Depression is a major public health problem that affects approximately 4.4% of the global population. Since conventional pharmacotherapies and psychotherapies are only partially effective, as demonstrated by the number of patients failing to achieve remission, alternative treatments are needed. Mindfulness meditation (MM) and psilocybin represent two promising novel treatments that might even have complementary therapeutic effects when combined. Since the current literature is limited to theoretical and empirical underpinnings of either treatment alone, the present review aimed to identify possible complementary effects that may be relevant to the treatment of depression. To that end, the individual effects of MM and psilocybin, and their underlying working mechanisms, were compared on a non-exhaustive selection of six prominent psychological and biological processes that are well known to show impairments in patients suffering from major depression disorder, that is mood, executive functioning, social skills, neuroplasticity, core neural networks, and neuroendocrine and neuroimmunological levels. Based on predefined search strings used in two online databases (PubMed and Google Scholar) 1129 articles were identified. After screening title and abstract for relevance related to the question, 82 articles were retained and 11 were added after reference list search, resulting in 93 articles included in the review. Findings show that MM and psilocybin exert similar effects on mood, social skills, and neuroplasticity; different effects were found on executive functioning, neural core networks, and neuroendocrine and neuroimmune system markers. Potential mechanisms of MM’s effects are enhanced affective self-regulation through mental strategies, optimization of stress reactivity, and structural and functional adjustments of prefrontal and limbic areas; psilocybin’s effects might be established via attenuation of cognitive associations through deep personal insights, cognitive disinhibition, and global neural network disintegration. It is suggested that, when used in combination, MM and psilocybin could exert complementary effects by potentiating or prolonging mutual positive effects, for example, MM potentially facilitating psilocybin-induced peak experiences. Future placebo-controlled double-blind randomized trials focusing on psilocybin-assisted mindfulness-based therapy will provide knowledge about whether the proposed combination of therapies maximizes their efficacy in the treatment of depression or depressive symptomatology.
Heuschkel, K., & Kuypers, K. P. (2020). Depression, Mindfulness, and Psilocybin: Possible Complementary Effects of Mindfulness Meditation and Psilocybin in the Treatment of Depression. A Review. Frontiers in Psychiatry, 11., https://doi.org/10.3389/fpsyt.2020.00224 Link to full text
Bonny Method of Guided Imagery and Music emerged following discontinuation of psychedelic therapy research in the early 1970s, but psychedelic therapy research has since revived. Music remains a vital component. This study examined participants’ experiences of music in psychedelic therapy research. A rapid review of qualitative and quantitative journal articles in four major databases was conducted in February to April, 2019, using the terms hallucinogens, psychedelic, “lysergic acid diethylamide,” psilocybin, ayahuasca, music, and/or “music therapy.” Of 406 articles retrieved, 10 were included (n = 180; 18-69 years old). Participants had varied backgrounds. Music was widely considered integral for meaningful emotional and imagery experiences and self-exploration during psychedelic therapy. Music transformed through its elicitation of anthropomorphic, transportive, synesthetic, and material sensations. Music could convey love, carry listeners to other realms, be something to “hold,” inspire, and elicit a deep sense of embodied transformation. Therapeutic influence was especially evident in music’s dichotomous elicitations: Music could simultaneously anchor and propel. Participant openness to music and provision of participant-centered music were associated with optimal immediate and longer-term outcomes. Many studies reported scarce details about the music used and incidental findings of music experienced. Further understanding of participants’ idiosyncratic and shared responses to music during drug therapy phases will inform optimal development of flexible music protocols which enhance psychedelic therapy. Music therapists could be involved in the psychedelic therapy research renaissance through assisting with research to optimize music-based protocols used. If psychedelics become approved medicines, music therapists may be involved in offering psychedelic therapy as part of therapeutic teams.
