Recommended Readings 2

Psychedelic-Assisted Therapy


This list was made by Jagoda Mackowiak in cooperation, and co-published, with Blossom

Recreational users have long recognized the positive effects of serotonergic hallucinogens, however, the history of academic research on the therapeutic potential of psychedelics has been turbulent, to say the least.

For more than a decade, we have been observing a Psychedelic Renaissance – a growing interest in exploring the potential of psychedelics in the treatment of mental health disorders. Substances such as psilocybin, LSD, and ayahuasca are being investigated the world over, from university research groups to forward-looking therapists’ offices—all with the hope of establishing effective methods for society at large to improve global mental health.

In this list, we will introduce the history and current state of the research on psychedelic-assisted therapy, as well as its challenges and future perspectives.

A straight-forward and down-to-earth briefing on some of the problems involved in psychedelic research was published by Ben Sessa in 2014. In ‘Why Psychiatry Needs Psychedelics and Psychedelics Need Psychiatry’ the UK-based psychotherapist argues that we have to reject the enthusiastic, yet naïve notion of creating a utopian society thanks to the use of psychedelics. Instead, researchers and healthcare professionals should focus on realistic and non-biased views of psychedelics as novel players in the pharmaceutical market.

Sessa, B. (2014). Why Psychiatry Needs Psychedelics and Psychedelics Need Psychiatry. Journal of Psychoactive Drugs, 46(1):57-62.

Without researching psychedelic drugs for medical therapy, psychiatry is turning its back on a group of compounds that could have great potential. Without the validation of the medical profession, the psychedelic drugs, and those who take them off-license, remain archaic sentiments of the past, with the users maligned as recreational drug abusers and subject to continued negative opinion. These two disparate groups—psychiatrists and recreational psychedelic drug users—are united by their shared recognition of the healing potential of these compounds. A resolution of this conflict is essential for the future of psychiatric medicine and psychedelic culture alike. Progression will come from professionals working in the field adapting to fit a conservative paradigm. In this way, they can provide the public with important treatments and also raise the profile of expanded consciousness in mainstream society.

The historical context of research on psychedelics is extensively discussed in ‘Psychedelics: Where we are now, why we got here, what we must do.’ In their 2018 commentary, Belouin & Henningfield travel through the rise, the fall, and the current renaissance of psychedelics as medical agents. Drawing conclusions from the historical context and paying close attention to health policymakers and their influence on science, the authors set a trajectory for the immediate future of clinical advances in the field of psychedelic research.

Belouin, S. J. and Henningfeld, J. E. (2018). Psychedelics: Where we are now, why we got here, what we must do. Neuropharmacology, 142:7-19.

The purpose of this commentary is to provide an introduction to this special issue of Neuropharmacology with a historical perspective of psychedelic drug research, their use in psychiatric disorders, research-restricting regulatory controls, and their recent emergence as potential breakthrough therapies for several brain-related disorders. It begins with the discovery of lysergic acid diethylamide (LSD) and its promising development as a treatment for several types of mental illnesses during the 1940s. This was followed by its abuse and stigmatization in the 1960s that ultimately led to the placement of LSD and other psychedelic drugs into the most restrictively regulated drug schedule of the United States Controlled Substances Act (Schedule I) in 1970 and its international counterparts. These regulatory controls severely constrained development of psychedelic substances and their potential for clinical research in psychiatric disorders. Despite the limitations, there was continued research into brain mechanisms of action for psychedelic drugs with potential clinical applications which began during the 1990s and early 2000s. Finding pathways to accelerate clinical research in psychedelic drug development is supported by the growing body of research findings that are documented throughout this special issue of Neuropharmacology. Accumulated research to date suggests psychedelic drug assisted psychotherapy may emerge as a potential breakthrough treatment for several types of mental illnesses including depression, anxiety, post-traumatic stress disorder, and addiction that are refractory to current evidenced based therapies. This research equally shows promise in advancing the understanding of the brain, brain related functioning, and the consequential effects of untreated brain related diseases that have been implicated in causing and/or exacerbating numerous physical disease state conditions. The authors conclude that more must be done to effectively address mental illnesses and brain related diseases which have become so pervasive, destructive, and whose treatments are becoming increasingly resistant to current evidenced based therapies.

A strictly medical perspective is offered by David Nichols, Matthew Johnson, and Charles Nichols in their state-of-the-art review from 2016. ‘Psychedelics as Medicines: An emerging new paradigm’ compares various clinical trials with patients suffering from several psychiatric disorders and presents the psychedelic mechanisms of action on a cellular level.

