Top Research Papers of the Psychedelic Renaissance
In no particular order:
Psilocybin with Psychological Support for Treatment-Resistant Depression
Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study (2016). Carhart-Harris RL, Bolstridge M, Rucker J, Day CM, Erritzoe D, Kaelen M, Bloomfield M, Rickard JA, Forbes B, Feilding A, Taylor D, Pilling S, Curran VH, Nutt DJ. Lancet Psychiatry.
Carhart-Harris et al. out of Imperial College London conducted an open-label study of psilocybin-assisted therapy on 12 patients with treatment-resistant depression (TRD) in 2016. The psilocybin was well tolerated and a significant decrease in depressive symptoms as measured by the Quick Inventory of Depressive Symptoms (QIDS) was observed both 1 week and 3 months after the treatment.
This trial was fundamental in supporting further exploration of psilocybin-assisted therapy as a potential treatment for depression. A long term follow-up study also showed maintenance of results out to 6 months.
Psilocybin for Depression and Anxiety in Life-Threatening Cancer
Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial (2016). Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, Mennenga SE, Belser A, Kalliontzi K, Babb J, Su Z, Corby P, Schmidt BL. J Psychopharmacol.
Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial (2016). Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, Cosimano MP, Klinedinst MA. J Psychopharmacol.
Two randomized, double-blind, placebo-controlled, crossover trials evaluating psilocybin-assisted therapy for the potential treatment of depression and anxiety associated with a life-threatening cancer were conducted separately out of New York University and Johns Hopkins University. Both published in November of 2016, these two studies provide the most robust and methodologically sound evidence for the potential use of psilocybin-assisted therapy as a treatment of mood-related disorders. Substantial reductions in measures of both depression and anxiety were observed up to 6 months after high dose (30 mg/70 kg) psilocybin administration.
The two studies caused massive waves in the media when they were published, and changed the tone of how research into psychedelics was seen by the academic communities of the world in the modern era. They undoubtedly played a major role in the establishment of the ‘Psychedelic Renaissance’.
Safety Guidelines for Human Halluginogen Research
Human hallucinogen research: guidelines for safety (2008). Johnson M, Richards W, Griffiths R. J Psychopharmacol.
This guideline thoroughly reviews the history of psychedelics, including indigenous use and early clinical research in the 1950s and 1960s, as well as the unique psychological and physiological risks involved with human hallucinogen research. Most notably, it provides comprehensive recommendations for the safe use and risk mitigation of psychedelic therapies, ranging from the proper selection of subjects to the preparatory and post-session procedures.
Pictured below is the living-room-like session room at Johns Hopkins University, emphasized because a comfortable setting is essential for decreasing the probability of acute psychological distress. The participant uses eyeshades and headphones playing supportive music to encourage an introspective psychedelic experience, while receiving interpersonal support from two or more trained monitors when needed. These guidelines have served as a seminal reference for the majority of modern psychedelic studies.
Review of Psychedelic Science
Psychedelics (2016). Nichols DE. Pharmacol Rev.
A comprehensive review of many aspects of psychedelic science, ranging from the chemistry, history of regulation, anthropology, and a review of studies conducted before psychedelics were scheduled as having no medical benefit. This paper serves as both an excellent starting point for learning about psychedelic pharmacology, as well as a scientifically rigorous resource for deep dives into very specific effects of psychedelics on the mind. Some rare examples include the observed effects on time dilation and sleep.
Psilocybin Brain Mechanisms in Depression
Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms (2017). Carhart-Harris RL, Roseman L, Bolstridge M, Demetriou L, Pannekoek JN, Wall MB, Tanner M, Kaelen M, McGonigle J, Murphy K, Leech R, Curran HV, Nutt DJ. Sci Rep.
Dr. Carhart-Harris again made waves in 2017 with this clinical study on 19 patients with Treatment-Resistant Depression (TRD) treated with psilocybin (10 mg followed by 25 mg, one-week apart). While this study’s psychological outcome measures are valuable, the results of the functional Magnetic Resonance Imaging (fMRI) research were ground-breaking. Carhart-Harris’s team measured the brain activity of the patients at baseline before any treatment, and then again 1 day after the higher-dose psilocybin session.
Though the study contains very complex neuroscience methods, a notable takeaway is that decreases in blood flow (indicating reduced activity) in the amygdala, an important brain area for emotional processing, 1 day after high dose psilocybin was predictive of an antidepressant response at 5 weeks. They also found a correlation between ‘peak’ or ‘mystical-type experiences’ and these brain activity changes, providing clues of a concrete link from experience -> brain changes -> behavioral response.
Interested readers may also want to check out this 2012 study by Carhart-Harris et al., where acute changes in brain blood flow were measured during psilocybin administration.
