlier studies with ayahuasca, see Dennis McKenna’s review of research256. For further reading on the anthropological aspects of human development alongside ayahuasca it is always a pleasure to read Graham Hancock’s book Supernatural: Meetings with the Ancient Teachers of Mankind257. Other good books on the subject include Ralph Metzner’s Ayahuasca: Human Consciousness and the Spirits of Nature258 and Sacred Vine of Spirits259. Plus, the extremely informative book by Luis Eduardo Luna and Steven White (editors), Ayahuasca Reader: Encounters with the Amazon’s Sacred Vine260, which has recently been re-released in 2016 in an updated mammoth 2nd edition, containing a rich variety of new reflections about this entangled and enthralling subject.
Also in South America, there is currently a long-term evaluation of the very well established ayahuasca treatment program at the Takiwasi Center in Peru. The director of Takiwasi, Jacques Mabit, wrote a good review of the history and ongoing efforts at the centre in the 2007 book Hallucinogens and Health261. The Takiwasi Center recently published its protocol for their outcome evaluation of ayahuasca-assisted addiction treatments262. Meanwhile, non-clinical research continues to explore the multiple mechanisms behind how ayahuasca exerts its anti-addictive effects263,264. Research suggests it is the combination of biochemical, physiological, psychological, and transcendent factors that are necessary for the healing properties of the sacred vine265.
And will come of no surprise to learn that given the vast market available for whoever comes up with an effective treatment for alcoholism, many of the new psychedelic start-up companies are targeting AUD in their R&D pipelines with New Chemical Entities (NCEs). Beckley-Psytech and Atai are exploring a new formylation of 5-MeO-DMT (BPL-003) for AUD, Cybin are looking into their new formulation of deuterated tryptamine for AUD, and Journey Colab are looking into a new chemical entity version of mescaline (JOUR 5700) for AUD. Let’s hope some of these products find their way into free public healthcare systems sometime soon.
Ketamine for Treating AUD
Moving now to the use of ketamine as an agent to treat alcoholism / AUD. This an area of particular interest to me, given the activities and research that came out of Awakn Clinics. And in a fascinating turn of events, despite the massive growth in the last ten years of ketamine infusions as a rapid acting antidepressant (RAAD), and the emergence of multiple ketamine clinics providing ketamine-assisted psychotherapy (KAP) for depression, PTSD, anxiety disorders and other psychiatric conditions, some of the earliest research with ketamine – before it was even discovered to have antidepressant qualities – was actually as an agent for treating alcoholism.
The work of Evgeny Krupitsky, the Clinical Director of Research for the Saint Petersburg Regional Center for Research in Addiction and Psychopharmacology was the pioneer in this work. I first met Evgeny at a conference in Vienna in 2007 when I was answering questions after a talk I’d given on psychedelic therapies. Someone in the audience asked me about ketamine and I answered that I was no expert on ketamine, but recommended they get in touch with Dr. Krupitsky in St. Petersburg266, the world authority on the subject. The questioner got to his feet, and replied, in his deep Russian accent, “I am Evgeny Krupitsky!” We went for a beer, got on well and I subsequently invited him to speak at Breaking Convention 2011.
Evgeny puts a lot of faith in the induction of a spiritual experience to explain his effective results, which fits with the importance of the mystical experience to effect positive personality change.
In the 1990s, Evgeny developed a model of ketamine-assisted psychotherapy to treat alcohol and opiate addictions and published results of research on a huge number of participants who benefitted. Krupitsky and Grinenko compared 111 alcoholic patients treated with ketamine-assisted psychotherapy (KPT) with 100 alcoholic patients treated with conventional treatment267. 66% of those treated with ketamine-assisted psychotherapy (KPT) remained sober after one year, compared to 24% of the control group. Krupitsky further developed his technique and applied it to treating heroin addiction. He showed that one single session of KPT (compared to a placebo session) was enough to significantly promote improved abstinence from heroin for one year without any adverse reactions. He went on to study whether follow-up sessions, with two further monthly KPT sessions after discharge from hospital following this initial KPT session, improved long-term outcomes compared to those randomly allocated into a placebo group.
At one-year follow-up there was a significantly higher rate of success in the multiple KPT group, with 50% of subjects remaining abstinent from heroin compared to just 22% in the single KPT group268. Another early example of the use of ketamine to treat addictions (in this case, opiate addiction) is the extraordinary study by Jovaisa et al. from Lithuania, who used low-dose ketamine, without combining it with psychotherapy, to demonstrate how the effects of the drug reduce the unpleasant withdrawal symptoms of heroin addiction269.
After Evgeny’s early work in the 1990s, he has since ceased clinical studies with psychedelics in St Petersburg, as the current Russian Federation prohibits such research. But there has been considerable research activity into ketamine therapy for AUD in recent years, with a further nine such studies, representing KAP for over 800 patients with alcohol problems. A recent systematic review demonstrated the positive results of this form of therapy270. Evgeny Krupitsky has continued to work with other international ketamine studies and was supportive of the work subsequently carried out Professor Celia Morgan at Exeter University. Professor Morgan ran the world’s first large scale double-blind placebo-controlled study outside of Russia to assess ketamine-assisted psychotherapy as a treatment for AUD. Celia’s phase 2 study, called the Ketamine for Reduction of Alcohol Relapse (KARE) study, was led by the University of Exeter and funded by the Medical Research Council. The initial study included 96 people with alcohol problems who were abstinent at the time of the trial. There were four treatment arms to the study, testing ketamine against placebo, with or without additional psychotherapy, to give a robust assessment of efficacy.
Results showed that people who had ketamine combined with therapy stayed completely sober for 162 of 180 days in the six-month follow-up period, representing 87% abstinence271. This was significantly higher than any of the other groups, indicating that the therapy may also have promise for preventing relapse. This group was more than 2.5 times more likely to stay completely abstinent at the end of the trial than those on placebo. The team also found some evidence that ketamine and therapy may prevent any drinking over six months, though the results were more mixed. Patients having ketamine also had lower depression after three months, and better liver function than those on placebo, regardless of whether it was combined with therapy or not272.
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Sharing the stage at the SSA meeting in 2017 in Newcastle, UK, with Celia Morgan. Our paths crossed long before we worked together at Awakn Life Sciences, where she came on board with her expertise in ketamine for AUD. Also pictured is Albert Garcia-Romeu, who is part of the psilocybin for nicotine cessation team, alongside Matthew Johnson, at Johns Hopkins University.
Celia’s work is of particular interest personally because she was part of the early scientific team at Awakn Life Sciences. Awakn acquired and licensed the therapy from University of Exeter to use in their clinics and partnerships. When the Bristol, London and Norwegian Awakn clinics were running – before closure in summer 2023 – we used Celia’s trademark KARE protocol for all our patients presenting with AUD. The next stage of development with Celia’s work is that her team are now expanding the initial study to a large, multicenter phase 3 trial in a tripartite partnership between Awakn, University of Exeter, and the UK Dept. of Health (NIHR & NHS). The phase 3 study represents an important part of Awakn’s R&D pipeline and will be jointly funded by Awakn and the NIHR Efficacy and Mechanism Evaluation (EME) Programme (NIHR150193), an MRC and NIHR273. It is the largest-ever trial of ketamine-assisted therapy for alcohol disorder, funded for £2.4 million, and being delivered across seven NHS sites across the UK.
Further contemporary reviews state the potential benefits of ketamine-assisted therapy for AUD, but often conclude that more research is needed to conclusively demonstrate its benefits274,275, which makes Professor Morgan’s ongoing far-reaching project all the more important.
B) Psychedelics for Opiate Use Disorder (OUD):
Moving on now to opiate use disorder, and the role that contemporary psychedelic research has had in exploring the condition and developing new treatment paradigms. Whilst a subject that gets a lot of press, and one that certainly involves a hugely destructive psychological, social, financial and public health burden – opiate use disorder was relatively low prevalence until recent times. The abuse of opiates in the form of street heroin, and the complex subject of opiate substitution inputs with methadone and buprenorphine, whilst a vital part of any country’s healthcare system, was never anywhere close to the prevalence of alcohol-related problems.
However, following the explosion of the ‘opioid crisis’ in America since the 1990s, we have seen a huge increase in the usage and harms associated with opioids. Indeed, the opioid epidemic is considered to be one of the worst public health disasters affecting the USA, Canada and the UK, with 600 000. deaths from an opioid overdose over the past two decades276. There are multiple factors that have contributed to the opioid crisis we now have – and it is beyond the scope of this book to explore them in detail. Many commentators point to the crisis emerging when the USA’s Food and Drug Administration (FDA) approved the powerful opioid OxyContin, promoted by Purdue Pharma, which led to widescale availability and overprescribing of opiates by the medical profession. Other factors involved in the development of the crisis were the proliferation of illegal opioids like heroin and synthetic opioids such as fentanyl. Between 1998 and 2016, opioid prescriptions increased by 34% in England (and by 127% when accounting for the total oral morphine equivalency), while opioid-related hospitalisations rose by 48·9% between 2008 and 2018, with an estimated health-care cost of £137 million277.
