The term psychedelic literally means ‘mind manifesting’ and was coined by Humphrey Osmond in correspondence with Aldous Huxley, in the 1950s. Prior to that they were known as ‘psychotimomimetics’ as they were thought to produce a model of psychosis. History tells us that narrative is key. At the present time the psychedelic psilocybin has a better reputation for medical use than LSD, a compound tarred with the reputation of its social history. Although the medical use of LSD continues to be explored, psilocybin is at the forefront of current trials and most likely to become licensed. Psilocybin’s natural occurrence, shorter duration of effects and lesser effects seem to lead to more positive attitudes. Like many tools of the medical world, it is also hard to spell, preserving its credibility! Psilocybin, like LSD and DMT, is what is termed a classic psychedelic. They are members of the tryptamine class of psychedelics that resemble serotonin and include most of the well-known naturally occurring drugs of this class. We now know that the classic psychedelics are those tryptamines that bind a specific type of serotonin receptor called the 5HT2A receptor.

The other major class of psychedelics are the phenethylamines which derive from mescaline and include the 2C class and MDMA. This class of psychedelics also modulate monoamine neurotransmitter systems but not via one particular action. Ketamine is a dissociative anaesthetic at high doses and has psychedelic effects at lower doses. Ketamine has long been used in medicine as an anaesthetic and one of its isomers, esketamine is the first of the psychedelics to have licensed medicinal use. MDMA is structurally related to amphetamines and increases the amount of serotonin, dopamine and noradrenaline in synapses. There is also interest in the use of ibogaine, THC and salvia as psychedelic medicines.

Although there are a great number phenethylamine and tryptamine compounds that may have medicinal use, here we will focus on three. Ketamine is being used now in the NHS in England for treatment-resistant depression and this may become widespread if it is licensed for this use later this year. MDMA is also used for the treatment of alcoholism in a UK addiction service and is expected to gain a license in 2021. There is great interest in the application of psilocybin to an array of conditions from nicotine dependence, through depression and end of life distress. This is the most likely of the classic psychedelics to gain licensed use.

It is said that psychiatry has moved from an age of the brainless to the mindless and there is great interest in the future of psychedelic psychotherapy. In this paradigm, pharmacology and psychotherapy are combined in a single transformative experience.

Aside from ketamine, pharmacological companies have little interest in this new age of medical use, where medicines are used on few occasions and the patents for these drugs expired long ago. Instead, charitable funds and psychedelic investors provide research and training. Investors include David Bronner (of Bronner’s magic soaps) and Timothy Ferris who have pledged to Multiagency Association for Psychedelic Studies (MAPS) and the Usona Institute in Wisconsin.

‘Overground’ and ‘Underground’

Whilst we consider the research and medicinal use of psychedelics it is important to remember that they are much more widely used. Esketamine is the first of the psychedelic drugs to achieve FDA approval for mental health treatment and stands alone at the tip of this pyramid but it is anticipated that it will be joined by MDMA and psilocybin in the coming years. Phase 3 clinical trials have been permitted by the FDA using MDMA for cancer. A multicentre trial is underway involving sixteen sites in the US, Canada and Israel treating 200 patients with post-traumatic stress disorder with MDMA. There are phase 3 trials of psilocybin for cancer patients and psychological distress at Johns Hopkins, NYU and six other sites. The PsiDeR (Psilocybin in Depression Resistant to Standard Treatments) trial led by Dr James Rucker at Kings College London is a randomised placebo-controlled trial and will examine the use of psilocybin for patients with current depression that is unresponsive to the usual treatments, such as selective serotonergic antidepressants (e.g. fluoxetine) and cognitive behavioural therapy (CBT). Robin Carhart Harris who heads the Centre for Psychedelic Research Institute at Imperial is also leading a trial in which psilocybin will be compared to escitalopram.

One step below licensed use is the off-label use of medicines that are already licensed for a different use. Ketamine’s background use as an anesthetic has paved the way for its clinical use for treatment-resistant depression. It is the first in a new class of “rapid acting antidepressants” and has been used intravenously in clinics in the US since 1990. This type of use is not cheap, or licensed, costing $5000-$7000 in first month. Two hundred clinics using ketamine this way cropped up in the US between 2015 and 2017. It is easier to use psychedelics for psychotherapy in the US where drugs can be allowed for ‘compassionate’ use ahead of their official licensing. As such, it is permissible for a number of psychedelics to be used in a variety of clinical settings at the present time. Whilst psychedelic use is legally sanctioned in a number of settings across the globe, much of the lay use of these drugs is prohibited, the classic psychedelics being Schedule 1 are deemed to have no medicinal use. At present there is an inevitable tension for those researchers, doctors and patients involved with their medicinal use. Naturally-occurring psychedelics have been used for thousands of years in social and religious rituals and there is growing interest in this type of use with a much wider array of compounds. They are used in recreation and for spiritual and personal growth in diverse settings across the globe.