The Relationship Between Psychedelics and Mental Health
Psychedelics and mental health: a population study (2013). Krebs TS, Johansen PØ.. PLoS One.
This paper analyzed data relating the use of psychedelics and the incidence of mental health disturbances reported by 130,152 people on the National Survey on Drug Use and Health from 2001-2004. 21,967 respondents (13.4% weighted) reported lifetime psychedelic use. Within this large sample, the authors found no significant associations between lifetime use of any psychedelics, lifetime use of specific psychedelics (LSD, psilocybin, mescaline, peyote), or past year use of LSD and an increased rate of any of the mental health outcomes.
This finding is significant in the context of the historical stigmatization of psychedelic drugs worldwide. Psychedelics have maintained a negative reputation for potentially causing mental illness since the 1970s, and this epidemiological study provides evidence rejecting these claims. In fact, this 2013 study provided early evidence that psychedelic use may actually lead to decreased incidence of mental health problems.
MDMA-Assisted Psychotherapy for Treatment of PTSD
MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials (2019). Mithoefer MC, Feduccia AA, Jerome L, Mithoefer A, Wagner M, Walsh Z, Hamilton S, Yazar-Klosinski B, Emerson A, Doblin R. Psychopharmacology (Berl).
Chemically speaking, MDMA is classified as an ‘entactogen’ (or alternatively, ‘empathogen’), rather than a classical psychedelic such as psilocybin, LSD, or DMT. For the purposes of this list, we include MDMA for a few reasons: MDMA-assisted psychotherapy has demonstrated similarly transformative outcomes as other psychedelic therapies and because the development of MDMA as a medicine has helped drive the procession of other psychedelic molecules through the drug development pathway.
This paper is a thorough overview of the phase III development plan for MDMA-assisted psychotherapy for the treatment of PTSD. It also includes a pooled analysis of 6 phase II clinical trials that found significant reductions in the Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV), which led to the FDA granting the Breakthrough Therapy designation for this promising treatment.
A long-term follow-up of six phase II trials showed a maintenance of the beneficial results out to at least 12 months post-treatment, the strongest evidence yet that psychedelic-assisted psychotherapy can make lasting changes in patients’ lives when they participate in a structured support program. Surprisingly, the number of participants who no longer met PTSD criteria actually increased from treatment exit (56%) to long-term follow-up (67%).
Ayahuasca for Treatment-Resistant Depression
Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial (2019). Palhano-Fontes F, Barreto D, Onias H, Andrade KC, Novaes MM, Pessoa JA, Mota-Rolim SA, Osório FL, Sanches R, Dos Santos RG, Tófoli LF, de Oliveira Silveira G, Yonamine M, Riba J, Santos FR, Silva-Junior AA, Alchieri JC, Galvão-Coelho NL, Lobão-Soares B, Hallak JEC, Arcoverde E, Maia-de-Oliveira JP, Araújo DB. Psychol Med.
In this 2019 study, Palhano-Fontes et al. developed the most well-controlled randomized double-blinded trial in the literature thus far, testing the antidepressant effects of the amazonian psychedelic brew, ayahuasca, in patients with treatment resistant depression. Ayahuasca, considered by some to be one of the most potent psychedelic drugs, has seen development far more in the religious communities of the world and has not yet seen the same boom of scientific research activity that is evident with psilocybin and MDMA. This study brings high-quality supportive evidence for the power of psychedelics in general, and ayahuasca specifically, to have an impact on treatment-resistant depression outcomes, showing a significant decrease in subject Montgomery-Åsberg Depression Rating Scale (MADRS) score at day 7 after treatment.
Perhaps more profoundly, the study shows that the Amazonian medicine can be studied under the lens of western science, using techniques such as developing a placebo formulation mimicking the taste, color, and nausea-inducing properties of ayahuasca so as to better maintain study blinding.
Dose-Response Study of N,N-Dimethyltryptamine (DMT)
Dose-response study of N,N-dimethyltryptamine in humans. I. Neuroendocrine, autonomic, and cardiovascular effects (1994). Strassman RJ, Qualls CR. Arch Gen Psychiatry.
Dose-response study of N,N-dimethyltryptamine in humans. II. Subjective effects and preliminary results of a new rating scale (1994). Strassman RJ, Qualls CR, Uhlenhuth EH, Kellner R. Arch Gen Psychiatry.
This study by Rick Strassman was in many perspectives responsible for kicking off the psychedelic research renaissance. Conducted in 1994, it was the first new human study of a psychedelic drug to be approved by the US government in a generation.
There are two parts to this study: the first part reviews the neuroendocrine, autonomic, and cardiovascular effects of DMT, and the second part is an evaluation of the subjective effects and the debut of one of the very important rating scales in psychedelic research – the Hallucinogen Rating Scale.
Compiled by Michael Haichin, PharmD and Kevin Lanzo, PharmD in February 2021