Nichols, D. E., Johnson, M. W., and Nichols, C. D. (2017). Psychedelics as Medicines: An Emerging New Paradigm. Clinical Pharmacology and Therapeutics, 101(2):209-219.

Scientific interest in serotonergic psychedelics (e.g., psilocybin and LSD; 5‐HT2A receptor agonists) has dramatically increased within the last decade. Clinical studies administering psychedelics with psychotherapy have shown preliminary evidence of robust efficacy in treating anxiety and depression, as well as addiction to tobacco and alcohol. Moreover, recent research has suggested that these compounds have potential efficacy against inflammatory diseases through novel mechanisms, with potential advantages over existing antiinflammatory agents. We propose that psychedelics exert therapeutic effects for psychiatric disorders by acutely destabilizing local brain network hubs and global network connectivity via amplification of neuronal avalanches, providing the occasion for brain network “resetting” after the acute effects have resolved. Antiinflammatory effects may hold promise for efficacy in treatment of inflammation‐related nonpsychiatric as well as potentially for psychiatric disorders. Serotonergic psychedelics operate through unique mechanisms that show promising effects for a variety of intractable, debilitating, and lethal disorders, and should be rigorously researched.

Four years later, two pioneers of psychedelic research in Brazil teamed up and published a detailed review of the therapeutic potential of LSD, psilocybin, and ayahuasca. ‘Therapeutic use of serotoninergic hallucinogens: A review of the evidence and of the biological and psychological mechanisms‘ (2020) scrutinizes the effects of psychedelics in substance use disorders, as well as in anxiety and depression related to cancer and other life-threatening diseases.

dos Santos, R. G. and Hallak, J. E. C. (2019). Therapeutic use of serotoninergic hallucinogens: a review of the evidence and of the biological and psychological mechanisms. Neuroscience & Biobehavioral Reviews, 108:423-434.

Serotoninergic hallucinogens include drugs such as lysergic acid diethylamide (LSD), dimethyltryptamine (DMT) and psilocybin. Recent trials with single/few doses of these compounds show that they induce rapid and sustained antidepressive, anxiolytic, and antiaddictive effects. These effects are also observed in religious groups using the DMT-containing brew ayahuasca. The agonist action of these substances on 5-HT2A receptors expressed in frontal and limbic areas increase glutamatergic transmission and neuroplasticity. These neurochemical effects are associated with acute alterations on self-perception and increases in introspection and positive mood, and with subacute and long-term decreases in psychiatric symptoms, increases in some personality traits such as openness, improvements in emotional processing, and increases in empathy. These are preliminary but promising results that should be further explored in controlled trials with larger sample sizes, especially considering that these compounds could be beneficial in the treatment of treatment-resistant psychiatric disorders.

Living with a life-threatening disease can lead to many mental health problems. General anxiety, loneliness, the anguish about unresolved personal relationships, and managing pain are but a few of these problems. In 2014 a joint effort of researchers from Switzerland and the US had led to a detailed investigation of the ‘Safety and Efficacy of Lysergic Acid Diethylamide-Assisted Psychotherapy for Anxiety Associated With Life-threatening Diseases.’ The study, partially funded by MAPS, resulted in a positive trend in reducing anxiety after only two LSD-assisted therapy sessions. In a follow-up study, they found that the effects persisted 12 months later.

Gasser, P., Holstein, D., Michel, Y., Doblin, R., Yazar-Klosinski, B., Passie, T., and Brenneisen, R. (2014). Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. Journal of Nervous and Mental Disease, 202(7):513-520.

A double-blind, randomized, active placebo-controlled pilot study was conducted to examine safety and efficacy of lysergic acid diethylamide (LSD)-assisted psychotherapy in 12 patients with anxiety associated with life-threatening diseases. Treatment included drug-free psychotherapy sessions supplemented by two LSD-assisted psychotherapy sessions 2 to 3 weeks apart. The participants received either 200 μg of LSD (n = 8) or 20 μg of LSD with an open-label crossover to 200 μg of LSD after the initial blinded treatment was unmasked (n = 4). At the 2-month follow-up, positive trends were found via the State-Trait Anxiety Inventory (STAI) in reductions in trait anxiety (p = 0.033) with an effect size of 1.1, and state anxiety was significantly reduced (p = 0.021) with an effect size of 1.2, with no acute or chronic adverse effects persisting beyond 1 day after treatment or treatment-related serious adverse events. STAI reductions were sustained for 12 months. These results indicate that when administered safely in a methodologically rigorous medically supervised psychotherapeutic setting, LSD can reduce anxiety, suggesting that larger controlled studies are warranted.

