Psilocybin (Magic Mushrooms)

"Psilocybin is a molecule present in over 200 species of psychoactive mushrooms. It has a dose-dependent capacity to facilitate the experience of non-ordinary states of consciousness, and together with compounds like lysergic acid diethylamide (LSD), mescaline, and N,N-Dimethyltryptamine (DMT), is part of a group of drugs called psychedelics. Psilocybin is a partial agonist of the 5HT group of receptors, including the 5HT2A receptor subtype. The activation of 5HT2AR results in subjective alterations of perception, mood and cognition during the acute effects of psilocybin. This has potential benefits for mood disorders, as perception and cognition appear to become more flexible, enabling opportunities for new perspectives and insights to be generated, potentially leading to new and novel solutions for ongoing psychological distress (1). Psilocybin effects generally peak around 90 min after ingestion, then gradually subside and resolve in 4–6 h.

"Psilocybin and other psychedelic compounds have attracted attention from researchers and clinicians for their potential to catalyze therapeutic change, when taken within a therapeutic setting, in people diagnosed with depression (1), obsessive-compulsive disorder (2), alcohol dependence (3), nicotine dependence (4), and anxiety associated with cancer (5–7). The effects of psychedelics in general, and specifically psilocybin, for other problems are currently being investigated in several pilot studies. Early research with psilocybin has shown signals of immediate, significant and often enduring clinical improvements in depression and anxiety. Such effects are thought to result from a combination of the psychopharmacological effects of psilocybin and the participants’ subjective experiences, including generation of insights and subsequent changes in cognition and behavior (8, 9)."

"In this randomized clinical trial of psilocybin-assisted psychotherapy treatment for AUD [Alcohol Use Disorder], psilocybin treatment was associated with improved drinking outcomes during 32 weeks of double-blind observation. PHDD [Percentage of Heavy Drinking Days] among participants treated with psilocybin was 41% of that observed in the diphenhydramine-treated group. Exploratory analyses confirmed a between-group effect across a range of secondary drinking measures. Although this was, to our knowledge, the first controlled trial of psilocybin for AUD, these findings are consistent with a meta-analysis³⁹ of trials conducted in the 1960s evaluating LSD as a treatment for AUD.

"Adverse events associated with psilocybin administration were mostly mild and self-limiting, consistent with other recent trials evaluating the effects of psilocybin in various conditions.^1-8 However, it must be emphasized that these safety findings cannot be generalized to other contexts. The study implemented measures to ensure safety, including careful medical and psychiatric screening, therapy and monitoring provided by 2 well-trained therapists including a licensed psychiatrist, and the availability of medications to treat acute psychiatric reactions."

"Several limitations of the study warrant discussion. First, diphenhydramine was ineffective in maintaining the blind after drug administration, so biased expectancies could have influenced results. Control medications such as methylphenidate,⁴² niacin,² and low-dose psilocybin¹ likewise did not adequately maintain blinding in past psilocybin trials, so this issue remains a challenge for clinical research on psychedelics. Second, EtG samples, used to validate self-reported drinking outcomes, were available for only 53.8% of treated participants. Third, the study did not have adequate power to evaluate effects in subgroups, such as women, ethnic and racial minority groups, and individuals with psychiatric comorbidity, nor was it designed to identify causal mechanisms, optimal dosing, or predictors of treatment response. Fourth, the study population was lower in drinking intensity at screening than in most AUD medication trials, and results cannot be assumed to generalize to populations with more severe AUD. Fifth, the 2-group design does not permit evaluation of the effects of psychotherapy or the interaction between psychotherapy and medication. Sixth, the study does not provide information on the duration of the effects of psilocybin beyond the 32-week double-blind observation period, which is important given the often chronic, relapsing course of AUD. Further studies will be necessary to address these questions and many others concerning the use of psilocybin in the treatment of AUD."

• "Among young adults (aged 15 to 34), recent national surveys show last year prevalence estimates for both LSD and hallucinogenic mushrooms equal to or less than 1 %. Exceptions for hallucinogenic mushrooms include Czechia (2.7 % in 2021), Finland (2.0 % in 2018), the Netherlands (1.9 % in 2021), Estonia (1.6 % in 2018, 16–34), Denmark (1.5 % in 2021), Spain (1.1 % in 2022) and Germany (1.1 % in 2021). Exceptions for LSD include Ireland (2.4 % in 2019), Finland (2.0 % in 2018), Estonia (1.7 % in 2018, 16–34), Latvia (1.4 % in 2020), Norway (1.3 % in 2021) and the Netherlands (1.2 % in 2021).
• "Among respondents to the European Web Survey on Drugs, 20 % of those who had used drugs within the last 12 months had used LSD, while 13 % had used ketamine.
• "Recent estimates of last year prevalence of ketamine use among young adults (15–34) range from 0.4 % in Denmark (2021, 16–34) to 0.8 % in Romania (2019). The Netherlands reported that ketamine use has increased among young people in nightlife settings.
• "In 2022, generally very low levels of ketamine residues in municipal wastewater were reported by 15 cities, with the highest mass loads being detected in cities in Denmark, Spain, Italy and Portugal (see the figure Ketamine residues in wastewater in selected European cities, 2022, below)."

