By Dr Hannah Thurgur an Honorary Research Assistant for Drug Science
As we welcome in the new year, Drug Science reflects on the year of 2020 for psilocybin research and celebrates these achievements. Here we focus on the use of psilocybin-assisted therapy in three different conditions to reflect the breadth of research currently taking place worldwide. This list is not exhaustive and there were many other notable clinical trials or psilocybin research papers not mentioned here, each providing insights into the effects and potential mechanisms of psilocybin.
Could psilocybin-assisted group therapy be used to tackle demoralisation in long-term AIDS survivors?
The AIDS epidemic in the 1980s and early 1990s resulted in devastating illness and mortality in the communities of bisexual and gay men. Older long-term AIDS survivors refer to the subset of patients diagnosed with HIV or AIDS prior to the clinical availability of effective HIV treatment. There is a myriad of complex psychiatric implications of living with a chronic disease, which when combined with the traumatic loss experienced by the AIDS survivors of the epidemic era has resulted in a population with a high prevalence of demoralisation. Demoralisation in the clinical sense is a form of existential suffering associated with feelings of helplessness and hopelessness, as well as a loss of meaning and purpose in life. This recent study1 was a single-arm, open-label pilot study of psilocybin-assisted group therapy over a period of seven weeks – which translated into simpler terms means that the trial was not blinded and that each participant received psilocybin. The study included 18 self-identified gay men with an average age of 59.2 years whom were split into three sequential cohorts of six for group therapy. At baseline each participant was assessed using a questionnaire-based assessment tool called the Demoralisation Scale-II (DS-II), consisting of 16 questions and with a total score of 32. Participants were required to have a total score of more than 8 to reflect moderate-to-severe demoralisation on the scale. Participants underwent 1.5 hours of individual psychotherapy prior to the first group therapy session, followed by two 2-hour weekly sessions of group psychotherapy for the period of seven weeks. Within this period there was one 8-hour individual psilocybin administration session (0.3-0.36 mg/kg), followed by a 2-hour individual psychotherapy session the following day.
The key aim of this study was to determine the feasibility of a group therapy model and the safety of psilocybin in this subset of patients. The rates of recruitment were high and the retention of participants throughout the period of group-therapy was 95%, which suggests that the group therapy was well received by the majority. Although there were no adverse effects attributed to psilocybin during the dosing session, there were two unexpected adverse reactions post-medication including a post-traumatic stress flashback and methamphetamine relapse. During the dosing session, temporary adverse effects including hypertension, anxiety and nausea were reported. However, the researchers emphasised that this was somewhat expected as the study included a clinically complex subset of patients. Clinically meaningful improvements in demoralisation scores were demonstrated with robust changes from baseline to end-of-treatment (mean reduction in DS-II score of 6.67) and to 3-month follow-up (mean reduction in DS-II score of 5.78). This study is pivotal in providing supportive evidence of psilocybin-assisted group therapy for a marginalized population with complex comorbid psychiatric conditions, whilst demonstrating the potential benefit of group therapy in populations with shared experience that could be applied to other subsets of patients. The study also acts as support for the feasibility of a group therapy approach, offering a more financially viable method of providing psychedelic-assisted therapy.
Psilocybin-assisted therapy could offer a long-lasting approach to address the emotional and spiritual needs of cancer patients
A cancer diagnosis is often associated with psychiatric and existential distress, including elevated levels of anxiety and depression reported in patients. The complex psychiatric consequences of living with a cancer diagnosis are a currently unmet patient need and severely impact the patient’s quality of life. The original study2, published in 2016, consisted of 29 adults with cancer-related emotional distress. It was a double-blind, placebo-controlled, crossover trial – which means participants were randomized and either initially received a 0.3 mg/kg single dose of psilocybin or 250 mg of niacin as the placebo control, after a cross over period all participants then received the alternative treatment. The treatment (psilocybin and niacin) was given in a psychotherapeutic framework, consisting of three preparatory sessions and three integration sessions. The initial study revealed an anti-depressant and anxiolytic effect of psilocybin-assisted therapy in 60-80% of participants at the 6.5 month follow up. The long-term follow-up study3 assessed participants at 3.2 and 4.5 years after the psilocybin-assisted therapy. The study included a subset of 15 participants from the original trial, excluding those who had died and one who declined to participate. Participants were asked to self-report on symptoms of depression, anxiety, existential distress, quality of life, spirituality, persisting effects of psilocybin and mystical experiences through questionnaire-based assessments.
This follow-up study provided novel evidence suggesting that a single dose of psilocybin given in a psychotherapeutic framework provides long-term improvements in the emotional and existential distress in those with life-threatening cancer. At the latest follow up at 4.5 years, approximately 60-80% of patients had clinically significantly antidepressant or anxiolytic responses. A pivotal finding from the study was that 71-100% of participants attributed positive life changes to the psilocybin-assisted therapy experience and rated it among the most personally meaningful and spiritually significant experiences of their lives. Although there are limitations to this study, including the lack of ethnic diversity in the study, the results offer evidence to support alternative approaches to address the emotional, psychological and spiritual well-being of patients with long-term cancer diagnosis. Critically, the long-term effects of psilocybin-assisted therapy on patients in this study are a novel finding that should be appreciated and used to inform future psychological care of cancer patients.