The role of psychedelics to treat OUD is not new278. A vintage research study by a veteran of the field, Charles Savage, described the use of LSD psychotherapy in an in-patient setting to treat heroin addicts279. But in the light of the current epidemic problems with OUD, there is now, more than ever, a strong push to find effective treatments for people suffering with OUD. And a considerable amount of psychedelic research has focused on the issue. And mostly involving the psychedelic compound Ibogaine.
Ibogaine for OUD
We touched on the ceremonial use of ibogaine amongst the West African Bwiti tribes earlier in this book, and how it has particular qualities that make it a good candidate for managing OUD. It works to treat OUD in two main ways.
Firstly, consumption of the drug – particularly in a ceremonial setting – induces an intense psychedelic experience, which in combination with focused psychotherapy allows the user to address difficult, challenging and often avoided psychological issues. In this way, it shares similarities with other psychedelics such as psilocybin, ketamine and MDMA, DMT etc.
But the unique thing about ibogaine is that not only is it a psychedelic, but it has specific qualities that combat the experience of opiate withdrawal symptoms. The therapeutic effects of ibogaine (in modern, Western, medicine) were discovered by the American scientific researcher Howard Lotsof in 1962. At the time, Lotsof was a heroin addict, and he discovered – along with some of his friends, who were also addicted to heroin – that when they used ibogaine, they experienced reduced cravings for heroin. Thereafter, Lotsof became a leading advocate for ibogaine therapy for OUD, and in the mid-1980s he worked with a company in Belgium to manufacture ibogaine in capsule form, which were offered to addicts in the Netherlands. Lotsof subsequently gained a patent in 1986 for the use of ibogaine as a treatment for heroin and cocaine addiction. And later began working with Jan Bastiaans, the Dutch psychiatrist who had famously used LSD therapy for Holocaust survivors. 280.
Since the late 1990s there has been increasing clinical research in the field, with Lotsof publishing data of a case series of ibogaine treatments for OUD in 2001281. An early paper by Kenneth Alper highlighted several pre-clinical animal studies describing its effectiveness as an agent to combat addiction282. And in an open-label study by Alper - alongside Lotsof and Bastiaans - ibogaine was explored as a treatment for opiate dependence. Thirty-three patients with previous intravenous heroin addiction were given a single dose of ibogaine on stopping their opiate drugs. Twenty-five of them showed a resolution of the signs of opiate withdrawal within 24 hours, which was maintained for a total of 72 hours283.
Since then, ibogaine treatment clinics, both underground and licensed, have sprung up all over the world. MAPS sponsored research at ibogaine clinics in Mexico (with investigator Thomas Brown284) and in New Zealand (with investigator Geoff Noller285). These observational studies gathered data on the outcomes of long-running clinical programs and concluded that a single ibogaine treatment reduced opioid withdrawal symptoms and achieved opioid cessation or sustained reduced use in dependent individuals over 12 months. MAPS also initiated a long-term ibogaine efficacy study in Canada, being evaluated by Leah Martin and Sandra Karpetas, which was unfortunately influenced by setbacks and clinics were forced to close for lack of funding286.
In the wake of the opioid crisis since the 1990s, research continues to be published demonstrating positive outcomes for ibogaine treatments287. And whilst contemporary research is eliciting useful new insights – including neuroscientific studies to understand the mechanism of its anti-addiction effects - in treating AUD288,289 and OUD290, ibogaine research and proposed interventions have certainly not been without their challenges. With the emergence of underground ibogaine centres, an ‘ibogaine subculture’ has arisen, with some unlicensed clinics often lack scrutiny, medical oversight and supervisory frameworks291. Ibogaine has a known cardiac risk if used without careful medical supervision in screened patients, and there have been a notable number of fatalities due to arrythmias 292,293. However, even in underground settings, with due care and attention the drug offers patients with OUD a valuable treatment option294 – and is perhaps one way out of the terrible opioid crisis of recent years.
Ketamine for OUD
Having already discussed how ketamine is being explored as an agent for treating alcohol use disorder (AUD) – and that it’s mechanism of action as an anti-addiction agent is linked to its capacity for inducing neuroplasticity – it is not surprising that ketamine is also considered a likely potential candidate for treating opiate use disorder (OUD) as well. Recent research has explored the common links between different types of addictions, and how ketamine might work broadly across all of them295. Another interesting link between ketamine therapies and OUD is that ketamine itself is used as a pain reliever – above and beyond it’s role as a psychedelic agent – which means it can, and often is, used instead of opiate analgesics (such as morphine), which in turn reduces the burden of opiate usage in patients requiring pain relief. This could have a beneficial effect on reducing the dependence on opiates and relieving the current opioid crisis296. Similarly, in patients who have become dependent on opioids through their medical need for regular morphine analgesia, such as chronic cancer patients, ketamine can be used to manage the subsequent opioid dependence they have developed297,298. And a single ketamine infusion – like the administration of ibogaine – appears to reduce the severity of opiate withdrawal syndrome299.
Interesting though these studies are, however, they are not specifically about using ketamine-assisted (psychedelic) therapy to treat people with OUD. But there has been some research in this area in modern times. A systemic review by Jones et al in 2018 reviewed seven studies exploring ketamine-assisted therapies to address addiction disorders. The studies of alcohol and opioid use disorders (which were not placebo-controlled trials) found improvement in abstinence rates in the ketamine group, with significant between-group effects noted for up to two years following a single infusion of ketamine300. Before we leave the subject of OUD and ketamine treatments, it is worth mentioning the co-morbidities that often accompany OUD. Up to a half of people with OUD seeking opiate substitution therapy (OST) with methadone301 or buprenorphine302 also have depression, which does not remit even after the patient is stabilised onto OST303. A study that is in the pipeline from Dr Eric Dobson will be looking at treating co-morbid depression in people with OUD using ketamine-assisted psychotherapy304. And another pilot study looking at a similar issue – using ketamine therapy to boost methadone management OST, and also managing co-morbid depression in people with OUD is also due soon305. I find it promising to see so much valuable research being directed towards people with OUD, who for too long have been neglected by the medical profession and suffered so much stigmatisation and criticism.
Other Psychedelics for OUD
In fact, opiate use disorder is getting quite a lot of attention from the field of psychedelic research these days, which may be – as mentioned, but trying not to be too cynical – because of the potential market available now that middle-America is suffering an opioid crisis. It is notable that there was never this much concern about OUD when it was primarily street heroin users. But that’s politics for you.
Ayahuasca is consistently touted as a positive option the management of substance use disorders, as described above regarding alcohol use disorder. It has also been studied as an agent for managing opiate use disorder. In their 2017 paper, Talin and Sanabria describe how methadone withdrawal symptoms are reduced after consumption of ayahuasca306. In a recent review by Arenson et al, ayahuasca is included alongside kratom and ibogaine as having benefits for opiate withdrawal syndrome307. However, ayahuasca is not without its adverse effects too, and it does not suit everyone. As with other classic psychedelic drug experiences, the risk of psychosis is a potential problem for certain vulnerable individuals308. There is sometimes a tendency for supporters of psychedelic therapies to play down adverse events. A large scale Global Ayahuasca Survey by Bouso and colleagues highlighted that amongst ayahuasca users, the rate of adverse events was common. But these were usually considered relatively minor and were tolerated by users – demonstrated by their willingness to repeat ceremonies despite some of the adverse experiences they went through309.
C) Psychedelics for Nicotine Use Disorder:
Psilocybin for Smoking Cessation
Nicotine use disorder – generally just known as ‘smoking cigarettes’ – is a hugely prevalent, highly addictive and extremely physically harmful. Furthermore, the current medical treatments are poor, with high rates of relapse. People find it very hard to stop smoking. These cardinal features (high prevalence, high risk, high addiction and poor treatment outcomes) making nicotine cessation therapy a very low hanging fruit when it comes to developing a new treatment that might actually work. It has always surprised me that more researchers don’t tackle the really big public health problems more vigorously. Issues such as smoking and obesity are not heavily researched. But when it comes to smoking, psychedelics could be the answer.
And one researcher who recognises the importance of developing an effective smoking cessation treatment is Matthew Johnson from Johns Hopkins University. I have always admired Matt’s work, so it was a great pleasure, therefore, when Matt and I wrote a jointly authored editorial for the British Journal of Psychiatry about psychedelic therapies for addictions, which appeared in that 2015 journal with Sasha Shulgin on the cover310.
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Matthew Johnson at the Vermont Psychedelic Society gathering in June 2022. A psychedelic research pioneer, and a man with a warm heart. Keeping everyone amused, especially Lynn Marie Morski, the president of the Psychedelic Medicine Association.