O’Callaghan, C., Hubik, D. J., Dwyer, J., Williams, M., & Ross, M. (2020). Experience of Music Used With Psychedelic Therapy: A Rapid Review and Implications. Journal of Music Therapy., https://doi.org/10.1093/jmt/thaa006 Link to full text
Research into the basic effects and therapeutic applications of psychedelic drugs has grown considerably in recent years. Yet, pressing questions remain regarding the substances’ lasting effects. Although individual studies have begun monitoring sustained changes, no study to-date has synthesized this information. Therefore, this systematic review aims to fill this important gap in the literature by synthesizing results from 34 contemporary experimental studies which included classic psychedelics, human subjects, and follow-up latencies of at least two weeks. The bulk of this work was published in the last five years, with psilocybin being the most frequently administered drug. Enduring changes in personality/attitudes, depression, spirituality, anxiety, wellbeing, substance misuse, meditative practices, and mindfulness were documented. Mystical experiences, connectedness, emotional breakthrough, and increased neural entropy were related to these long-term changes in psychological functioning. Finally, with proper screening, preparation, supervision, and integration, limited aversive side effects were noted by study participants. Future researchers should focus on including larger and more diverse samples, lengthier longitudinal designs, stronger control conditions, and standardized dosages.
Aday, J. S., Mitzkovitz, C. M., Bloesch, E. K., Davoli, C. C., & Davis, A. K. (2020). Long-term effects of psychedelic drugs: A systematic review. Neuroscience & Biobehavioral Reviews., 10.1016/j.neubiorev.2020.03.017 Link to full text
There are few medications with demonstrated efficacy for the treatment of posttraumatic stress disorder (PTSD). Treatment guidelines have unequivocally designated psychotherapy as a first line treatment for PTSD. Yet, even after psychotherapy, PTSD often remains a chronic illness, with high rates of psychiatric and medical comorbidity. Meanwhile, the search and development of drugs with new mechanisms of action has stalled. Therefore, there is an urgent need to explore not just novel compounds, but novel approaches for the treatment of PTSD. A promising new approach involves the use of psychedelic drugs. Within the past few years, two psychedelics have received breakthrough designations for psychiatric indications from the US Food and Drug Administration, and several psychedelics are currently being investigated for the treatment of PTSD. This review discusses four types of compounds: 3,4-methylenedioxymethamphetamine (MDMA), ketamine, classical psychedelics (e.g. psilocybin and LSD) and cannabinoids. We describe the therapeutic rationale, the setting in which they are being administered, and their current state of evidence in the treatment of PTSD. Each compound provides unique qualities for the treatment of PTSD, from their use to rapidly target symptoms, to their use as adjuncts to facilitate psychotherapeutic treatments. Several questions are formulated that outline an agenda for future research.
Krediet, E., Bostoen, T., Breeksema, J., van Schagen, A., Passie, T., & Vermetten, E. (2020). Reviewing the Potential of Psychedelics for the Treatment of PTSD. International Journal of Neuropsychopharmacology., https://doi.org/10.1093/ijnp/pyaa018 Link to full text
Recent years have seen a renaissance of research into the use of psychedelic compounds to address various psychiatric conditions. The study of these substances went dormant in 1970 when the United States government passed the Controlled Substances Act, which categorized lysergic acid diethylamide, commonly known as LSD or acid, as a Schedule I drug. The rise of psychedelics in research settings raises questions regarding their risks outside of clinical trials. The available data on the impact of psychedelic use on interpersonal violence and other criminal behavior remain scant. Although Timothy Leary’s work of the 1960s failed to clearly demonstrate a reduction in criminal recidivism with psychedelic-assisted psychotherapy, recent studies suggest that the use of psychedelics may reduce individuals’ risk of interpersonal violence. Forensic psychiatrists should be aware of this research, as well as the role that psychedelics may play in various forensic assessments. This article summarizes basic information that the forensic practitioner should know about psychedelic substances, including their various effects and proposed mechanism of action; describes historical and recent research into psychedelics and criminal behavior; and offers evaluators a practical means by which to assess individuals’ psychedelic use in forensic contexts.
