Psilocybin history, action and reaction: A narrative clinical review

Abstract

Hallucinogenic mushrooms have been used in religious and cultural ceremonies for centuries. Of late, psilocybin, the psychoactive compound in hallucinogenic mushrooms, has received increased public interest as a novel drug for treating mood and substance use disorders (SUDs). In addition, in recent years, some states in the United States have legalized psilocybin for medical and recreational use. Given this, clinicians need to understand the potential benefits and risks related to using psilocybin for therapeutic purposes so that they can accurately advise patients. This expert narrative review summarizes the scientific basis and clinical evidence on the safety and efficacy of psilocybin-assisted therapy for treating psychiatric disorders and SUDs. The results of this review are structured as a more extensive discussion about psilocybin’s history, putative mechanisms of action, and recent legislative changes to its legal status. There is modest evidence of psilocybin-assisted therapy for treating depression and anxiety disorders. In addition, early data suggest that psilocybin-assisted therapy may effectively reduce harmful drinking in patients with alcohol use disorders. The evidence further suggests psilocybin, when administered under supervision (psilocybin-assisted therapy), the side effects experienced are mild and transient. The occurrence of severe adverse events following psilocybin administration is uncommon. Still, a recent clinical trial found that individuals in the psilocybin arm had increased suicidal ideations and non-suicidal self-injurious behaviors. Given this, further investigation into the safety and efficacy of psilocybin-assisted therapy is warranted to determine which patient subgroups are most likely to benefit and which are most likely to experience adverse outcomes related to its use.

In vivo validation of psilacetin as a prodrug yielding modestly lower peripheral psilocin exposure than psilocybin

“…For clinical studies using human participants, there is less likelihood of accelerating progress through substitution alone, given the additional regulatory considerations involved. However, there may be other compensatory benefits to the pursuit of psilacetin or other novel psilocin prodrug strategies as alternatives to psilocybin for human research studies, such as the possibility of reduced ethical, legal, and sustainability concerns by avoiding the commercialization of a natural product with a long documented history of sacramental use by indigenous peoples ( 18 , 43 , 44 ).…”

“…In human studies, the pharmacokinetics and exposure of psilocin have been well validated in vivo after administering psilocybin in accordance with both fixed-dose and weight-based protocols (13)(14)(15)(16). While psilocybin has the longest history of human consumption of any known psilocin prodrug, as this natural product found in Psilocybe mushrooms has been available since antiquity, it is not the only psilocin prodrug known (Figure 1) (1,(17)(18)(19)(20).…”

Current Understanding on Psilocybin for Major Depressive Disorder: A Review Focusing on Clinical Trials

“…While there were positive research results as mentioned above, the misuse use of psychedelics including lysergic acid diethylamide (LSD) and psilocybin increased drastically in the United States (US), which resulted in a growing negative perception and criticism in the media [ 9 ]. Thus, production, trade, or consumption of hallucinogenic drugs became prohibited in 1963 in the US [ 10 ]. Furthermore, in 1970, psilocybin and LSD were classified as Schedule I illegal substances, leading to stricter regulations on the use of hallucinogens.…”

Psilocybin for depression

“…Conversely, suggestions by some stakeholders that psychedelics such as psilocybin cause only negligible side effects contrast with concerning reports of confusional states, substance misuse, intentional self-harm, suicidal behaviour, and psychotic symptoms, especially in people with pre-existing vulnerability 18. Owing to inconsistent reporting across clinical trials, this review did not quantitatively assess the safety of psilocybin use in people with depression 10.…”

“…Psilocybin and other psychedelics are under investigation for use in several mental health conditions, including depression 1. Psilocybin, a prodrug that naturally occurs in “magic” mushrooms (genus Psilocybe ), has been used for ritualistic purposes by indigenous populations of Central-North America for thousands of years 2. Its active metabolite, psilocin, targets 5-hydroxytryptamine type 2A receptors, whose potent activation of serotonergic pathways is largely responsible for producing psychedelic effects 3.…”