Mechanisms of Therapeutic Action of Psilocybin Cubensis in Treating Patients with Depression, Stephan Tap, 2018

Mechanisms of Therapeutic Action of Psilocybin Cubensis in Treating Patients with Depression

Stephan Tap,

Universiteit Leiden, Sociale Wetenschappen, 2018



Depression is a serious mental illness affecting over 300 to 350 million people worldwide (WHO, 2018; Cipriani et al., 2018). People suffering from depression experience a wide variety of symptoms, including a depressed mood, loss of interest, and reduced energy. There are many different therapeutic approaches to treat depression, of which cognitive behavioral therapy (CBT) and the use of antidepressants (e.g. SSRI’s) are probably the most prominent. Both seem to be efficacious in alleviating the symptoms of depression (Butler et al., 2006; Driessen & Hollon, 2010; Cipriani et al., 2018). However, a more recent review suggests that the effects of CBT might be overestimated until now (Cuijpers et al., 2013).

Likewise, the exclusive use of antidepressants seems to have some significant effects on alleviating depressive symptoms, but they sometimes seem to improve spontaneously, which happens in particular to placebo responders in antidepressant trials (Cipriani et al., 2018). In addition, trials that were included in the metaanalysis by Cipriani et al. (2018) were of short duration and it usually takes a few weeks for antidepressants to exert their full effect, including any adverse effects. Thus, it can be hard to infer any causality from the use of an antidepressant or a placebo. Despite these seemingly efficacious resources, the fact remains that 300 to 350 million people worldwide are still depressed. Do they simply lack resources? Are antidepressants not as effective as they seem or do people ordinarily neglect them due to their adverse effects? More importantly, are these the only options for patients when treating depression?

Recently, studies involving the classic psychedelics (i.e. psilocybin, lysergic acid diethylamide, and DMT) are showing tremendous potential in treating people with depression and other disorders like addiction, end-of-life anxiety, and alcoholism (Carhart-Harris et al., 2012; dos Santos et al., 2016; Johnson et al., 2014; Bogenschutz et al., 2015; Griffiths et al., 2016; Ross et al., 2016; Johnson et al., 2017). How is this possible and what are the possible mechanisms behind these psychedelic drugs? This paper will specifically look at the psychedelic compound psilocybin cubensis and its role in alleviating depressive symptoms by offering insight into both qualitative and quantitative mechanisms of therapeutic action. It may further do this, albeit indirectly, to the other classic psychedelics as well, since their overall experience and effect seem quite similar due to their neurochemical structure.

From Disconnection to Connection

Psilocybin cubensis (from the genus psilocybe) is a tiny mushroom that contains the naturally occurring psychedelic prodrug psilocybin and converts to psilocin (4-hydroxy-dimethyltriptamine) in the body when taken orally. It is a serotonin receptor agonist and its psychoactive effects are mediated by serotonin 2A (5-HT2a) receptor agonism. Lastly, psilocybin is non-toxic and non-addictive, and is not associated with drug-seeking behavior (Carhart-Harris et al, 2016). The following study (Carhart Harris et al., 2016). aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression. Participants had depression for an average of 18 years, tried three to eleven different antidepressants, and had up to six courses of psychotherapy. After only two oral doses of psilocybin (10mg and 20mg), six people (N=20) went into remission while the symptoms of eleven participants returned, but were hopeful again despite this unfortunate occurrence. The remaining three participants did not respond at all. Next to alleviating symptoms of depression, there were also marked and sustained improvements in anhedonia and anxiety. Finally, psilocybin was well tolerated by all patients and there were no serious or adverse events, thereby proving its feasibility, efficacy, and safety.

Six months later, Watts et al. (2017) conducted a follow-up study where Dr. Rosalind Watts, a clinical psychologist, interviewed all the participants to ask about their (psychedelic) experience that occured during the psilocybin session. Using a thematic analysis to identify the patients’ experiences of treatment – and how it compared with previous treatments (i.e. psychotherapy and antidepressants) – she discovered one theme, or spectrum rather, which showed itself as both a poetic and noetic phenomenon in all the participants’ interviews : “connection versus disconnection.”

Disconnection was inferred from the interview data as follows: “disconnected from the world, others, self, senses, and trapped in the mind.” Conversely, connection was defined as: “an intellectual, empathic and embodied closeness to self, others, and world” and was further subdivided into the following domains: mind, senses, emotions, body, identity, others, and world (Watts, 2017). One participant said the following about the psilocybin session: “During the session, I was everybody, unity, one life with six billion faces. I was the one asking for love and giving love. I was swimming in the sea, and the sea was me.” Another individual said: “Being absolutely connected to myself, to everything in the universe.” Watts et al. (2017) argue that this strong feeling of connection seems to be a fundamental change process. Thus, connection seems to be a qualitative mechanism of therapeutic action of psilocybin.