Holoyda, B. (2020). The Psychedelic Renaissance and Its Forensic Implications. The journal of the American Academy of Psychiatry and the Law, 48(1), 87-97., 10.29158/JAAPL.003917-20 Link to full text
5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) is a potent, fast-acting psychedelic. Anecdotal reports from 5-MeO-DMT users suggest that they employ a variety of benefit enhancement (BE) strategies aimed to increase positive effects and decrease any potential challenging effects of the substance, but no empirical study has investigated this claim. We examined the prevalence of BE strategy use using secondary data from a survey of 5-MeO-DMT users (n = 515; Mage = 35.4, SD = 11.7; Male = 79%; White/Caucasian = 86%). Results indicated that BE strategy use was common in this sample. As a secondary aim, we assessed whether the use of BE strategies was associated with acute subjective (i.e., mystical-type, challenging) and persisting effects of 5-MeO-DMT among a subset of respondents who reported using 5-MeO-DMT once in their lifetime (n = 116). Results showed that the use of several BE strategies were associated with significantly more intense mystical-type effects and enduring beliefs about the personal meaning and spiritual significance of their experience, and some BE strategies were associated with less intense or challenging experiences. Data suggests that BE strategies are commonly used, and that the use of BE strategies may be associated with increases in positive mystical-type and enduring effects. The causal influence of BE strategies on acute/persisting effects of 5-MeO-DMT should be examined in longitudinal research.
Lancelotta, R. L., & Davis, A. K. (2020). Use of benefit enhancement strategies among 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) users: Associations with mystical, challenging, and enduring effects. Journal of Psychoactive Drugs, 1-9.,10.1080/02791072.2020.1737763 Link to full text
The κ-opioid receptor has recently gained attention as a new molecular target in the treatment of many psychiatric and neurological disorders including epilepsy. Salvinorin A is a potent plant-derived hallucinogen that acts as a highly selective κ-opioid receptor agonist. It has unique structure and pharmacological properties, but its influence on seizure susceptibility has not been studied so far. Therefore, the aim of the present study was to investigate the effect of salvinorin A on seizure thresholds in three acute seizure tests in mice. We also examined its effect on muscular strength and motor coordination. The obtained results showed that salvinorin A (0.1-10 mg/kg, i.p.) did not significantly affect the thresholds for the first myoclonic twitch, generalized clonic seizure, or forelimb tonus in the intravenous pentylenetetrazole seizure threshold test in mice. Likewise, it failed to affect the thresholds for tonic hindlimb extension and psychomotor seizures in the maximal electroshock- and 6 Hz-induced seizure threshold tests, respectively. Moreover, no changes in motor coordination (assessed in the chimney test) or muscular strength (assessed in the grip-strength test) were observed. This is a preliminary report only, and further studies are warranted to better characterize the effects of salvinorin A on seizure and epilepsy.
Socała, K., Doboszewska, U., & Wlaź, P. (2020). Salvinorin A Does Not Affect Seizure Threshold in Mice. Molecules (Basel, Switzerland), 25(5), 1204. https://doi.org/10.3390/molecules25051204
Increasing prevalence and burden of major depressive disorder presents an unavoidable problem for psychiatry. Existing antidepressants exert their effect only after several weeks of continuous treatment. In addition, their serious side effects and ineffectiveness in one-third of patients call for urgent action. Recent advances have given rise to the concept of psychoplastogens. These compounds are capable of fast structural and functional rearrangement of neural networks by targeting mechanisms previously implicated in the development of depression. Furthermore, evidence shows that they exert a potent acute and long-term positive effects, reaching beyond the treatment of psychiatric diseases. Several of them are naturally occurring compounds, such as psilocybin, N,N-dimethyltryptamine, and 7,8-dihydroxyflavone. Their pharmacology and effects in animal and human studies were discussed in this article.
Benko, J., & Vranková, S. (2020). Natural Psychoplastogens As Antidepressant Agents. Molecules, 25(5), 1172., https://doi.org/10.3390/molecules25051172 Link to full text
The Old World has had its own remarkable history concerning psychedelic research – it was after all the continent where Albert Hofmann first discovered LSD and where Dutch professor Jan Bastiaans treated the trauma of Holocaust survivors with the same substance for many decades. Now, the psychedelic wave has washed ashore again in Europe, and we’re here to witness it first-hand. In this piece, we have attempted to give the most complete overview of the current wave of psychedelic science that’s happening on the European continent.