"Psilocybin is a non-addictive classic psychedelic (22, 23) with neuroplasticity-inducing properties (24, 25). It is consistently ranked as one of the least harmful illicit psychoactive substances (4, 5), despite being among the most highly regulated substances globally. Psilocybin is a tryptamine alkaloid with serotonin 2A receptor (5-HT2A) agonism (26)—and complex pharmacology at many additional serotonin and non-serotonin receptors—that induces marked transitory changes in perception, cognition, and affect. Early phase clinical trials demonstrate that one to three moderate-to-high doses (20 mg to 30 mg/70 kg or more) of psilocybin combined with a brief course of psychotherapy (i.e., psilocybin-assisted psychotherapy) is safe, feasible, and preliminarily efficacious at alleviating symptoms of major depressive disorder, anxiety and depression associated with end-of-life diagnoses, and alcohol and tobacco use disorder (27–30). Psilocybin-assisted psychotherapy received a ‘Breakthrough Therapy’ designation from the United States Food and Drug Administration for both major depressive disorder and treatment-resistant depression. This designation was created to expedite the development and review of drugs intended to treat serious or life-threatening conditions for which preliminary evidence suggests substantial improvement over available options."

"This paper presents updated and extended data from an open-label clinical trial assessing psilocybin with psychological support for treatment-resistant depression. Findings corroborate our (Carhart-Harris et al. 2016) and others’ previous results (Griffiths et al. 2016; Ross et al. 2016; Grob et al. 2011) supporting the safety and efficacy of psilocybin for depressive and anxiety symptoms. A fast and sustained response exceeding what might be expected from a placebo response was observed in many of the patients (see Carhart-Harris and Nutt (2016) for a relevant discussion). Notably, all 19 completers showed some reductions in the QIDS-SR16 scores at 1-week post-treatment and (nominally) maximal effects were seen at 5 weeks. Other interventions, not formally part of the present trial, confounded outcomes at 3 and 6 months, although safety was maintained and a sizeable proportion of the sample continued to demonstrate benefit (see Watts et al. (2017) for more details). Conclusions on efficacy are limited by the absence of a control condition in this trial, however.

"Recent studies (Griffiths et al. 2016; Ross et al. 2016; Carhart-Harris et al. 2016), including the present one, help demonstrate the feasibility of treating patients with major depressive disorder with psilocybin plus psychological support. Two recent double-blind randomised control trials (RCTs) of psilocybin for depression and anxiety symptoms in a combined sample of 80 patients with life-threatening cancer found consistent safety and efficacy outcomes with those reported here (Griffiths et al. 2016; Ross et al. 2016). Only a subset of patients recruited into these studies met the criteria for major depressive disorder however, and symptoms were not of the same severity as those seen here (i.e. mean baseline BDI scores were 18.1 and 16 in the Griffiths et al. and Ross et al. studies, respectively, whereas they were 35 in the present study). A comprehensive RCT designed to properly assess psilocybin’s efficacy for major depressive disorder, with some form of placebo control, is therefore warranted (Carhart-Harris and Goodwin 2017)."

"Our investigations provided no cause for concern that administration of PY [psilocybin] to healthy subjects is hazardous with respect to somatic health. However, as our data revealed tendencies of PY to temporarily increase blood pressure, we advise subjects suffering from cardiovascular conditions, especially untreated hypertension, to abstain from using PY or PY-containing mushrooms. Furthermore, our results indicate that PY-induced ASC [altered states of consciousness] are generally well tolerated and integrated by healthy subjects. However, a controlled clinical setting is needful, since also mentally stable personalities may, following ingestion of higher doses of PY, transiently experience anxiety as a consequence of loosening of ego-boundaries."

"Despite the limitations, this study demonstrates that the careful and controlled use of psilocybin may provide an alternative model for the treatment of conditions that are often minimally responsive to conventional therapies, including the profound existential anxiety and despair that often accompany advanced-stage cancers. A recent review from the psilocybin research group at Johns Hopkins University describes the critical components necessary for ensuring subject safety in hallucinogen research.³⁶ Taking into account these essential provisions for optimizing safety as well as adhering to strict ethical standards of conduct for treatment facilitators, the results provided herein indicate the safety and promise of continued investigations into the range of medical effects of hallucinogenic compounds such as psilocybin."

"Because this was a small-scale feasibility study with an open-label design, strong inferences cannot be made about the treatment's therapeutic efficacy. However, the data do suggest that further research is warranted. The response rate to psilocybin was 67% (n=8) at 1 week after treatment (HAM-D and BDI), and seven of these eight patients also met criteria for remission. Moreover, 58% (n=7) of the patients maintained their response for 3 months, and 42% (n=5) remained in remission. It is also worth noting that psilocybin has a favourable toxicity profile and is not associated with compulsive drug-seeking behaviours in animals or human beings. The side-effects that we noted were minor, and expected in light of previous studies of psilocybin.²⁷

"Spontaneous recovery in refractory depression is rare, and many of the patients in the present study reported having depression for much of their adult lives (mean estimated illness duration 17·8 years [SD 8]). Key questions for future research therefore should address why the therapeutic effect observed in the present study is so large, and if it can be replicated when tighter experimental controls are introduced. Because the treatment in our study consisted of not just two psilocybin administrations but also psychological support before, during, and after these sessions, as well as a positive therapeutic environment for the sessions, the relative effects of these factors need to be determined, which can only be done by conducting further trials with appropriate control conditions."