There is a community of researchers and therapists using therapeutic techniques with psychedelics that have been developing since they were pioneered in the 1950s. When their use went underground in the 1970s some of these therapists remained active. Hence there are divergent practices between the ‘under’ and ‘over-ground’ therapists. In the Western medical model ‘the guide never gets ahead of the medicine’. The use of psychedelics in that culture has arisen from research settings with the need for standardization and ethical approval. Thousands of therapists have now been trained at the California Institute of Integral studies (CIIS), training that spans nine months and costs around $7800. Participants of this course are vetted to weed-out underground therapists. Professional standards have also been sent within the underground community and until recently could be found on Wikipedia. Underground sessions may be more active, bringing in elements of ceremony and customizing use. Many guides have studied in Brazil, Mexico and Peru to learn from shamans.

Although there is restricted ‘above ground’ use of psychedelics in the UK right now, this field is expanding and the more attractive these drugs are as medicine, the more likely healthy people will use them. An awareness of the therapeutic potential might encourage patients to bring material from their own psychedelic experience into therapy. There are two ‘Integration groups’ running in the UK (London and Brighton) where members of the public process their psychedelic experiences with the assistance of a group of therapists and doctors. Therapists and doctors are preparing for the licensed use of psychedelic psychotherapy in the UK. COMPASS Pathways is a London-based pharmaceutical company planning to provide the package of training for professionals alongside protocols and pharmaceuticals in order to provide psilocybin for treatment-resistant depression.

Historical Perspective

Psychedelic plants and fungi have long been used in human history including ergot, muscaria and ayahuasca. This ancient use is sometimes termed ‘The First Wave’. The psilocybe ‘magic mushrooms’ of which there are over 200 species have been used for over 7000 years. The sacred ritual use of ‘flesh of the gods’ in Mexico was suppressed by the Spanish and ‘rediscovered’ by the western world when the JP Morgan executive George Wasson and his paediatrician wife, Valentina, travelled to Mexico in 1955 to take the psilocybe mushroom. Their experience was written up in Life magazine and the mushroom sent to Albert Hoffman who identified psilocybin in 1958. There had been interest from the 1890s to the 1940s in a number of psychedelic drugs including nitrous oxide and mescaline, which was synthesized from peyote in 1919. The second wave of psychedelic history had begun when Hoffman, working for Sandoz, had discovered LSD in 1938 and serendipitously had the world’s first LSD trip in 1943. During an era of self-administration, between 1939 and 1966, LSD was supplied to freely to ‘researchers’- psychiatrists, doctors and therapists all over the world, as Sandoz searched for an applied use. Humphrey Osmond, a doctor from Surrey, was an early pioneer of LSD therapy. He moved to Saskatchewan, Canada in the 1950s where LSD was trialed extensively. It has been used in a variety of settings around the world, treatments including alcoholism, obsessive-compulsive disorder, depression and end of life distress in cancer. Overall, there were 1000 studies of 40,000 patients. Hoffman himself described the drug as “medicine for the soul”. Sasha Shulgin reintroduced MDMA in the late 1970s. It was known as ‘empathy’ and was used in couples therapy and post-traumatic stress disorder. Psychedelics were used in two psychotherapeutic paradigms. In ‘psychedelic’ psychotherapy, favoured in the US, high doses of LSD were used in a single drug session to create a ‘peak experience’. In the UK ‘psycholytic’ psychotherapy sessions involved low doses used in weekly sessions.

The era of self-administration ended in 1966 when Sandoz withdrew the drug at a time there was concern about the negative aspects of counter-cultural use of LSD. The above ground medicinal use of classic psychedelics petered out from this time. MDMA itself was not banned until 1985. There was no licensed psychedelic research between 1971 and 1990.

During the second wave of psychedelic research there was a thriving community of doctors and therapists with centres treating swathes of patients from Saskatchewan, Canada to Spring Grove, Maryland, Harvard and Europe. Some therapists from the second wave provide a bridge to the third and include Bill Richards a psychologist in his 80s who has probably guided more psychedelic trips than any other alive today. He worked at Spring Grove in the 1960s and was a founder member of the Johns Hopkins Psychedelic research institute where he works alongside Professor Roland Griffiths and at the CIIS where he trains and mentors the current generation of psychedelic therapists.

The third wave of psychedelic medicine began around 1986 when Rick Doblin formed the Multiagency Association for Psychedelic Studies (MAPS). Resurgence in psychedelic research began in the late 1990s in centres including Johns Hopkins and NYU. There is an infrastructure that supports training, research and the promotion of psychedelic medicine and includes MAPS, CIIS and the Usona Institute. There is over a decade of contemporary research in the UK, with health and academic centres leading clinical trials. There is a proliferation of publication of research papers in the field, academic networks, lobbyists for psychedelic reclassification and psychedelic research centres, including the Imperial Centre for Psychedelic Research that launched in April this year.