Key Words: LSD, psychedelic, psycholytic therapy, hallucinogen, anxiety disorder

Parallel to LSD, psilocybin has also been investigated in order to establish its potential in reducing depression and anxiety in patients suffering from life-threatening cancer. Scientists from Johns Hopkins University School of Medicine established that ‘Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial’ (2016), while producing no adverse effects. The reported improvements in quality of life, life meaning, death acceptance, and optimism persisted for at least 6 months after psilocybin administration.

Griffiths, R. R., Johnson, M. W., Carducci, M. A., Umbricht, A., Richards, W. A., Richards, B. D., Cosimano, M. P., and Klinedinst, M. A. (2016). Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. Journal of Psychopharmacology, 30(12):1181-1197.

Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. The effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up. Instructions to participants and staff minimized expectancy effects. Participants, staff, and community observers rated participant moods, attitudes, and behaviors throughout the study. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes.

Studying the effects of psychedelics in patients in terminal life stages is, however, extremely challenging, not only because of the delicate nature of the subject, but also because of the study design and sample size. ‘Serotonergic hallucinogens in the treatment of anxiety and depression in patients suffering from a life-threatening disease: A systematic review’ (2018) written by Simon Reiche and colleagues (including Henrik Jungaberle – the founder of MIND Foundation) analyzed over 50 years of clinical trials and discussed their significance, safety, and limitations, while also bringing to the reader’s attention that there are still many questions to be answered.

Reiche, S., Hermle, L., Gutwinski, S., Jungaberle, H., Gasser, P., and Majic, T. (2018). Serotonergic hallucinogens in the treatment of anxiety and depression in patients suffering from a life-threatening disease: A systematic review. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 81:1-10.

Anxiety and depression are some of the most common psychiatric symptoms of patients suffering with life-threatening diseases, often associated with a low quality of life and a poor overall prognosis. 5-HT2A-receptor agonists (serotonergic hallucinogens, ‘psychedelics’) like lysergic acid diethylamide (LSD) and psilocybin were first investigated as therapeutic agents in the 1960s. Recently, after a long hiatus period of regulatory obstacles, interest in the clinical use of these substances has resumed. The current article provides a systematic review of studies investigating psychedelics in the treatment of symptoms of existential distress in life-threatening diseases across different periods of research, highlighting how underlying concepts have developed over time. A systematic search for clinical trials from 1960 to 2017 revealed 11 eligible clinical trials involving a total number of N = 445 participants, of which 7 trials investigated the use of lysergic acid diethylamide (LSD) (N = 323), 3 trials investigated the use of psilocybin (N = 92), and one trial investigated the use of dipropyltryptamine (DPT) (N = 30). The 4 more recent randomized controlled trials (RCTs) (N = 104) showed a significantly higher methodological quality than studies carried out in the 1960s and 1970s. Evidence supports that patients with life threatening diseases associated with symptoms of depression and anxiety benefit from the anxiolytic and antidepressant properties of serotonergic hallucinogens. Some studies anecdotally reported improvements in patients´ quality of life and reduced fear of death. Moreover, low rates of side effects were reported in studies that adhered to safety guidelines. Further studies are needed to determine how these results can be transferred into clinical practice.

Psychedelic therapy can involve the use of not only LSD or psilocybin, but often also of ayahuasca. Although originally only found in the Amazon jungle, the plant-based brew has been consumed by users worldwide. In 2017, recent ayahuasca users (527 participants) filled out a survey prepared by an international team of researchers. ‘Well-being, problematic alcohol consumption and acute subjective drug effects in past-year ayahuasca users: a large, international, self-selecting online survey’ shone a light on self-rated contentment, drinking habits, and trip-related experience of those who drank ayahuasca in the recent past.

Lawn, W., Hallak, J. E. C., Crippa, J. A. S., dos Santos, R. G., Pory, L., Barratt, M. J., Ferris, J. A., Winstock, A. R., and Morgan, C. J. (2017). Well-being, problematic alcohol consumption and acute subjective drug effects in past-year ayahuasca users: A large, international, self-selecting online survey. Scientific Reports, 7:15201.

Ayahuasca is a natural psychedelic brew, which contains dimethyltryptamine (DMT). Its potential as a psychiatric medicine has recently been demonstrated and its non-medical use around the world appears to be growing. We aimed to investigate well-being and problematic alcohol use in ayahuasca users, and ayahuasca’s subjective effects. An online, self-selecting, global survey examining patterns of drug use was conducted in 2015 and 2016 (n = 96,901). Questions were asked about: use of ayahuasca, lysergic acid diethylamide (LSD) and magic mushrooms; demographics, current well-being and past-year problematic alcohol use of past-year ayahuasca users and comparison drug users; and subjective effects of ayahuasca and comparison drugs. Ayahuasca users (n = 527) reported greater well-being than both classic psychedelic users (n = 18,138) and non-psychedelic drug-using respondents (n = 78,236). Ayahuasca users reported less problematic drinking than classic psychedelic users, although both groups reported greater problematic drinking than the other respondents. Ayahuasca’s acute subjective effects usually lasted for six hours and were most strongly felt one hour after consumption. Within our online, self-selecting survey, ayahuasca users reported better well-being than comparison groups and less problematic drinking than classic psychedelic users. Future longitudinal studies of international samples and randomised controlled trials are needed to dissect the effects of ayahuasca on these outcomes.