In 2012 Matt, who was one of the team at Johns Hopkins who had worked with Roland Griffiths on the now-famous 2006 psilocybin mystical experiences studies, turned his hand to a psilocybin study for addictions. He started an open-label pilot study to determine the safety and feasibility of psilocybin as an adjunct to tobacco smoking cessation treatment. Smoking is by far and away the biggest killing drug humans have, taking around 55,000 lives each year in the UK – which is equivalent to one person dying every five minutes311. As addictive pharmacological compounds go, one must take one’s hat off to nicotine. It is staggeringly addictive. One could say it is the perfect dangerous addictive drug: it has an immensely high dopamine-mediated affinity for the nucleus accumbens pleasure centre — meaning the compulsion to dose is intense (much higher than crack cocaine and heroin — I have heaps of patients who have successfully beaten heroin and crack addictions but cannot stop smoking). Each cigarette provides a mild but clearly noticeable stimulant effect that enhances cognitions, is alerting and boosts focus and concentration. Yet at the same time each cigarette also provides a subtle sense of relaxation and calmness. Indeed, smokers can control the extent to which the cigarette is a stimulant or a relaxant depending on hard they pull each drag, a remarkable system of idiosyncratic drug titration.
Furthermore, nicotine is a very short-acting drug; to maintain a steady blood level of nicotine one would need to smoke a cigarette every four minutes. This means that smokers are constantly in a rollercoaster cycle of dose-withdraw-dose-withdraw all day long. The withdrawal syndrome itself is subtle but noticeably unpleasant, with irritability, poor focus and an intense craving to re-dose. But above all, the ‘best’ thing about nicotine that makes it the perfect damaging drug is that the delivery method, cigarette smoking, is spectacularly bad for you. The alveoli of the lungs are arguably the most delicate and fragile tissue in the body. And the way people extract the drug nicotine (which itself is relatively harmless) from its bound state in the leaves of the Solanaceae (nightshade) family plant, Nicotiana tabacum, is by setting alight to the dried leaves and pulling that hot cauldron of burning smoke between the teeth, through the soft palette, down through the trachea and pumped into the furthest reaches of all the lobes of the lungs, in order that the nicotine molecules — alongside the another 6,000 chemicals, of which at least 400 are known to be highly toxic — can pass into the circulating blood of the alveoli and carry the nicotine to the brain for three seconds. You can see why it has caught on.
So, in his initial pilot study, Matt Johnson took 15 psychiatrically healthy nicotine-dependent smokers (10 males; mean age of 51 years), who were smoking on average 19 cigarettes per day for an average of 31 years and who had made an average of six previous lifetime attempts to quit their addiction. He administered a course of psilocybin-assisted psychotherapy using psilocybin doses between 20mg and 30mg, delivered as part of a structured 15-week smoking cessation treatment protocol. He used biomarkers to provide definitive proof of smoking behaviour as well as collecting self-report measures. The results of the pilot study showed that 12 of 15 participants (80%) showed seven-day point prevalence abstinence at 6-month follow-up. This substantially exceeds the recovery rates of all other current psychotherapeutic or pharmacological therapies for smoking cessation (which on average manage about 35% success rates) — by a very long way312. A long-term follow-up study followed in 2017. At 12-month follow-up, 67% of participants were abstinent from smoking. At long-term follow-up (over 16 months), 60% were still abstinent313. These results are extremely favourable compared to typical treatments for smoking cessation. More research is needed – and I am surprised more people are not pursuing this line of research.
Following the success of the pilot study, a further paper came out looking at qualitative reports from those participants that underwent the study314. Matthew Johnson and his team are now running a large-scale double-blind study with psilocybin therapy for smoking cessation. The study at Johns Hopkins University is going ahead following a grant of nearly $4 million - being awarded the first federal grant for psychedelic treatment research in more than 50 years, to be funded by the National Institutes of Health’s National Institute on Drug Abuse 315. If Johnson and his team are able to come up with a viable treatment for helping people to stop smoking cigarettes, they could have found the greatest breakthrough for public healthcare that has ever been made. A footnote about Johnson’s findings are that, as with many other studies using psychedelics as tools for addictions (i.e. Osmond’s LSD studies in the 1950s, Krupitsky’s ketamine studies in the 1990s and Bogenshutz’s psilocybin studies more recently), Johnson found that the patients who reported the most profound spiritual experiences when they took a psychedelic drug to tackle their addiction, had the greater rates of abstinence.
Wow. It’s true (and this next statement is intended to wrestle a phrase of the godawful Westboro Church, and give it an new, positive slant. It only works if you know the British slang): When it comes to cigarettes, God really does hate fags.
Other Psychedelics for Smoking Cessation
As mentioned, other than Johnson’s studies, there is certainly a paucity of research with psychedelics therapies for smoking cessation. But there have been a few pieces of research. On online survey in 2022 from Brazil showed that rates of cigarette smoking amongst ayahuasca users is reduced316. And in a final word about smoking and psychedelics – though not (very obviously) related to clinical applications, it has been discovered that MDMA and nicotine have a peculiar relationship. Nicotine appears to increase memory consolidation in rats when it is administered together with MDMA317. The authors propose this might account for the heavy use of cigarette smoking that accompanies recreational ecstasy use. And another similarly related theme emerged in a study published in 2021 showing that co-administered nicotine appeared to reduce the potentially neurotoxic effects of MDMA (in rats)318. It is difficult to understand the implications of these studies, but I know I have come across plenty of ravers who tell me, “I only smoke when I’m off my face on pills.” There could be something going on here… Whatever it is, MDMA is certainly safer than cigarettes, and most people recognise that.319
D) Psychedelics for Stimulant Abuse Problems:
Similar to the case regarding cigarettes, there is a relative lack of psychedelic research focusing on methamphetamine and cocaine abuse. This may in part be because those addictions are traditionally thought of not having the same level of physical dependence as drugs like alcohol and opiates, but rather their addictions are primarily psychological – though no less destructive when the substances are used to the exclusion of other activities in one’s life, and certainly cocaine use is associated with significant cardiac risk factors320 and overdose risk321.Furthermore, whilst there has been some research into pharmacological ‘cocaine substitution therapies’322,323, (like we have methadone and buprenorphine for opiate substitution therapies), treatments for stimulant abuse are primarily psychological /psychotherapies. This might suggest that psychedelic therapy could be a useful potential approach for stimulant abuse, as we know that psychedelics are effective non-specific adjuncts to psychotherapy, for whatever the indication. But there remains little psychedelic research into the problem. However, there have been some studies in recent years. Ketamine has certainly shown some promise.
In the Jones et al systematic review of ketamine treatments for substance uses disorders, mentioned earlier, of the seven studies looked at two focused on cocaine use disorder, and found that ketamine therapy showed improvements in craving, motivation, and decreased cocaine use rates324. In a study by Dakwar et al (2017), a single dose of ketamine reduced self-administration of cocaine325. And the same authors showed in 2019 that when the ketamine dose is given in combination with a 5-week course of mindfulness-based therapy, cocaine users had greater abstinence success than the control group326.
Regarding other psychedelics for managing stimulant abuse, animal studies with ayahuasca have shown that the Amazonian brew reduces methylphenidate (a stimulant used to treat ADHD, with similarities to methamphetamine) preference in mice, which may have implications for a mechanism behind ayahuasca’s benefits for treating stimulant use327. Studies have demonstrated cocaine users have a decreased affinity for cocaine after ingesting ayahusca328. However, a population-based survey by Jones et al (2022) looked at cocaine use amongst users of three classic psychedelics – peyote (mescaline), psilocybin and LSD. Only naturalistic use of peyote showed reduced levels of cocaine use amongst the population studied329. A good review of the potential role for psilocybin in treating methamphetamine abuse was published in 2023 from researchers, including Paul Liknaitzky, in Australia330. And psilocybin therapy for methamphetamine is currently being studied by Peter Hendricks at the University of Alabama at Birmingham, USA, with a pilot double-blind placebo controlled trial331. And finally, a fascinating study in New Zealand under Dr Mitchell Head, a neuroscientist based at Waikato University, will be exploring the use of their indigenous Psilocybe weraroa fungus as a potential treatment for methamphetamine addiction amongst members of the hāpori community332. So, there are stimulating advances being made in the field of psychedelics for stimulant abuse problems. It’s worth staying up to watch this space.
E) Psychedelics for Gambling and Sex Addictions:
Gambling Disorder (GD) and sex addiction - more correctly called compulsive sexual behaviours (CSBs) are increasingly being recognised as significant clinical syndromes. Both GD and CSBs are likely neurobiologically related to substance use disorders333, and are often associated with one another334. In recent years, Gambling Disorder and other behavioural disorders have become possible targets for psychedelic therapies335,336. Whilst working at Awakn Life Sciences, Celia Morgan, Awakn's Head of Ketamine-Assisted Therapy, and Professor of Psychopharmacology at the University of Exeter, completed the world’s first study exploring the potential role for ketamine-assisted therapy for treating GD337. And a study is underway at Imperial College London, involving my colleagues David Nutt, David Eritzoe and Rayyan Zafar, using fMRI to explore the neurobiological substrate behind how psilocybin could treat gambling disorder338.
