The development of chronic pain is a complex mechanism that is still not fully understood. Multiple somatic and visceral afferent pain signals, when experienced over time, cause a strengthening of certain neural circuitry through peripheral and central sensitization, resulting in the physical and emotional perceptual chronic pain experience. The mind-altering qualities of psychedelics have been attributed, through serotonin 2A (5-HT2A) receptor agonism, to ‘reset’ areas of functional connectivity (FC) in the brain that play prominent roles in many central neuropathic states. Psychedelic substances have a generally favorable safety profile, especially when compared with opioid analgesics. Clinical evidence to date for their use for chronic pain is limited; however, several studies and reports over the past 50 years have shown potential analgesic benefit in cancer pain, phantom limb pain and cluster headache. While the mechanisms by which the classic psychedelics may provide analgesia are not clear, several possibilities exist given the similarity between 5-HT2A activation pathways of psychedelics and the nociceptive modulation pathways in humans. Additionally, the alterations in FC seen with psychedelic use suggest a way that these agents could help reverse the changes in neural connections seen in chronic pain states. Given the current state of the opioid epidemic and limited efficacy of non-opioid analgesics, it is time to consider further research on psychedelics as analgesics in order to improve the lives of patients with chronic pain conditions.
Castellanos, J. P., Woolley, C., Bruno, K. A., Zeidan, F., Halberstadt, A., & Furnish, T. (2020). Chronic pain and psychedelics: a review and proposed mechanism of action. Regional Anesthesia & Pain Medicine., http://dx.doi.org/10.1136/rapm-2020-101273 Link to full text
Psychedelic substances are currently experiencing a renaissance in interest for both therapeutic as well as recreational applications. It has been proposed that microdosing, i.e., ingesting sub-perceptual doses of a psychedelic, could confer some of the benefits of these substances to users while minimizing the risks associated with full-dose use. This review aimed to summarize and examine the extant literature on psychedelic microdosing. Exploratory evidence published to date indicates a variety of benefits reported by microdosers including improvements in mood, focus, and creativity, with some null reports, and a minority of people reporting selective negative consequences such as increased anxiety and physiological discomfort. Methodological limitations of current evidence, however, make definitive conclusions hard to draw. Recommendations for future research are given.
Bornemann, J. (2020). The Viability of Microdosing Psychedelics as a Strategy to Enhance Cognition and Well-being-An Early Review. Journal of Psychoactive Drugs, 1-9., https://doi.org/10.1080/02791072.2020.1761573 Link to full text
Psilocybin is being developed for treating major depressive disorder. Psilocybin is readily dephosphorylated to psilocin upon absorption. The potential for psilocin proarrhythmic effect was assessed using a concentration-QTc interval (C-QTc) analysis from an open-label single ascending dose study of psilocybin. Psilocybin doses ranged from 0.3 to 0.6 mg/kg. This trial showed a significant but shallow C-QTc relationship. At the clinical dose of 25 mg, the mean psilocin maximum concentration is 18.7 ng/mL, and the associated mean (upper 90% confidence interval of mean) QTcF change is 2.1 (6.6) milliseconds. Given the short half-life of psilocin of about 4 hours, there would be no accumulation after monthly oral doses used in clinical trials. The upper limit of the 90% confidence interval of the model-predicted mean ΔQTcF crossed 10 milliseconds at a psilocin concentration of 31.1 ng/mL. At a supraclinical psilocin maximum concentration of about 60 ng/mL, ΔQTcF remains low, with a mean (upper limit of the 90% confidence interval) of 9.1 (17.9) milliseconds. This analysis enabled the characterization of the C-QTc relationship and prediction of QTc prolongation at the expected clinical and possible higher psilocybin doses.
Dahmane, E., Hutson, P. R., & Gobburu, J. V. (2020). Exposure‐Response Analysis to Assess the Concentration‐QTc Relationship of Psilocybin/Psilocin. Clinical Pharmacology in Drug Development.; 10.1002/cpdd.796
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
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
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
This post hoc analysis assessed the benefit-risk profile of esketamine nasal spray + oral antidepressant (AD) induction and maintenance treatment in patients with treatment-resistant depression (TRD). The Benefit-Risk Action Team framework was utilized to assess the benefit-risk profile using data from three induction studies and one maintenance study. Benefits were proportion of remitters or responders in induction studies and proportion of stable remitters or stable responders who remained relapse-free in the maintenance study. Risks were death, suicidal ideation, most common adverse events (AEs), and potential long-term risks. Per 100 patients on esketamine + AD vs. AD + placebo in induction therapy, 5-21 additional patients would remit and 14-17 additional patients would respond. In maintenance therapy, 19-32 fewer relapses would occur with esketamine. In both cases, there was little difference in serious or severe common AEs (primarily dissociation, vertigo, and dizziness). These findings support a positive benefit-risk balance for esketamine + AD as induction and maintenance treatment in patients with TRD.
McIntyre, R. S., Rosenblat, J. D., Nemeroff, C. B., Sanacora, G., Murrough, J. W., Berk, M., … & Stahl, S. (2021). Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation. American Journal of Psychiatry, appi-ajp., https://doi.org/10.1002/cpt.2024 Link to full text
Psilocybin has shown promise as a treatment for depression but its therapeutic mechanisms are not properly understood. In contrast to the presumed actions of antidepressants, we recently found increased amygdala responsiveness to fearful faces one day after open-label treatment with psilocybin (25 mg) in 19 patients with treatment-resistant depression, which correlated with treatment efficacy.
AIMS:
Aiming to further unravel the therapeutic mechanisms of psilocybin, the present study extends this basic activation analysis. We hypothesised changed amygdala functional connectivity, more precisely decreased amygdala-ventromedial prefrontal cortex functional connectivity, during face processing after treatment with psilocybin.
METHODS:
Psychophysiological interaction analyses were conducted on functional magnetic resonance imaging data from a classic face/emotion perception task, with the bilateral amygdala and ventromedial prefrontal cortex time-series as physiological regressors. Average parameter estimates (beta weights) of significant clusters were correlated with clinical outcomes at one week.
RESULTS:
Results showed decreased ventromedial prefrontal cortex-right amygdala functional connectivity during face processing post- (versus pre-) treatment; this decrease was associated with levels of rumination at one week. This effect was driven by connectivity changes in response to fearful and neutral (but not happy) faces. Independent whole-brain analyses also revealed a post-treatment increase in functional connectivity between the amygdala and ventromedial prefrontal cortex to occipital-parietal cortices during face processing.
CONCLUSION:
These results are consistent with the idea that psilocybin therapy revives emotional responsiveness on a neural and psychological level, which may be a key treatment mechanism for psychedelic therapy. Future larger placebo-controlled studies are needed to examine the replicability of the current findings.
Mertens, L. J., Wall, M. B., Roseman, L., Demetriou, L., Nutt, D. J., & Carhart-Harris, R. L. (2020). Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression. Journal of Psychopharmacology, 10.1177/0269881119895520 Link to full text
16 May - Pathway to Access Summit | Pre-event Online Q&A
