Psilocybin and other 5-hydroxytryptamine2A agonist classic psychedelics have been used for centuries as sacraments within indigenous cultures. In the mid-twentieth century they were a focus within psychiatry as both probes of brain function and experimental therapeutics. By the late 1960s and early 1970s these scientific inquires fell out of favor because classic psychedelics were being used outside of medical research and in association with the emerging counterculture.
However, in the twenty-first century, scientific interest in classic psychedelics has returned and grown as a result of several promising studies, validating earlier research. Today, we review therapeutic research on psilocybin, the classic psychedelic that has been the focus of most recent research. For mood and anxiety disorders, three controlled trials have suggested that psilocybin may decrease symptoms of depression and anxiety in the context of cancer-related psychiatric distress for at least 6 months following a single acute administration.
An Overview of the History of Psychedelic Research
Various indigenous societies have used classic psychedelic compounds (e.g., psilocybin, mescaline, dimethyltryptamine) for centuries, typically incorporating them into sacramental contexts. Arthur Heffter isolated mescaline, the principal psychoactive constituent of the peyote cactus, in 1897, but it was only after the synthesis and identification of psychoactivity of lysergic acid diethylamide (LSD) in 1943 that these compounds received significant attention from the scientific community.
- There were > 1000 clinical papers published on classic psychedelics, collectively involving approximately 40,000 patients between 1950 and the mid-1960s. Aside from basic research studies, this period generated exciting preliminary evidence that classic psychedelics, when administered in the context of psychotherapy, showed particular promise for 2 disorders: end-of-life psychiatric distress secondary to cancer and addiction. While some initial results were promising, most studies did not employ rigorous designs by current standards.
- Nonmedical classic psychedelic use, and the association between classic psychedelics and the emerging counterculture, prompted a political backlash whereby human classic psychedelic research was marginalized, government funding for classic psychedelic research ended, and regulations made such research difficult, putting an end to nearly all human classic psychedelic research.
Modern research with classic psychedelics has reinitiated interest in the treatment of both cancer-related distress and addiction, with promising initial results. Although LSD was the most studied classic psychedelic compound in the earlier era of research, recent clinical research has been primarily focused on the classic psychedelic psilocybin, which is closely pharmacologically related to LSD. Here we focus on these two potential indications for psilocybin medication development.
Therapeutic Benefits of Psilocybin
Cancer-related Psychiatric Distress
- A recent study examined a larger dose of psilocybin in the treatment of depression and anxiety in patients with cancer. Patients were 51 individuals diagnosed with one of multiple possible DSM-IV mood or anxiety-related disorders in relation to a life-threatening cancer diagnosis.
- The study showed the high psilocybin dose to result in numerous improved clinical outcomes over the very-low-dose condition at 5 weeks. Moreover, the Hamilton Anxiety Rating Scale, the STAI, the Hamilton Depression Rating Scale, and the BDI all showed large and persisting reductions at a 6-month follow-up.
- These results are remarkable not only because they show persistent benefits for many months after a single medication administration, but also because of the large magnitude of clinical effects. Approximately 80% of participants at the 6-month follow-up continued to show clinically significant decreases in depressed mood and anxiety, and approximately 60% showed remission: in other words, symptom levels in the normal range.
Treatment Resistant Depression
- Depressive symptoms, as measured by the Quick Inventory of Depressive Symptoms, the BDI, and other measures, were significantly decreased at 1 week and 3 months post-treatment, when compared with baseline scores. The same pattern was found for anxiety symptoms as measured by the STAI.
- Every individual participant showed reduction in depression severity at 1 week that was sustained in the majority for 3 months. According to standard criteria for determining remission with the BDI, 8 of 12 met threshold for complete remission, and 5 of 12 were in remission at the final 3- month follow-up
Obsessive-Compulsive Disorder (OCD)
- One pilot study in 9 participants examined the effect of oral psilocybin in patients with obsessive-compulsive disorder. Doses administered were 0.025, 0.1, 0.2, and 0.3 mg/ kg. A week elapsed between each session. All participants showed substantial symptom reduction during at least one session as assessed by the Yale–Brown Obsessive Compulsive Scale.
- At a 6-month follow up, 1 participant showed long-term improvements. Although these results might suggest psilocybin efficacy, it should be noted that a similar magnitude of symptom reduction was observed at all dose conditions, including the extremely small dose intended to have little or no effect. The similar response across such a wide range of doses Potential Therapeutic Effects of Psilocybin 737 raises the possibility that placebo (e.g., expectancy) effects may have driven results. Otherwise, the symptom reductions at the lowest dose would appear remarkable. Only follow-up experimental studies involving a placebo or active comparator control will be able to disentangle these two possibilities.
- One published case series of 53 self-medicating patients suggested that psilocybin-containing mushrooms, in addition to LSD, may be effective in terminating cluster headaches or preventing the regular occurrence of cluster headaches. This is exciting because approved therapies show limited efficacy in treating this disorder, and the pain resulting from the disorder is often severe and debilitating.
- If rigorous clinical trials confirm these results, this therapeutic application would likely be distinct from the other classic psychedelic therapies, in that positive therapeutic outcomes do not appear to rely on subjective experiences after psilocybin administration. In addition to the case series publication, a survey study of 496 individuals with cluster headaches suggested that psilocybin and related classic psychedelics may provide comparable or better treatment responses than existing approved therapies.
The current state of modern research suggests considerable therapeutic promise for psilocybin.
If future trials with larger numbers of participants continue to show such persisting therapeutic effects and a favorable adverse effect profile, psilocybin may garner regulatory approval for use as a medicine in the USA and other nations. If approval is obtained, regulations governing clinical use should closely mirror the screening, preparation, monitoring, and follow-up procedures used in research studies to maximize efficacy and minimize medical and behavioral risks.
However, as compelling evidence mounts for safety and efficacy, it will be important for government agencies to take a leadership role in supporting cautious and scholarly research on classic psychedelic therapeutics. The recent research with psilocybin, especially evidence of long persisting therapeutic effects that may stem from a single medication administration, suggests that therapy with classic psychedelics may constitute a major new area of medicine that might eventually alleviate suffering across multiple potential disorders.