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For many years I have been an avid collector of quotations and compendia thereof, in the expectation that they might come in useful in one or more of my presentations. The first one to strike a chord with me was from the Spanish-American philosopher George Santayana, who wrote in 1905 that “those who cannot remember the past are condemned to repeat it”. It was used by William Shirer to introduce his 1960 epic history The Rise and Fall of the Third Reich, which is how I came across it. I was reminded of the quote upon reading a series of recent papers on the use of psychedelics (hallucinogens) in psychiatry. My instinctive reaction was one of horror, because we’ve been down this road before, so why are people even thinking about such a thing now? 

My concern arises from proposals to use psilocybin in psychotherapy-assisted treatment of a variety of conditions, especially major depression. Psilocybin is an alkaloid found in so-called ‘Magic Mushrooms’. It is actually a pro-drug that is converted in the body into the pharmacologically active molecule psilocin. Both alkaloids are tryptamines chemically related to 5-hydroxytryptamine (5-HT or serotonin). Psilocybin was originally isolated from psilocybe mushrooms in 1958 by Albert Hoffman (who also synthesised and discovered the hallucinatory effects of LSD). He also reported the synthesis of psilocybin that same year. 

Following oral administration of psilocybin, peak effects occur after about one hour and last for up to six hours. Psilocin itself is rapidly metabolised by monoamine oxidase. It acts as an agonist at a variety of 5-HT receptors because of its serotoninergic effects. Those effects range from mild feelings of relaxation, giddiness, euphoria and visual disturbances, to more worrying delusions, hallucinations, anxiety, depersonalisation, panic reactions and psychotic states. 

A 2020 paper by David Nutt, Professor of Psychopharmacology at Imperial College London in JAMA Psychiatry, reviewed the status of psychedelics in psychiatry. Nutt noted the revolution in brain science and psychiatry arising from the availability to researchers and clinicians of Sandoz products containing lysergic acid diethylamide (LSD) and psilocybin during the 1960s. Prior to the possession and supply of both coming under the 1971 UN Convention on Psychotropic Substances, over 130 studies had been funded in the US suggesting clinical value in anxiety, depression and alcoholism. However, because of their misuse in so-called ‘recreational’ settings, and possibly also their association with the countercultural ‘Flower Power’ and ‘Hippie’ opposition to the Vietnam War, the worldwide ban on these hallucinogens meant that until recently, newer research on potential medical uses was neither possible nor permissible. 

A 2006 study on psilocybin changed negative attitudes, when a single oral dose of 25mg administered in a psychotherapeutic setting produced long-lasting and positive changes in mood and wellbeing in people who did not have depression. Follow-up neuro-imaging studies showed alterations in brain function consistent with an antidepressant effect. Further studies gave positive outcomes in patients with resistant depression. This led to two companies funding further trials and by April 2020, there were 30 such trials registered, mostly involving psilocybin, with a few using LSD and MDMA (‘Ecstasy’). These include patients with anorexia, OCD, addictions and depression. Some are randomised, but many are only observational feasibility studies. Significant precautions are required to exclude patients with a personal or family history of psychosis or bipolar disorder and those with hypertension that could be increased by the psychedelic. According to Nutt, the published trials have yielded “promising” tolerability and efficacy data, with few adverse effects reported. 

Prof Nutt’s own research team reported in the NEJM (2021) on the results of a comparative trial of psilocybin versus escitalopram (Cipralex, Lexapro) in 59 patients with moderate-to-severe major depression. After six weeks, there was a two-point difference in the Quick Inventory of Depressive Symptomology-Self Report in favour of psilocybin. The researchers concluded that this small-scale trial, in which the escitalopram group also received two small (1mg) doses of psilocybin, did not show any significant difference between psilocybin and escitalopram. 

Another group reported on an RCT of psilocybin-assisted therapy in major depressive disorder in a 2021 paper in JAMA Psychiatry. Interestingly, this study was not financed by a company but through crowd-funding. A highly selective group of just 15 patients with a diagnosis of major depressive disorder, but who were not currently using antidepressants and with no history of psychosis, serious suicide attempt or hospitalisation, were randomised to receive two doses of psilocybin plus 11 hours of psychotherapy, with a further 12 patients acting as controls on a delayed treatment list. After four weeks, a modified Hamilton Depression Scale was used to assess depression severity. The mean values in the immediate treatment group were significantly lower than in the control group (HAMD 8.5 versus 23.6). A majority were deemed to be in remission. Adverse events included transient increases in diastolic BP, feelings of fear and sadness, trembling and mild transient headache. 

If ever a proper risk-benefit evaluation was needed, then this is it

The extremely small numbers enrolled in these trials and the highly restricted selection of participants makes an overall conclusion difficult at this stage. This is surely one of the occasions when a call for further large-scale studies is not just the usual ritual cop-out. Given what we already know about the adverse effects of psilocybin, the mushroom species containing it and also LSD, a highly restrictive approach to patient recruitment is more than understandable. We learned the hard way during the 1960s that the psychotic states caused by psilocybin and LSD mimic acute schizophrenia and may lead to accidents, self-harm or suicide attempts. Deaths linked to psilocybin or the magic mushrooms have largely involved accidents where individuals have jumped from windows or self-harmed. LSD is much more potent than psilocybin and is characterised by panic reactions and dysphoria, involving feelings of terror, fear of insanity or death. Prolonged psychoses have been reported as has a Hallucinogen Persisting Perception Disorder (HPPD) that takes the form of re-occurrences of the hallucinations, months or even years after the original ‘trip’. HPPD can also happen after exposure to psilocybin. 

While small-scale feasibility trials rightly exclude vulnerable individuals, it is difficult to believe that ‘real world’ clinical use of psilocybin and other psychedelics could ensure that such patients are not prescribed a psychedelic, or that they do not self-medicate with readily-available magic mushrooms or psilocybin products sold over the Internet. If ever a proper risk-benefit evaluation was needed, then this is it.