7. Psychedelics to Treat Eating Disorders
The three most common eating disorders (EDs) are:
Anorexia nervosa, which presents with significantly low body weight and a failure to gain weight, due to persistent restrictive eating or purging, coupled with an extreme fear of weight gain, and an excessive preoccupation with body weight and shape.
Bulimia nervosa, which involves frequent binge eating episodes where patients feel a loss of control in their eating, followed by inappropriate compensatory behaviours to prevent weight gain.
Binge Eating Disorder is characterised by frequent episodes of binge eating, occurring at least once a week for three months, where individuals feel a loss of control overeating. Unlike bulimia, these episodes are not followed by compensatory behaviours.
EDs are typically treated by a range of psychotherapies, including CBT and Family Therapy. There are no drugs approved to treat eating disorders in the UK, but co-existing mental health conditions can be treated with drugs, including adjunctive SSRIs and atypical antipsychotics339.
The efficacy outcomes for these traditional treatments is not great, and anorexia nervosa carries a significant mortality rate – one of the highest in all of psychiatry – so, as described earlier, this makes EDs a good target for psychedelic therapies. There has been a flurry of research in recent years. A good online survey review in 2021 by Meg Spriggs and Robin Carhart-Harris – when he was at Imperial College London – showed improvements in depression and wellbeing scores in participants who had used psychedleics340. Another review of a community sample looked at wellbeing and mental health measures – including disordered eating patterns – and found positive responses to classic psychedelics341. The same researcher, Adele Lafrance, also looked at ayahuasca users with eating disorders and found a reduction or cessation of ED and mental health symptoms, shifts in body perception, and the importance of a ceremonial setting and after-care when using ayahusaca342, as did another team looking at ayahuasca effects on diminishing the symptoms of EDs343.
Ketamine appears to be useful for managing EDs, with several case studies published demonstrating positive results344,345,346. A clinical trial showed that ketamine infusions reduced compulsive eating behaviours and depression in fifteen patients with anorexia nervosa347. And a phase 1 open-label feasibility study with psilocybin therapy published in 2023 showed that the treatment was safe and tolerated well348. MDMA therapy has also been explored – not in a specific ED population, but in patients with severe PTSD and associated ED symptoms. Results in this MAPS-sponsored trial showed improvements in ED symptoms in the ninety individuals who participated349.
There are also a number of studies in the pipeline presently exploring psychedelics for EDs. Meg Spriggs’s team at Imperial College London are carrying out a pilot study with three sessions of psilocybin therapy, with associated fMRI exploration, in a population of patients with anorexia nervosa350. And the folk at Johns Hopkins University, are also running an open-label pilot study with psilocybin therapy for anorexia nervosa351. Psychedelic biotech companies are also getting involved, with Tryp Therapeutics conducting a safety and feasibility clinical trial using their psilocybin product TRP 8802 for patients with Binge Eating Disorder352. Another commercial company, Compass Pathways are branching out from their psilocybin-depression studies to explore their compound Comp 360 (psilocybin) at a dose of 25mg, in a double-blind study against low dose (1mg) psilocybin as a control group353. And Lykos Therapeutics (formerly MAPS PBC) are planning a large scale open-label phase 2 MDMA therapy study for people with anorexia and binge eating disorder.
With all this exciting new research going on, we could be edging closer to finding some real breakthroughs for people with eating disorders in the coming years. Psychiatry could really do with more effective treatments for these devastating conditions.
8. Psychedelics to Manage Personality Disorders
As described earlier in this book, the concept of personality being ‘fixed and rigid once formed’ has represented a challenge in psychiatry. Personality disorders (PDs) are notoriously difficult to treat and have been considered incurable by many commentators over the years.
The most clinically significant personality disorders are borderline personality disorder (BPD), (which is now increasingly called Emotionally Unstable Personality Disorder, or EUPD), and Dissocial Personality Disorder, which used to be referred to as antisocial personality disorder or psychopathic personality disorder. There are many other forms of PD, including narcissistic PD, obsessive-compulsive PD (or anankastic PD) and more.
People diagnosed with PD have frequently experienced a history of trauma, often going back to childhood. And in recent decades the concept of Complex-PTSD (or C-PTSD) has arisen. Before the understanding of C-PTSD arose, we tended to think of PTSD, as it appears in its ‘simple’ form (usually associated with a single, life-threatening discrete trauma such as a one-off assault, a fire, flood or natural disaster or war-based trauma / post-combat-PTSD). Complex-PTSD, on the other hand, refers to a history of trauma in which a person might not necessarily have had a single life-threatening traumatic episode but might instead have suffered multiple episodes of non-life-threatening but equally frightening experiences of trauma — such as repetitive episodes of child sexual abuse. Such a history can lead to an emotionally unstable (for example, borderline) personality disorder (BPD), which is often very difficult to treat.
There are high rates of treatment resistance for BPD because the effects of repeated abuse render the sufferer highly prone to dissociative episodes in which they readily re-experience the frightening memories of their abuse. Whenever they attempt to ‘go back there’ in their thoughts, they dissociate, which may happen spontaneously at any time of the day, or in their nightmares. This makes undergoing trauma-focused psychotherapy (where the subject is expected to reflect upon their experience of abuse) extremely difficult. In such cases, an agent such as MDMA could be useful.
Clinically, I have seen many teenagers with emerging BPD, or C-PTSD. They so often present with a horrendous clinical picture of repetitive self-harm and suicide attempts. They have all the hallmark features of simple-PTSD (hypervigilance, avoidance of cues that remind them of their abuse, flashbacks and nightmares), as well as drug including alcohol problems and a worrying tendency to seek out new abusive relationships that maintain them in the cycle of trauma. All of this develops as an attempt to mask the symptoms of C-PTSD. It is very difficult to treat these young people because they are so terrified of their memories of trauma that they go out of their way to avoid therapies aimed at encouraging them to discuss their past. Their sense of being stuck is painful to watch. I have known several tragic cases of teenagers taking their life despite all their own hard work and good intentions, as well as the help and support of their families, their social workers and the committed psychiatric staff caring for them.
In the early days of MAP’s MDMA-PTSD studies, there has always been careful exclusion criteria to avoid enrolling patients with too many rigid borderline tendencies. This is understandable, as the last thing researchers need at this crucial early stage of modern psychedelic research is patients suffering episodes of high-profile self-harm or even completed suicide.
Ultimately, however, this is the group of patients I would like to help the most with MDMA-assisted psychotherapy. I think it could be just what is needed to allow these fragile and desperate people the kind of psychological protection they need to allow them to break through their heavily fortified defences; it might enable them to stare their histories of abuse in the face, while feeling sufficiently bolstered by MDMA’s effects to be able to do the trauma-focused work.
MDMA has unique properties to augment trauma-focused psychotherapy. It acts like a life raft or a rubber ring. It can buffer the most intense and frightening aspects of the traumatic memories, yet it still allows the patient to experience enough of the pain to carry out real-time trauma-focused psychotherapy. This is a hugely valuable tool for patients who, up until now, have been unable to approach their past without being overwhelmed by negative affect and subsequently fleeing the therapy, back into their ‘safe’ world of self-harm, drug abuse and severe self-neglect.
This does not mean that trauma-focused therapy with MDMA is a walk in the park. Indeed, one of Mithoefer’s patients told him: ‘I don’t know why they call this ecstasy!’ Under MDMA-therapy, these traumatised patients certainly do still experience the pain of their memories. But the MDMA acts as cushion to make doing this work possible. As a psychiatrist who has seen too many young patients give up their fight against the past, I am very excited by the prospect of a clinical tool that can assist them to do this. In recent years, psychiatrists have likened the potentially paradigm-shifting effect that MDMA could hold for psychiatry as comparable to the impact the discovery of antibiotics had on general medicine one hundred years ago354. This was the theme of a TEDx talk I gave in Bristol in 2016. It fits well with the treatment-resistance of BPD.
There are no single and clear pharmacological interventions for any of the personality disorders. Rather, patients tend to find themselves on wild cocktails of multiple psychiatric drugs, targeting co-morbidities and individual symptoms, rather than effecting an overall cure355. However, in line with psychedelic drugs’ neuroflexibility-inducement356, and their subsequent ability to uniquely shift rigid patterns of thinking and move people on from aspects of themselves that they have always considered stuck and immovable, psychedelic research in this area is of great interest. The work of Roland Griffiths – demonstrating lasting personality shifts after being administered psilocybin – kickstarted this area of research, and there are now a number of research pathways taking this forward.
There are many contemporary review papers exploring the potential of psychedelic therapies for managing personality disorders. Some of these reviews focus on PDs in general357, and others focus on specific PDs, such as Borderline PD358. The excitement of finding a therapeutic treatment for the rigidity of personality disorder has even led to come commentators proposing the psychedelics could be used to address political fanaticism359. An interesting paper reporting on two observational cohort studies, involving over 75 participants in total, with personality disorder showed that after using psychedelics participants reported favourable reductions in anxiety, without significant increases in suicidal risk. Patients also showed improvements in cognitive flexibility, which is in line with the hypothesis that psychedelics could offer new mechanisms for tackling rigidity360.