The past decade has seen a new wave of academic research into psychedelics – a fledgling but true renaissance of this scientific frontier. Currently, phase 2 trials are underway for the study of MDMA-assisted psychotherapy in the treatment of PTSD in Europe, psilocybin studies are underway in more than one nation, and multiple academic hubs facilitate growth of the field.
Below we summarize the experimental psychedelic studies in the fields of (clinical) psychology, psychiatry and neuroscience in Europe. Many of these studies are still young, and will take years to complete. Still, this decade will likely harbor historic moments in moving psychedelics into the mainstream in Europe – because psychedelics science has only just started scratching the surface of what’s possible.
In addition to the research carried out at these universities, two multi-site trials – sponsored by the non-profit organisation MAPS (mdma) and the for-profit Compass Pathways (psilocybin) – are underway in Europe, thereby involving various academic treatment centers in Europe in psychedelics research.
There are a few main research hubs in Europe where most of the psychedelics research is concentrated. At these locations, multiple studies below are performed.
Experimental research
Below we summarize the current European research into three psychedelic substances: LSD, psilocybin or mdma3.
Experimental research can be broken down into two basic categories. The first are the clinical trials, in which psychedelics are administered to patient populations. The other is neurobiological research, in which the effect of psychedelics on healthy participants are studied.
Of course, the field of psychedelic research is much broader and includes naturalistic, historical and qualitative research methods such as used in the social sciences and humanities. For lack of a central registry in which such studies are enlisted, it is harder to keep track of ongoing non-experimental (social scientific) research.
Clinical Studies 👩🏫First, let’s look at all the clinical studies that are going on.
LSD studies in Switzerland
“LSD is a Baseler product,” said Matthias Liechti to the Guardian about the most famous product from Basel, Switzerland. Liechti – a professor in clinical pharmacology at University Hospital Basel and speaker at ICPR 2020 – studies the effects of LSD on the human mind and body. “It’s tied to Basel’s history as a centre of pharmacology and innovation.”
How fitting that almost all research with LSD is taking place in the substance’s ‘place of birth’, Basel.
LSD as Treatment for Cluster Headache – University Hospital Basel
Cluster headaches are the most painful and debilitating form of headache, for which available medication often does not work sufficiently. LSD has been reported to abort cluster headache attacks and to decrease their frequency. Headed by lead investigator Professor Matthias Liechti and conducted by Yasmin Schmid, MD, this double-blind, placebo-controlled crossover study will administer LSD (or a placebo) to 30 patients suffering from cluster headaches. They will receive three doses of 100 micrograms within a three week period.
LSD Therapy for Major Depression – University Hospital Basel.
This study will test the efficacy of LSD therapy in patients with Major Depressive Disorder and is recruiting 60 patients. The treatment group will undergo two sessions with LSD (100 & 200 μg) and the control group will undergo two sessions with an active placebo (25 μg and 50 μg LSD). This study is lead by Prof. Dr. med. Stefan Borgwardt and has just started recruiting. It is estimated to be completed by the summer of 2023.
LSD Treatment for Anxiety in Severe Somatic Diseases – University Hospital Basel
In this study, 40 patients with an Anxiety Disorder will be given a single dose of LSD. Due to its cross-over within-subjects design, all patients will receive both a placebo dose and an active dose: 200 μg LSD. This study is a collaboration between University Hospital Basel and the private practice of Peter Gasser, MD, who is also the study’s principal investigator.