Major depressive disorder (MDD), commonly referred to as depression, is a substantial public health concern and results in a heavy economic burden. Although recent studies have investigated the effect of psilocybin-assisted therapy in treatment-resistant depression, MDD, which effects a larger population, had yet to be investigated. This was a small study4 of 24 adults with MDD and the average age of the participant was 39.8 years. It was a randomized, waiting list-controlled trial, whereby participants were randomized to begin treatment immediately or after an 8-week delay in order to determine the effect of psilocybin-assisted psychotherapy from spontaneous symptom improvement. The participants underwent 8 hours of preparatory sessions across a period of three weeks, followed by a psilocybin session on two consecutive weeks. There were follow up sessions at 1 week and 4 weeks after the final psilocybin session. Depression assessments using the GRID-Hamilton Depression Rating Scale (GRID-HAMD), a commonly used questionnaire-based assessment, were performed at enrolment and at both follow up sessions after the psilocybin-assisted therapy. On the scale, scores of 0–7 are considered as no depression, 8–16 suggest mild depression, 17–23 moderate depression and scores over 24 are indicative of severe depression. At the beginning of the study, participants had an average depression scale rating of 23.
The study revealed that two doses of psilocybin given alongside supportive psychotherapy produced a large and rapid anti-depressant effect. At four weeks after treatment, 71% of the participants showed a clinically significant response, determined as a 50% or more reduction in the GRID-HAMD score, and 54% of participants were considered in remission and didn’t clinically qualify as depressed on the GRID-HAMD scale. Comparisons between current MDD treatments and psilocybin-assisted therapy can be drawn, specifically the effect sizes of psilocybin-assisted therapy are 2.5 times greater than the effect sizes found in psychotherapy alone and more than 4 times greater than the effect sizes found in the current psychopharmacological depression treatment studies. The findings in this study are particularly promising as the broad population of patients with MDD present varying types and degrees of MDD. Future studies investigating psilocybin-assisted therapy in MDD will need to implement a placebo-control and long-term follow ups, as well as larger and more diverse population of participants.
Psilocybin therapy clinical trials are often the focus of mainstream media rather than the finer details of fungal chemistry research. Although magic mushrooms are well-known for their production of psilocybin, the other compounds produced by psilocybe mushrooms has been relatively understudied. This study5 determined the natural-product profiles, essentially the cocktail of products synthesised, of four psilocybe species including P. Mexicana, P. cubensis, P. cyanescens and P. semilanceata. The study incorporated an extraction step to isolate the natural products and a purification step. Nuclear Magnetic Resonance (NMR) spectroscopy, an analytical chemistry technique, to identify and characterise the components in the mushroom mixtures.
The study confirmed the presence of known compounds including psilocybin, psilocin, baeocystin, norbaeocystin, and norpsilocin. The new compounds isolated were beta-carbolines including cordysinin C, cordysinin D, harmane, harmol, norharmane, and perlolyrine. beta-carbolines are alkaloid compounds found across various animals and plants. The beta-carboline containing plant Banisteriopis Caapi is typically used in ayahuasca and inhibits monoamine oxidase (MAO) enzymes to prevent the breakdown of DMT in the gut and liver, altering the onset and duration of DMT. Interestingly, MAOs are also responsible for the degradation of psilocin (the active form of psilocybin). Therefore, the findings in the study that psilocybin is produced alongside beta–carbolines in psilocybe mushrooms, raises the question whether there is an entourage effect, whereby the onset and duration might be altered by the presence of the MAOI. However, it is unknown whether the presence of the beta-carbolines will alter the psychotropic effects of psilocybin and whether there would be an effect at the relatively low levels of beta–carbolines detected in the study. This paper acts a poignant reminder of the unknowns in the research of psilocybe mushrooms and whether there are differences in consuming natural mushrooms compared to synthetic psilocybin.
Drug Science remains optimistic for the year ahead and looks forward to the upcoming psilocybin research due to be published in 2021. We will do our best to keep you up to date so keep your eyes peeled!
1 Anderson, B. T., Danforth, A., Daroff, P. R., Stauffer, C., Ekman, E., Agin-Liebes, G., Trope, A., Boden, M. T., Dilley, P. J., Mitchell, J. and Woolley, J. (2020). Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study. EClinicalMedicine, 24(27), 100538.
2 Ross, S., Bossis, A., Guss, J., Agin-Liebes, G., Malone, T., Cohen, B., Mennenga, S. E., Belser, A., Kalliontzi, K., Babb, J., Su, Z., Corby, P. and Schmidt, B. L. (2016). Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: A randomized controlled trial. Journal of Psychopharmacology, 30(12), 1165–1180.
3 Agin-Liebes, G. I., Malone, T., Yalch, M. M., Mennenga, S. E., Ponté, K. L., Guss, J., Bossis, A. P., Grigsby, J., Fischer, S. and Ross, S. (2020). Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer. Journal of Psychopharmacology, 34(2), 155–166.
4 Davis, A. K., Barrett, F. S., May, D. G., Cosimano, M. P., Sepeda, N. D., Johnson, M. W., Finan, P. H. and Griffiths, R. R. (2020). Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry, 1–9.
5 Blei, F., Dörner, S., Fricke, J., Baldeweg, F., Trottmann, F., Komor, A., Meyer, F., Hertweck, C. and Hoffmeister, D. (2020). Simultaneous Production of Psilocybin and a Cocktail of β-Carboline Monoamine Oxidase Inhibitors in ‘Magic’ Mushrooms. Chemistry – A European Journal, 26(3), 729–734.