Drawing from the REBUS model proposed by Robin Carhart-Harris, Max Wolff et al., (2020) constructed a cognitive-behavioral model to explain the mechanisms of beneficial effects in psychedelic interventions. ‘Learning to Let Go: A Cognitive-Behavioral Model of How Psychedelic Therapy Promotes Acceptance’ proposes that the relaxation of avoidance-related beliefs can be achieved during a psychedelic-assisted therapy session. It allows the patient to reach an emotional breakthrough, which is an insightful and rewarding experience able to re-wire the previous avoidance patterns. The relaxed-belief state can potentially induce ego-dissolution, leading to long-term improvements in overcoming anxiety-provoking situations through revision and remodulation of pathological belief systems.

Wolff, M., Evens, R., Mertens, L. J., Koslowski, M., Betzler, F., Grunder, G., and Jungaberle, H. (2020). Learning to Let Go: A Cognitive-Behavioral Model of How Psychedelic Therapy Promotes Acceptance. Frontiers in Psychiatry, 11:5.

The efficacy of psychedelic-assisted therapies for mental disorders has been attributed to the lasting change from experiential avoidance to acceptance that these treatments appear to facilitate. This article presents a conceptual model that specifies potential psychological mechanisms underlying such change, and that shows substantial parallels between psychedelic therapy and cognitive behavioral therapy: We propose that in the carefully controlled context of psychedelic therapy as applied in contemporary clinical research, psychedelic-induced belief relaxation can increase motivation for acceptance via operant conditioning, thus engendering episodes of relatively avoidance-free exposure to greatly intensified private events. Under these unique learning conditions, relaxed avoidance-related beliefs can be exposed to corrective information and become revised accordingly, which may explain long-term increases in acceptance and corresponding reductions in psychopathology. Open research questions and implications for clinical practice are discussed.

A very pragmatic analysis has been presented in ‘The cost-effectiveness of MDMA-assisted psychotherapy for the treatment of chronic, treatment-resistant PTSD’ (Marseille et al., 2020). The article focuses on the costs of medical care required for patients suffering from PTSD – a disorder affecting almost 12 million Americans, many of which experience it chronically or recurringly, while the response to standard pharmaceuticals is often inadequate. The developed model of medical care cost suggests that MDMA-assisted psychotherapy is highly cost-effective and therefore beneficial not only to the patients, but also to the society and healthcare providers.

Marseille, E., Kahn, J.G., Yazar-Klosinski, B. and Doblin, R. (2020) The cost-effectiveness of MDMA-assisted psychotherapy for the treatment of chronic, treatment-resistant PTSD. PLoS ONE 15(10):e0239997

To assess the cost-effectiveness of MDMA-assisted psychotherapy (MAP) from the health care payer’s perspective, we constructed a decision-analytic Markov model to portray the costs and health benefits of treating patients with chronic, severe, or extreme, treatment-resistant PTSD with MAP. In six double-blind phase 2 trials, MAP consisted of a mean of 2.5 90-minute trauma-focused psychotherapy sessions before two 8-hour sessions with MDMA (mean dose of 125 mg), followed by a mean of 3.5 integration sessions for each active session. The control group received an inactive placebo or 25–40 mg. of MDMA, and otherwise followed the same regimen. Our model calculates net medical costs, mortality, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. Efficacy was based on the pooled results of six randomized controlled phase 2 trials with 105 subjects; and a four-year follow-up of 19 subjects. Other inputs were based on published literature and on assumptions when data were unavailable. We modeled results over a 30-year analytic horizon and conducted extensive sensitivity analyses. Our model calculates expected medical costs, mortality, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio. Future costs and QALYs were discounted at 3% per year. For 1,000 individuals, MAP generates discounted net savings of $103.2 million over 30 years while accruing 5,553 discounted QALYs, compared to continued standard of care. MAP breaks even on cost at 3.1 years while delivering 918 QALYs. Making the conservative assumption that benefits cease after one year, MAP would accrue net costs of $7.6 million while generating 288 QALYS, or $26,427 per QALY gained.