Imperial College in London has recently founded the world’s first Centre for Psychedelics Research
Psilocybin studies in Europe
About a third of all experimental studies with psilocybin are happening in Europe. All of the European psychedelic research hubs – University of Zurich, University Hospital Basel and Imperial College London – are currently involved in clinical or neurobiological research with psilocybin. Europe also hosts 11 of the 21 sites of the clinical study on psilocybin therapy for treatment resistant depression – for which its sponsor Compass Pathways was granted a breakthrough therapy status by the FDA in 2018. Clinical studies with patients:
Psilocybin vs Escitalopram for Major Depressive Disorder – Imperial College, London
This study is recruiting 50 patients suffering from depression in order to compare the efficacy and mechanisms of action of psilocybin with the SSRI Escitalopram. Principal investigator of this study is Professor David Nutt.
Clinical and Mechanistic Effects of Psilocybin in Alcohol Addicted Patients – University of Zurich
This study will test the efficacy of psilocybin for treating alcohol use disorder and study its underlying neurobiological mechanisms in a randomized, placebo controlled, double blind study. 60 participants are recruited for this study. Six weeks after undergoing a withdrawal treatment, they will either receive a single dose of placebo or a single dose of psilocybin (25 mg, orally). Dr. Katrin Peller is the principal investigator in this study.
The Safety and Efficacy of Psilocybin in Participants with Treatment Resistant Depression. This is a multi-site clinical trial with 21 study locations in North America and Europe, sponsored by the (for profit) organization Compass Pathways. The following European sites are involved in this study:
Enhed for Psykiatrisk Forskning, Psykiatrien i Aalborg – Aalborg, Denmark Tallaght University Hospital – Dublin, Ireland Groningen University Medical Centre – Groningen, the Netherlands Leiden University Medical Centre – Leiden, the Netherlands Utrecht University Medical Centre – Utrecht, the Netherlands Hospital de Dia Numancia – Barcelona, Spain Institute Hospital del Mar of Medical Research (IMIM) – Barcelona, Spain Clinical Research and Imaging Centre – Bristol, United Kingdom Wolfson Research Centre, Campus for Ageing and Vitality – Newcastle Upon Tyne, United Kingdom Kings College London, Institute of Psychiatry, Psychology and Neurology – London, United Kingdom Greater Manchester Mental Health Foundation Trust – Manchester, United Kingdom MDMA studies by MAPS
The Multidisciplinary Association for Psychedelics Studies from the United States -and headed by Rick Doblin- is planning phase 2 and phase 3 clinical trials to develop MDMA-assisted psychotherapy into an approved treatment for PTSD. In order to conduct part of these trials in Europe, MAPS has created a European-based subsidiary.
Six study sites in five European countries are involved in the “Open Label Multi-Site Study of Safety and Effects of MDMA-assisted Psychotherapy for Treatment of PTSD With Optional fMRI Sub-Study”:
Czechia – NUDZ – National Institute of Mental Health, Klecany
Norway – Sykehuset Østfold Hf, DPS Norder, Moss
Netherlands
Maastricht University, Dept of Neuropsychology and Psychopharmacology – Maastricht
Stichting Centrum ’45/Arq – Oestgeest
Portugal – Fundação de Anna de Sommer Champalimaud, Lisbon
United Kingdom – University Hospital of Wales – Research Facility, Cardiff
The University of Bristol and Imperial College London are collaborating in an ongoing study on mdma as a treatment for alcoholism. The “Bristol Imperial MDMA in Alcoholism Study (BIMA)” is an open label within-subject feasibility study in 20 patients with Alcohol Use Disorder who have recently undergone detoxification. The study is conducted by Ben Sessa, MD and its principal investigator is Professor David Nutt.
🧠 Studies into the psychedelic state itself
LSD AND PSILOCYBIN
Direct Comparison of Altered States of Consciousness Induced by LSD and Psilocybin – University Hospital Basel
Both LSD and psilocybin are used as pharmacological tools in neuroscience. However, there are no modern studies comparing these two substances directly within the same clinical study and using validated psychometric tools. In this study the researchers will compare the acute effects of LSD, psilocybin and placebo. 30 Healthy participants will be administered various dosages of these psychedelics, the effects of which will be measured with various assessment tools.The study is conducted by Friederike Holze and Professor Matthias Liechti.