Present-day Psychedelic psychotherapy

a) Selection and preparation

The psychedelic state is one of profound psychic vulnerability and as such a great deal of effort goes into the selection and preparation of participants. Preparation sessions themselves often take eight hours. Ego strength is a consideration, as is the personal and family history of mental illness. In order for a therapeutic session to occur there must be adequate set, setting and dose and protocols ensure this. The setting for the sanctioned medicinal use of psychedelics is one that is legal, safe and supported. The ideal mindset is one in which a strong ego makes a choice to trust unconditionally with ones mind. Trust and rapport are essential to the psychedelic session in which patients may feel like they are dying or going crazy. Participants are encouraged in qualities of openness, curiosity, courage to explore, suffer, relinquish control and to experience beyond levels of usual understanding. Personal intentions are set and participants are given a set of flight instructions. These would typically involve surrendering to the process whatever it brings, “ Trust, Let Go, Be Open” (TLO). They are briefed on possible experiences, including ego death and it is suggested that they hold experience lightly. As Bill Richards says “If you feel if you are dying, dissolving, melting, exploring, going crazy- go ahead “.

b) Psychedelic session

The psychedelic journey itself is an inward journey free of distraction. Two trained therapists (often one male and one female) are present throughout an eight-hour session. They provide a comforting hand and look after physical well-being. The therapists say very little. They aim to be empathic, respectful, genuine, non-anxious and competent. The qualities of humility, patience and restraint permit the therapist to be “focused on one individual as if that’s all that exists in the world”. They may meditate during the session but never leave the room, providing a constant presence. They are an aid to the collecting of the experience and may jot down the experiences reported by the patient. In this setting it is the drug and mind that lead the session and not the therapist. The psychedelic session is an inward journey, assisted by the use of an eye-mask and music. The session is like a download of experience, supported by the therapist. The room is cozy and although in a hospital setting is designed to look like the study of a well-travelled doctor, containing symbols of all the world’s religions. The drug itself is of adequate dose and certain purity. Physical observations may be made through the session depending on protocol.

Psychedelic Phenomenology

The psychedelic experience is different for every person on every occasion but the phenomenology is well described. Perceptual changes occur at low dosage. Panic and confusion are rare in a clinical setting, less so in unguided use. There is often psychodynamic content: age regression, guilt, anger, and the processing of interpersonal conflict and life traumas. Awe-inspiring visions occur and encounters with archetypes, gods, landscapes, the cosmos. During these visionary archetypal experiences there is a retained sense of the self, approaching something outside, with the subjective preserved. This, however, disappears in the unitive- mystical experiences where there is an experience of ego death or dissolution. In research trials experiences are rated as important and sustained. There is frequently a feeling that one is bigger than oneself and a deep sense of meaning. The unitive-mystical experience can be assessed on six items of the Walter Pahnke rating scale and include:

Qualities of the mystical experience:

1. Ineffability and paradoxicality. People commonly find writing about the experience frustrating, as if words are not adequate to describe it. Paradoxical experiences are common.

2. Transcendence of time and space. There is a realisation that consciousness survives this transcendence. Feeling as if you are part of something bigger than yourself occurs.

3. Intuitive- Sense of ultimate reality. Like something has been revealed.

4. Sense of sacredness.

5. Deeply held positive mood/ love/ joy.

6.Unity.

c) Integration

In the days and weeks following the psychedelic session there is a process of integration, facilitated by the therapist. There is typically a session the following day. Integration is a process of making sense. The themes of the experience provide meaning. Bill Richards describes a process of transforming the “flashes of illumination” into “abiding light”.

The process involves writing up experiences, sharing with others, meditation practice and initiating changed behaviours. The patient is encouraged to have a sensitivity to the mystical experience - what is the experience going to do with you? Some participants have described sixteen years of integration that have followed trials in the 1990s. There are changes in self-worth and self-concept. People describe a certainty of acceptance, forgiveness, inner resources and the freedom to change behaviour. There is often a sense of connectedness or belonging and a loss of fear of death. Participants describe gratitude for the pure awe at beauty and the gift of life.

The Future

The contemporary, third wave of psychedelics looks set to exceed that of the second wave. The modern tools of neuroscience combined with rigorous research methods promise richer insights. Outside the community of psychedelic researchers and practitioners, we are yet to see what this new wave of research means for the general population. There appears to be great enthusiasm for this approach in the community and media coverage has often been positive. Outside the realm of research studies, patients and practitioners must await the appraisal of phase 3 clinical trails. We are yet to see whether we are on the cusp of a new era of medicine or on the crest of a new wave set to break and wane.

For more information about Dr Sarah Flowers, you can visit her website here.