Borderline PD (BPD) has received the most research attention with psychedelics, as it represents a large challenge for clinical psychiatry. BPD, which is more common in women, is characterized by extreme swings of emotion, ‘emotional instability’, the rapid formation and break-up of relationships, feelings of chronic emptiness and an association with repetitive acts of self-harm, suicidal threats and substance misuse problems. It is often – but not always – associated with childhood trauma, such as sexual abuse.
Studies have shown that ayahuasca improves emotional regulation in individuals with BPD-traits361. At Imperial College London, the team have demonstrated that psilocybin has a beneficial effect on shifting the rigidity of maladaptive personality traits362. And a trial is underway at the University of Chicago evaluating the safety and efficacy of psilocybin in adults with major depressive disorder and borderline personality disorder363.
In line with the description above about MDMA’s potential value in managing BPD, there is increasing commentary about MDMA therapy trials for BPD. One such focus/review article in 2022 from Jenna Traynor and team speculates on the overlap between BPD and PTSD364. And in a fascinating paper by Inouye et al, published in the Journal of Psychedelic Studies in 2023, a qualitative exploration on the overlap in aetiology and conceptualization between BPD and PTSD provided new perspectives, when the authors interviewed two clinicians who focus their treatment with BPD diagnosed individuals and two MDMA-assisted therapy clinicians365.
More research looking into MDMA for BPD/EUPD is planned. In the last few years, I have been fortunate to be part of a team led by consultant psychiatrist Simon Graham at the Mersey Care NHS Trust in Liverpool, UK. We are planning a trial using MDMA therapy in a population of patients presenting with EUPD. And I have had a number of wonderful discussions with an inspiring psychedelic academic, Natalia Rustom from Beirut, Lebanon, who occupies a rather niche area of research, as her subject of expertise is the study of Emotionally Unstable personality traits amongst people in the Lebanese LGBTQ+ community who have been traumatised by the Arab-Israeli conflict in her locality. We have worked on. Paper together and she is in the process of planning a study to explore this area of research with MDMA therapy.
Another psychedelic that has been explored extensively as a potential agent for addressing BPD is ketamine – perhaps because there are now so many ketamine clinics around the world. Several studies are looking at the co-morbidities between depression and BPD, and the role for ketamine infusions or ketamine-assisted psychotherapy366,367,368. And good review article on ketamine for BPD was published by Wiedlocha et al in 2024369. A randomised placebo-controlled trial (using midazolam as the placebo) versus ketamine infusions, at Yale University, was planned, but was disrupted by the Covid-19 pandemic370. Before we leave BPD, it is worth mentioning a fascinating contemporary study in 2020, from the team at the University of Basal, Switzerland, who administered weekly doses of LSD in ascending doses to a 39-year-old female patient with complex personality issues. She experienced no significant subjective drug effects – even at adequate doses of LSD – but nevertheless showed, “rapid and significant improvement with most notable changes in depressed mood, emotional instability, loss of energy, and suicidal ideations”371. So, LSD appeared to manage her PD symptoms, even though she got no notable psychedelic effects from the drug. Make of that what you will!
Looking now at dissocial/psychopathic/anti-social PD and narcissistic PD, these are again difficult conditions to manage for traditional psychiatry. Dissocial PD, which is more common in men, is characterized by ‘a callous unconcern for others’ and lack of empathy. The disorder is often associated with substance misuse, and violence, with perpetrators frequently showing no remorse for their violent actions towards others. Dissocial PD (as is over-represented in the criminal population372. As with all PDs, it is the fixedness or stuckness of the personality, once formed, that makes dissocial PD so difficult to manage in modern medicine. Which is where psychedelic therapy, with its capacity to help a patient break through from rigid personality structures, that could hold therapeutic promise. Psilocybin therapy has been shown to increase empathy and boost moral decision-making in this population373. Like dissocial PD, narcissistic PD shares many of the same traits, including domineeringness, vindictiveness, and intrusiveness374. Ayahuasca and other classic psychedelics have been shown to reduce narcissistic traits375,376.
But classic psychedelics are not for everyone. And some studies have shown worsening of psychiatric symptoms in some patients, particularly those with personality disorder, using psychedelics377. It would seem we are still a fair way off seeing psychedelics representing a ‘cure’ for personality disorder, but given how difficult it is to manage this population of vulnerable patients, psychedelic therapies are certainly worth considering as an important tool for the future.
9. Psychedelic Research associated with Neurodiversity and Autism Spectrum Disorders
Autism Spectrum Disorder (ASD) is, as the name suggests, a continuum of different syndromes, from most severe, to more high-functioning presentations, characterized by inflexibility, impairments in social functioning and language and restricted ranges of behaviour. At the most severe end of the spectrum people with ASD may have no use of language, significant learning disabilities and require a lot of support to live normal lives. At the higher functioning end of the spectrum (sometimes called Aspergers Syndrome, though in fact this is not the same as high-functioning ASD) people may have high intelligence and function well, and sometimes even better than neurotypical people. The areas where impairments tend to occur is in the formation and maintenance of relationships with others, which require high degrees of empathy and theory of mind, which are often lacking in people with ASD.
In recent years the public profile of ASD has risen sharply, and we (rightly) ought not see ASD as a medical condition that needs to be ‘cured’, but rather as a form of neurodiversity, simply a ‘different’ form of typical brain and mind. Support, inclusivity and understanding are required, not cures378. However, many people with neurodiversity – which includes ADHD as well as ASD – also frequently suffer with co-morbidities, such as a social anxiety disorder and depression, which we can – and ought to – aim to treat, for people to lead happier and more stable lives. And as for personality disorders, the potential role for psychedelic therapies in improving the lives of people with neurodiversity has been studied in recent years379.
MDMA Therapy for Social Anxiety in people with ASD
The idea of using MDMA to relieve social anxiety associated with ASD is has been studied by Charles Grob and Alicia Danforth in a MAPS-sponsored randomised, double-blind, placebo-controlled exploratory pilot study in collaboration with the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center and Stanford University380,381,382.
Picture HERE:
Alicia Danforth, using MDMA’s capacity for boosting empathy to develop innovative approaches for treating social anxiety in adults with autism. Enjoying the Open Foundation’s conference in Amsterdam in 2016.
One of the cardinal features of ASD is a tendency for a sufferer to lack empathy. That is, they do not appear to recognise the emotional responses of others and may appear aloof and disinterested in other people’s worlds. In this book, we have already described how MDMA has the effect of increasing levels of empathy in the user. Danforth and Grob’s motivation to carry out such a study started came out of the observed anecdotal positive effects that autistic adults experience after taking recreational Ecstasy. Many demonstrate reduced empathy impairments during, and for some time after, the intoxication with the drug. This is certainly, therefore, an avenue worthy of further study. The current treatments for autism are largely either educational, social, functional or purely symptomatic — with the full range of psychiatric drugs used as and when they are needed. If MDMA can offer a way out of the ‘locked in/locked out’ aspect of social impairments secondary to autism, it would be greatly welcomed by those clinicians working with the condition.
Psilocybin Therapy for Social Anxiety in people with ASD
As with MDMA, psilocybin therapy has been recognised to increase prosocial behaviour383,384. And psilocybin therapy has also been explored as a potential therapy to treat co-morbid social anxiety in people with ASD385. Animal studies have also demonstrated an increase in pro-social behaviour in mice after being administered LSD386. Compass Pathways are currently sponsoring a study at Kings College London to explore the potential for their compound Com360 as a treatment for anxiety in people with autism387.
The psychedelic research scene, which rightly strives to be inclusive, has welcomed the neurodiverse community. And there are many groups working at the intersection of psychedelics and ASD. One person who has been instrumental in taking this issue forward is Aaron Orsini. He was diagnosed with autism in his early 20s, and found anecdotally that after taking LSD, psilocybin or MDMA, he experienced increased pro-social behaviour and greater connectedness with others. He went on to write the fantastic and highly influential book, Autism on Acid388, and formed a website that has galvanised the ASD community in the field of psychedelic research389.
10. Psychedelics, Psychosis, Schizophrenia and HPPD Research
Psychosis – in all its forms, but particularly a history of schizophrenia, bipolar 1 disorder or drug-induced psychosis – has historically been considered a major red flag / contraindication for treatment with psychedelic therapies. Reports of ‘acid casualties’ date back to the early 1960s390. The assumed association is easily to understand, as both psychedelics and psychosis may involve the experience of altered perceptions, and the psychedelic experience is certainly a radical life experience, which could certainly trigger a psychotic-like episode in people with a genetic vulnerability to schizophrenia391. Yet the scientific community have also always noted that the presenting nature of the psychedelic experience is also qualitatively different from that of a schizophrenic psychotic episode, primarily in the experience of insight, which is usually present in the former, but lacking in the latter392,393,394. And more recent research has suggested that the link between psychedelics causing psychosis may not be as solid as once thought. Indeed, large population surveys have demonstrated that regular classic psychedelic users are no more likely than non-users to have 395,396. Nevertheless, usually in response to restrictions imposed by medical ethics boards, people with a personal history or first-degree relative history of psychosis have almost always excluded from participating in psychedelic drug research studies in modern times397,398, which is understandable. It is notable that in the very early years of psychedelic research, there were some research studies on children with schizophrenia, which would be unlikely to be approved in today’s research climate399,400.