Effects of Serotonin Transporter Inhibition on the Subjective Response to Psilocybin in Healthy Subjects – University Hospital Basel The aim of the study is to investigate the effects of psilocybin after Escitalopram and placebo pretreatment. Subjective and physiological effects as well as effects on gene expression will be assessed. This study is recruiting 24 healthy participants who will be pretreated with either Escitalopram or a placebo. On each of the 2 study days, participants will receive psilocybin 25 mg orally. Professor Matthias E. Liechti is the principal investigator in this study.
Comparative Acute Effects of LSD, Psilocybin and Mescaline –University Hospital Basel This study compares the acute effects of LSD, psilocybin, mescaline and placebo in a double-blind, placebo-controlled, 4-period cross-over design. In four separate sessions, the 25 healthy participants will receive 100 μg LSD, 20 mg psilocybin, 300 mg mescaline and a placebo. Professor Matthias E. Liechti is the principal investigator in all three of the above psilocybin studies taking place in Basel.
Beyond the Self and Back: Neuropharmacological Mechanisms Underlying the Dissolution of the Self – University of Zurich
In terms of the number of participants in a single study, this is currently the largest experimental study with psilocybin in Europe. 140 Healthy participants are divided into 4 groups, each with it’s own double-blind, placebo-controlled setup. One of the groups consists of long-term and short-term meditators during a 5-day group retreat. The aim of the study is to identify neural signatures, behavioral and phenomenological expressions of self-related processes.
Characterization of Altered Waking States of Consciousness in Healthy Humans– University of Zurich This study uses a combination of transcranial magnetic stimulation (TMS) and high density electroencephalography (hd-EEG) to measure the level of consciousness in a pharmacologically altered waking state of consciousness (induced by psilocybin).Lead investigator Professor Franz X. Vollenweider and his team are recruiting 25 healthy participants for this study.
MDMA and fear
University Hospital Basel is currently recruiting healthy participants for a study called “The Effect of MDMA (Serotonin Release) on Fear Extinction”. Fear extinction is a psychological process that plays a crucial role in treating disorders such as PTSD. Although MDMA has been shown to enhance the extinction of fear in animals, no data exists on the effect of MDMA on fear extinction in humans. The lead investigator in this study is Professor Matthias E. Liechti, MD.
Should you be interested in contributing to science by participating in a clinical/neuroimaging study: most of these studies are still recruiting. Look them up on this website to study their inclusion and exclusion criteria and to find out more.
This overview only covers the research that has been registered at clinicaltrials.gov and is therefore not exhaustive. Do you know of other ongoing experimental studies in Europe, feel free to reach out to us!
1 The FDA (Food and Drug Administration in the US) granted the label ‘breakthrough therapy’ to mdma-assisted psychotherapy for PTSD (sponsored by MAPS) in 2017. In 2018 the treatment of depression with psilocybin (sponsored by Compass Pathways) was granted the breakthrough therapy status, followed by a designation for the research by Usona in 2019, also for the treatment of major depression with psilocybin assisted therapy. 2 Of course there are other psychedelics, but for the scope of this article we focus on the most popular substances for clinical research. We also focus on trials that induce psychedelic effects – unlike for example many ketamine trials where sub-psychedelic dosages are used.
Psilocybin, an active component in “magic mushroom”, may have the potential to meet the therapeutic needs for a number of indications without the addictiveness and overdose risk of other mind-altering drugs, such as cocaine, heroin, alcohol, methamphetamine, and so forth. The need for new therapies is urgent because addiction, overdose, and suicide deaths have risen throughout the United States and around the world. Anecdotal and contemporary pharmacological reports have provided some indication about the therapeutic use of psilocybin for the treatment of mental health disorders such as major depressive disorder and addiction disorders. In this Viewpoint, I summarize the current state of psilocybin therapeutic research and attempt to provide some insight into future directions on which the scientific community may wish to focus.
Kargbo, R. B. (2020). Psilocybin Therapeutic Research: The Present and Future Paradigm. ACS Medicinal Chemistry Letters, 11(4), 399-402.; 10.1021/acsmedchemlett.0c00048