However, the potential role for psychedelic research in understanding psychosis, and even as a treatment for psychosis has been studied more recently401. In a return to the very early days of LSD science, when LSD was thought to be a useful agent for mental health professionals to better understand what it feels like to be psychotic – as a psychotomimetic drug402 – we have seen in recent years propositions that ketamine could be considered a more useful psychotomimetic drug, which could improve our understanding of schizophrenia, and assist in the development of new antipsychotics.
To appreciate how this works, one must first understand that ketamine is an NMDA-antagonist (a glutamate receptor antagonist) and that it mimics both positive and negative symptoms of schizophrenia. This has led psychopharmacologists to search for an effective glutamate receptor agonist as a potential treatment for psychosis. Using this ketamine psychotomimetic hypothesis as a model in healthy human subjects, we can give ketamine, induce psychotic symptoms and then test potential antipsychotic drugs against these induced effects. The role that ketamine plays in this kind of research can significantly push forward our understanding of schizophrenia (just as LSD did in the 1950s). This was carried out for the first time successfully in a 2012 study published by D’Souza et al403. And since then, the links between glutamate, psychedelics and psychosis have been of significant interest in researching new approaches to treating psychosis404,405.
Another example of psychedelic research furthering our understanding of psychosis comes from a study in 2010 by Joel Porfírio Pinto of the University of Sao Paulo published his thesis studying the fMRI, SPECT scans and neuropsychological changes in healthy volunteers given ayahuasca. SPECT showed activation of the frontal and temporal cortex and limbic areas. Cerebral blood flow decreased in a region of the right cerebellar hemisphere, and fMRI data showed decreased activation of areas involved in language processing. Pinto suggests ayahuasca could be useful for the study of the neurobiology of psychosis406. There were a further series of pre-clinical and neurophysiological studies with ayahuasca that have been carried out by the late Jordi Riba in Spain.
Schizophrenia of course – like ASD – is known to exist on a spectrum, with a mixture of both positive symptoms (such as hallucinations and delusions) and what are called negative symptoms (such as emotional blunting and restricted social functioning). These negative symptoms of schizophrenia could well respond to the pro-social, empathogenic effects of MDMA therapy407, which is currently being explored by a trial at UCLA in the USA408. In this open-label, ascending-dose, within-subject trial, the investigators plan to first assess the tolerability of the drug in patients with schizophrenia in doses of 40 mg, 80 mg, or 120 mg. The doses will be given in ascending order, and doses will be stopped if subjects experience moderate or greater levels of psychotic symptoms at 24 hours409.
Psychedelics and Hallucinogen Persisting Perceptual Disorder (HPPD)
Whilst not a psychotic disorder (it appears in DSM and ICD under the chapter on substance-induced disorders), HPPD shares some of the perceptual features of psychosis, so, for wont of knowing where else to put it, I am including it here in this book. Of note, the presentation of HPPD symptoms is not restricted only to having taken psychedelic drugs – it can also occur after taking cannabis and SSRIs.
HPPD typically presents with hallucinations and perceptual changes, including trails and after images, visual snow, intensified colours, altered motion perception, light fractals on flat surfaces, and micropsia and macropsia (things appears too small or too large). Although any classic psychedelic, or an entactogen like MDMA, or a dissociative drug such as ketamine, have been shown to be associated with HPPD, it appears to be more prevalent following LSD than the other psychedelic drugs410.
The phenomenon of HPPD qualities was first described in the 1950s at the start of LSD research, by Ronald Sandison411, and it has interested psychedelic researchers ever since, partly because of the lack of understanding of the condition or how best to manage it in sufferers of HPPD412. The term ‘(acid) flashbacks’, which is similar to, but not identical to HPPD was introduced by the researcher Michael Horwitz in 1969413. Flashbacks are usually short-term, non-distressing, spontaneous, reversible and benign, which are not necessarily considered as unpleasant. This presentation is sometimes called HPPD-1. Many people will say things like, “Oh man, after taking LSD as a teenager, from then on, whenever I look at clouds, I see them differently. It’s cool!” In contrast, HPPD-2 is generally distressing, recurrent, pervasive, and also sometimes irreversible, and one that results in a person seeking clinical inputs for support. The four most important things to know about HPPD, in my opinion, are that:
1. (Despite what has been said about the disorder in the past), HPPD is relatively common. Around 60% of psychedelic users report persisting visual perception experiences long after a psychedelic drug has worn off, and around 4% of people who have used psychedelic users actually end up seeking help because of disabling clinical symptoms of HPPD414. This is not rare.
2. Neither the mechanism behind it, nor it’s aetiology, are well or definitively understood. Multiple possible mechanisms have been proposed415. Current biological theories suggest that psychedelic users (particularly LSD users) might experience persisting visual disturbances as a result of reversible (or irreversible) “dysfunction” in the cortical serotonergic inhibitory inter-neurons with GABA-ergic outputs. And further research from Julie Holland and Torsten Passie suggests there is an interaction between specific environmental triggers related to the original psychedelic experience in some users416.
3. HPPD is often associated with additional co-morbidities, such as depression417, anxiety418, bipolar disorder419, and perhaps unsurprisingly, schizophrenia420.
4. HPPD is difficult to treat, with many patients undergoing multiple attempts at trying to manage the disorder with drugs including SSRIs, benzodiazepine, antipsychotics and mood stabilizers, but finding little relief of symptoms421.
In the light of all these difficult issues, there have been some challenges to the psychedelic research community to do more to research the condition, leading to the emergence of some activism groups, such as the Perception Restoration Foundation, launched in 2021 to raise awareness of HPPD amongst the psychedelic community422.
And finally…
Before we leave the subject of the potential role for psychedelics in treating psychotic disorders, I wish to mention Benjamin Mudge, an Australian psychedelic researcher whose PhD I am currently supervising. He is carrying out a very ambitious project looking at whether ayahuasca ceremonies can have a positive effect on reducing symptoms for people with Bipolar 1 affective disorder423. This is a brave move, as usually participants with any form of psychosis are excluded from psychedelic research studies. However, Mudge is responding to a raft of anecdotal reports that some people with Bipolar (and I stress, not everyone) who has had genuine and well-facilitated ayahuasca ceremonies do improve after drinking the ceremonial tea. Mudge’s work looks set to broaden the horizons of how we look at psychedelics as potential treatments for psychosis. Exciting stuff.
Picture HERE:
Benjamin Mudge, pictured way back 2014 in my house. Mudge is pushing the boundaries in proposing that ayahuasca may have benefit in treating bipolar 1 disorder. His PhD thesis is eagerly awaited.
11. Psychedelics Informing Neuroscience
There have been so many pre-clinical and neurophysiological studies conducted in recent years. In the earlier years of the psychedelic renaissance, some of the most pivotal neuroscience projects came out of the laboratories of Franz Vollenweider and Dave Nichols, from projects overseen by the Heffter Research Institute on both sides of the Atlantic. The Heffter Research Institute’s laboratories in Switzerland, run by Franz Vollenweider, have been responsible for some of the world-leading neurophysiological studies with psilocybin in the early renaissance years. This work, with both humans and animals, has taught the scientific world a lot about the mechanisms of the 5-HT2A receptor and the role it, and other mechanisms, play in the psychedelic experience and the neurophysiological basis for consciousness424 to 432. And Roland Griffith’s early work at Johns Hopkins University provided the world with some of the most striking contemporary glimpses of the power and significance of the mystical-like experience aspect of the psychedelic experience433,434.
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With Robin Carhart-Harris, the late Roland Griffiths and Franz Vollenweider; the brain teams of the psychedelic renaissance, trying not to get run over by trams, at the Beyond Psychedelics conference in Prague in 2016. Since then, the study of psychedelic neuroscience has broadened considerably further.
Then we had Imperial College London, under the auspices of David Nutt and Robin Carhart-Harris, with financial and promotional support from Amanda Feilding and the Beckley Foundation, also provided many pioneering science projects, especially around the use of neuroimaging to elucidate the neurobiological substrate of the classic psychedelic drugs. I was privileged to be injected with intravenous LSD, psilocybin and DMT – and also administer the drugs to other participants (not on the same days!) - and have my brain scanned as part of these ten years of studies. I must thank Robin again for the opportunity to enjoy some particularly colourful train journeys back to Bristol because of this work.
Starting with psilocybin, then LSD, then DMT, Robin’s work added international awareness of the functional neuroscience of psychedelics to the previous work of Vollenweider and Nichols. The basic rationale for Robin’s first fMRI psilocybin project was to measure the functional activity in the medial prefrontal cortex after psilocybin435. Large decreases in activity and blood flow were observed, contrary to popular assumptions that under the influence of psychedelic drugs there is an increase in brain blood flow and activity. Because the medial prefrontal cortex is known to exert a top-down inhibitory control over limbic activity (the site of the brain that governs emotional experiences), it was postulated that a psilocybin-induced deactivation of the medial prefrontal cortex leads to a disinhibition of limbic activity and an associated increased emotional response.
Further psilocybin studies by Robin’s team with fMRI measured the subjective psychological effects of psilocybin when a subject was experiencing recall of positive emotional memories. Subsequent studies used Magnetoencephalography (MEG) and infused psilocybin436. They found decreased frontoparietal connectivity consistent with the previous fMRI findings. The reason these studies were so important for psychiatry is because they finally proved what had been known anecdotally for the last 60 years, since psychotherapists first began using LSD as a tool to enhance psychotherapy, namely, that psychedelic drugs increase access to repressed emotional memories437. The results became extremely helpful for future psychedelic psychotherapy studies. Robin had demonstrated graphically that this is how these drugs work, with his aforementioned Entropic Brain Theory438.
The Imperial team then moved onto LSD, using increasingly well-honed neuroimaging techniques, and in 2016 published their seminal, award-winning paper in PNAS showing the neural correlates of the LSD expericnce439. The subsequent REBUS theory paper by Carhart-Harris and Karl Friston came out in 2019 and has continued to inspire a new generation of psychedelic neuroscientists440. In more recent times, the way LSD alters dynamic integration and segregation in the human brain, shown by neuroimaging has advanced further441. After LSD, Robin, Chris Timmerman and Leor Roseman at Imperial turned their attention to demonstrating that DMT, that other classic psychedelic, has a similar neurobiological effect on the brain442. Many further DMT neuroscience studies have emerged since then from the same team443,444,445, each piece of research getting closer to understanding how DMT creates it’s subjective psychological effects, and how this can inform science about the nature of normal consciousness.
The work of the Imperial team since 2016 has become a beacon of inspiring light for neuroscientists all over the world, and the field of psychedelic neuroscience would not be the same today without them. It is a field of research that started in the 1950s, lost track for 30 odd years, and now is a force to be reckoned with understanding how the brain creates mind and how mind is underpinned by brain446. And underpinning all this contemporary research is the field of neuroimaging.
Neuroimaging and Psychedelic Neuroscience
It now feels like a very long time ago when I was wheeled under a wooden mock MRI scanner in Clinic 17 (now a Costa Coffee outlet) at the Bristol Royal Infirmary, to be injected with psilocybin as a precursor to Robin Carhart-Harris’s first study in 2009, published in 2011447. And since then, the field of neuroimaging has advanced. It was Robin’s team that revolutionised the concept of multimodal imaging – combining fMRI and EEG – and then MEG – scanning to provide not only an anatomical structure of the brain, but a chemical, electrical and functional representation of how the brain changes in real-time in response to participants undergoing psychedelic experiences.
Much of the subsequent imaging technology and expertise that emerged from the early Imperial trials came from the labs of Invicro – based at Imperial College London, in collaboration with University College London – and the team of graduate and post-grads surrounding Matthew Wall, including Dr Rayyan Zafar and Natalie Ertl, who have written some excellent reviews of the role of neuroimaging in psychedelic research448,449.
Pictures HERE:
With Natalie Ertl and Rayayan Zafar at a psychedelic conference in Toronto, Canada, in May 2022. And with Matt Wall in London speaking at the Institute of Chemistry in May 2023, on the weekend of the coronation of King Charles the 3rd. These individuals have done a lot to further the use of neuroimaging alongside psychedelic neuroscientific research in the UK in recent years.
It is arguable that an important driver in why we are having a renaissance of psychedelic research in the last 30 years is down to the ability of the scientific world to capture the imagination of the public and approval agencies through producing pretty pictures of brain activity that make great headlines and encourage funders to get involved in the field. Not to mention what it adds to our scientific understanding. With new neuroscientific imaging studies emerging all the time, it seems we are edging ever closer to understanding how classic psychedelics work through the desynchronization of brain networks450, induced changes in brain network integrity and segregation451, and reductions in the hierarchical differentiation of unimodal and transmodal cortex452.
Following Imperial’s and Compass Pathway’s earlier work with psilocybin for depression, imaging studies have added further to our understanding of how clinical interventions with psychedelics impact on the brain and result in therapeutic improvements for patients453,454,455. In recent research, psychedelic neuroimaging has also been used to emphasise the importance of spirituality states in psychedelic users456 and to better understand the neurobiology of meditation457.
MDMA Neuroscience Advances in Recent Years
Throughout this book we have discussed at length the clinical advances of MDMA therapy, particularly the work from MAPS and their mission to see MDMA licensed as a treatment for PTSD. Many contemporary MDMA clinical studies will add a neuroimaging component to their protocol design – making the most of having been approved to give patients MDMA to also take the opportunity to scan their brains. Back in 2015 the team at Imperial carried out a pivotal study using arterial spin labelling and seed-based resting state functional connectivity (RSFC) to produce spatial maps displaying changes in cerebral blood flow (CBF) and RSFC after MDMA administration458. And MDMA neuroscience research has continued to progress since then, with neuroimaging playing an important part in our better understanding of how MDMA works in the brain459, its long-term effects460,461, whether it carries significant toxicity risks462,463, and how it works in combination with therapy as a clinical tool through extinction of traumatic memories464 and its pro-social effects465.
Advances in the Neuroscience of Ayahuasca and DMT
It is fifteen years since Joel Porfírio Pinto of the University of Sao Paulo published his research with fMRI, SPECT in healthy volunteers given ayahuasca in 2010, in which he suggested ayahuasca could be useful for the study of the neurobiology of psychosis. Other earlier studies with ayahuasca includes the work in 2005 of Charles Grob and Marlene Dobkin de Rios, who published a qualitative evaluation of Brazilian teenagers of the União do Vegetal Church who ritually use ayahuasca and compared them to local matched non-users. Data showed that the ayahuasca-using teenagers appeared to be healthy, thoughtful, considerate and bonded to their families and religious peers, with no evidence of any harm caused by their use of the plant compounds466. Interestingly, contemporary groups are increasingly exploring the intersection between plant medicines, children and happy families. It’s worth checking out the group Plant Parenthood for more details467.
One of the studies that is often credited as being the first psychedelic renaissance human trial is that of Rick Strassman’s pioneering human DMT study of 1995. launched the new renaissance of psychedelic research, there have been very few other published human studies of its use468. DMT research was a little slow to get going following Rick’s initial study. One paper, however, by Daumann et al. in 2008, described a study in which healthy human volunteers were given both DMT and ketamine under fMRI conditions. This paper explores the potential role for DMT as a psychotomimetic to assist researchers developing drug models for studying schizophrenia469. Another important pre-clinical DMT study that followed was by Fontanilla et al., published in the journal Science in 2009, which postulated that DMT binds to the sigma-1 receptor in the brain470. This is an important discovery because the sigma-1 receptor was previously considered an ‘orphan receptor’, as no endogenous chemical had been found that binds to it. In their biochemical, physiological, and behavioural experiments with mice, they suggest DMT is an endogenous agonist for the sigma-1 receptor. This opened the debate further made by McKenna, Strassman and others about endogenous DMT. Further work emerged proposing DMT’s role as a neuroprotective agent, saving the brain from death in the context of hypoxic stress, is being hotly pursued by Ede Frecska and others471.
Picture HERE: DMT Study Group at Tyringham Hall in 2015.
Left to Right: Erik Davis, Cosmo Feilding Mellen, Bernard Carr, Jeremy Narby, Luis Eduardo Luna, Ede Frecska, Andrew Gallimore, Amanda Feilding, Dennis McKenna, Santha Hancock, Graham Hancock, Jill Purce, Dar Pan, Rory Spowers, Rupert Sheldrake, Peter Meyer, Graham St John, Tony Wright and David Luke.
And then DMT research really took off in 2017, with the work of Chris Timmerman at Imperial, described above. It is worth mentioning here the valuable early contribution to the science of ayahuasca and DMT studies by Jordi Riba, the Spanish pharmacologist who worked at Sant Pau hospital in Barcelona. Jordi gained approval for the world’s first pharmacology study of healthy volunteers under the influence of ayahuasca in 1998. The MAPS-sponsored study provided vital information about ayahuasca’s pharmacokinetics and tolerability in humans, as well as collecting data about its neurophysiological and subjective effects. Using EEG, Jordi aimed to model the relationship between DMT plasma levels and changes observed in the brain’s electrical activity472.
Jordi since went on to publish more widely in the field473,474. Jordi Riba’s team in Barcelona went on to conduct research, sponsored by the Beckley Foundation, investigating the role of glutamate transmission in ayahuasca’s effects using MRI and spectroscopy, and showed that ayahuasca facilitates aspects of mindfulness475. Jordi was also part of the team that published early research with ayahuasca showing it could play a role in neurogenesis; the growth of new nerve cells, with a preliminary study suggesting that harmine and tetrahydroharmine, alkaloids present in ayahuasca, increase the differentiation and maturation of stem cells into neurons476. This scientific work could eventually advance the development of therapies to treat physical brain damage and stroke. Jordi’s tragic death in recent years has saddened the whole community. A moving tribute to his work was written by Rafael do Santos477.
Picture HERE:
The late Jordi Riba, whose work in collaboration with the Beckley Foundation is trail-blazing advances in the field of neuro-regeneration. Here at the ICPR conference in Amsterdam in 2016, alongside psychedelic researcher Iker Puente. Jordi is greatly missed.
In February 2016, I gave a positive recommendation to the Journal of Psychopharmacology for publication of an excellent systemic review of 28 peer-reviewed papers on ayahuasca up to 2015, written by Dos Santos et al478. The review analyzed multiple published papers exploring the acute, subacute, and long-term effects of ayahuasca in terms of safety and toxicity and included published research on neuropsychological functioning and neuroimaging. The review described (and I quote some of the paper’s abstract here) that ayahuasca administration was well tolerated, increased introspection and positive mood, altered visual perceptions, activated frontal and paralimbic regions and decreased default mode network activity. It also concluded that ayahuasca improved planning and inhibitory control improved working memory and showed anti-depressive and anti-addictive potentials. Long-term ayahuasca use was associated with increased cortical thickness of the anterior cingulate cortex and cortical thinning of the posterior cingulate cortex, which was inversely correlated to age of onset, intensity of prior ayahuasca use, and spirituality. Subacute and long-term ayahuasca use was not associated with increased psychopathology or cognitive deficits, instead being associated with enhanced mood and cognition, increased spirituality, and reduced impulsivity. In summary, ayahuasca is shown to have low toxicity and multiple potential benefits to the user. It did also conclude, however, that many of the studies lacked good methodological robustness and a lot more research is needed.
Since those earlier years of ayahuasca and DMT research contemporary neuroscience has taken up the mantle. Today there are thousands of papers on the subject, from near death experiences on DMT479,480, to encounters with entities481.
11. Contemporary Microdosing Research
I have touched briefly on microdosing already, in the chapter about creativity and psychedelics, and in describing the studies I participated in with Eleusis Benefit Corp some years ago, in which elderly people were administered with microdoses of LSD482. It is certainly the case that using sub-threshold (non-psychedelic) doses of classical tryptamine psychedelics has become flavour of the month in recent years within the psychedelic community. The internet is now awash with positive anecdotal stories of people (mainly in West Coast America, it seems) going to work on LSD doses of 5 to 20 mcg; having no obvious psychedelic effects but reporting back improved connectivity with their work colleagues, a greater clarity of thinking and an improved ability to focus and concentrate. This role of psychedelics as cognitive enhancers is certainly an area in need of more research. I am sure it will get this in coming years.
One researcher who thankfully just refuses to give up his work, is James Fadiman, who was involved in many of the ground-breaking studies of the 1960s. In recent years, he has turned his attention to microdosing and is bringing some promising results to the field.
One clinical application for cognitive enhancement is for dementia in the elderly. Most grandparents do not want to be burdened with daily psychedelic experiences (although I can think of some who wouldn’t mind), but if it turns out that low dose LSD can improve their ailing cognitions, this could herald a huge leap forward for psychiatry. As we see our populations living longer to experience the gradual destruction of their brains, the race is on by pharmaceutical companies to develop more and more sophisticated cognitive enhancers. How ironic it would be, therefore, if it turns out LSD — a generic, non-patented substance — could be what they are reaching for in a few years.
The science of microdosing has been fraught with problems. Seeing the huge growth of users, and the thousands of anecdotal reports emerging of the benefits of microdosing, researchers have been trying to find ways to effectively test – in a rigorous scientific methodology – how to demonstrate that reported beneficial effects are genuinely pharmacological, and not just due to expectancy effects and lack of blinding. Or even, what is it we even mean by microdosing?483. There have been some important steps forward in the science of microdosing, but it is fair to say that the jury remains out and more research is needed484.
Self-report and semi-structured interview studies do consistently demonstrate that microdosers feel better, happier, more creative and more focused when they undergo microdosing regimemns485,486,487. Some modern (double-blind) studies have shown that microdosing with psilocybin mushrooms produces noticeable subjective effects and altered EEG rhythms, but without evidence to support enhanced well-being, creativity and cognitive function488. And microdosing with LSD produces altered sense of time perception, in the absence of subjective alterations of consciousness489. Other (naturalistic observational) studies have shown a clear positive benefit on mood and cognition490. Whereas other studies have found no beneficial effects. A phenomenon that crops up again and again in microdosing studies is the potential confounding of results due to expectancy effects, and some studies have demonstrated this very well. Essentially, unless studies are meticulously double-blinded, if the microdosing user wants and expects positive effects, they will tend to get them491,492. An attempt to rigorously blind subjects in a placebo-controlled study carried out by David Eritzoe and colleagues at Imperial College London, found no benefit of microdosing over placebo, and concluded that self-reports in less methodologically sound studies or through anecdotal use are likely to be a placebo effect only493. Another potential issue with people microdosing is that of taking too much – and self-administering regular threshold doses of LSD or psilocybin, rather than true microdoses. I have certainly had the frequent experience of people coming up to me at conferences and saying, “Oh man, Dr Ben, I’m on a wicked microdose buzz today!” If you feel a buzz. It isn’t a microdose. One useful recent study found the ideal LSD microdose to be 13 mcg. In that study, by Bershad et al in 2019, whilst users noticed the LSD experience at higher doses, there were no reported improvements in mood and cognitions494.
In the meantime, microdosing research continues earnestly, including news of a new study underway at Maastricht University looking at the potential role for microdosing psychedelics to manage menstrual-related symptoms495. And in a development announced in July 2024, Red Light Holland Corp, a private company engaged in the growth and sale of mushrooms and mushroom home grow kits in North America and psilocybin truffles to the legal, recreational market within the Netherlands, has announced the results of a research collaboration with David Nutt and Drug Science496. Using real-world data from 929 individuals legally using psilocybin truffles in the Netherlands', results showed significant gender differences in dosing schedules, with females showing higher adherence in certain age brackets. The study states there could be potential therapeutic implications for conditions disproportionately affecting women, such as PMS, menopause, and migraines. This, like many other areas of clinical research are something that is worth exploring.
Picture HERE:
With Jim Fadiman, Alan Badiner, Sarah Sessa and Huxley Sessa at the MAPS 2017 conference in California, USA.
In the context of such variable results, I personally find it hard to know where to stand on microdosing. I have great admiration for the likes of Paul Stamets and Jim Fadiman, who know about as much as there is to know on this subject and are clearly firm believers in microdosing. So, for now it is probably best to take a nibble and wait
In Conclusion Regarding Contemporary Psychedelic Research
Firstly, well done for getting to the end of this mammoth chapter. This section was always going to be the biggest part of this 3rd edition if the book, given how much has happened since the last edition in 2017. I have, of course, not even slightly covered all the exciting new developments in the field, but I hope we have touched on a few of the bigger – and stranger – things going on in the psychedelic research community of recent years.
As with all research, planning new projects using drugs that have a contentious history needs to be done cautiously to avoid the (often inaccurate) preconceptions about the relative usefulness and harm of these substances. However, common to all these drugs, there exists a rich wealth of anecdotal studies from up to 60 years ago that were abandoned prematurely before their full therapeutic potential was adequately reported or discounted. Going forward, it seems clear that psychedelic research provides benefits for furthering our understanding of neuroscience and developing new treatments for our patients. If we are to strive to comprehend the brain in its entirety, these areas are worth revisiting with modern research methods. It is a pleasure to see this happening in so many places throughout the world today.
The biggest challenge for the future appears not be that of further work to demonstrate the safety and efficacy of psychedelic therapies – that feels pretty much in the bag as far as I can see. But rather, what psychedelics need is better Public Relations, more attention paid to safeguarding and inclusivity issues, broader availability to everyone for free on public healthcare systems and insurance policies and changes to legislation that are holding back the progress that has been made. All these issues will be explored in the next chapters.
I finish this chapter with the wonderful breaking news for psychedelic research in Europe, as I write this in 2024, that a European consortium of 19 partners has been awarded over €6.5M by the European Union to study psilocybin to treat psychological distress in people with four progressive diseases: chronic obstructive pulmonary disease, multiple sclerosis, amyotrophic lateral sclerosis and atypical Parkinson’s disease, requiring palliative care. This is the first time the EU has funded a multi-site clinical study into psychedelic-assisted therapy497. This is the first time the EU has fully funded a study of a psychedelics through the EU’s Horizon Europe program. So, things are looking good as we move forward.