Psychedelic Research Recap March 2022
As the first quarter of 2022 has come to an end, we continue to discover more about psychedelics and their therapeutic potential. March was another busy month for psychedelic research with notable publications including a direct comparison of the effects elicited by psilocybin and LSD, escalating doses of LSD were safely administered in a novel intervention paradigm, while MDMA was shown to reduce eating disorder symptoms in patients with PTSD.
You can find all the papers in our database and those that weren’t added in our March Link Overview.
Clinical Trials Continue to Yield Positive Results
March brought it with the results of various clinical trials as researchers continue to put psychedelics to the test. One of the most significant trials was a head-to-head comparison of the effects of psilocybin and LSD. In a separate study, LSD was found to be safe and well-tolerated when delivered in a streamlined version of psychedelic-assisted therapy, which could be more cost-effective for both patients and healthcare providers.
Led by Matthias Liechti, the team at the University of Basel compared the effects of psilocybin (15 & 30mg) and LSD (100 & 200µg) to placebo in healthy volunteers. Surprisingly the trial found that both doses of LSD and the high dose of psilocybin produced qualitatively and quantitatively very similar subjective effects, indicating that alterations of mind induced by LSD and psilocybin do not differ beyond the effect duration. The researchers concluded that any differences between LSD and psilocybin are dose-dependent rather than substance-dependent.
Using both an open-label and double-blind placebo-controlled design, researchers in this trial assessed the safety, tolerability, pharmacokinetics, and subjective effects of varying doses of LSD. Participants (n=32) received 50 (n = 3), 75 (n = 7), 100 (n = 3) LSDµg followed by 75 µg LSD (n = 9) 1 week apart, or a placebo followed by a 75 µg LSD (n = 10) one week apart. This Eleusis sponsored study used a novel intervention paradigm that was considered to be more scalable than the current PAP treatment protocols. Overall, LSD was found to be safe and well-tolerated within this paradigm.
The same research group conducted interviews with the trial participants to assess participants’ expectations, experiences, and thoughts on the safety and efficacy of the trial. Participants endorsed support for the clinical utility of LSD in controlled environments, expressing the belief that LSD is safe and has the potential to help others.
A study conducted by MAPS (n=90) used the Eating Attitudes Test (EAT-26) to assess the impact MDMA-assisted therapy has on symptoms of eating disorders (ED) in participants with PTSD. There was a significant reduction in total EAT-26 scores in the total group of PTSD participants following MDMA-AT versus placebo (p = .03). Overall, MDMA-AT significantly reduced ED symptoms compared to therapy with placebo among participants with severe PTSD.
In another randomised-controlled trial (n=330), the efficacy of low-dose ketamine (17.5mg/70kg) administered during caesarean section in preventing postpartum depression (PPD) was assessed. No significant differences were found in the prevalence of PPD between the active group and the placebo group at 3 days and 6 weeks after delivery. Pain scores were significantly different at 6 weeks only.
At the University of Maastricht, researchers assessed the effects of psilocybin (12mg/70kg) on measures of creative thinking (n=60). Psilocybin increased ratings of (spontaneous) creative insights while decreasing (deliberate) task-based creativity. Seven days after psilocybin, the number of novel ideas increased. It was found that the acute and persisting effects were predicted by within- and between-network connectivity of the default mode network.
What’s Going On in the Brain?
A trial (n=15) assessed the effects of LSD on a number of receptors in the brain, including the 5HT1a, 5HT1b, 5HT2a, D1 and D2 receptors. Receptor-enriched analysis of functional connectivity by targets (REACT) found that LSD produced differences in functional connectivity. The serotonergic and dopaminergic systems were associated with perceptual effects and perceived selfhood as well as cognition, respectively.
This neuroimaging study (n=18) used a novel Independent Component Analysis (ICA) approach and fMRI to examine psilocybin-induced changes in intrathalamic (within the thalamus) functional organisation and thalamocortical connectivity. Several intrathalamic components showed significant psilocybin-induced alterations in intrathalamic spatial organisation, localised mainly to the mediodorsal and pulvinar nuclei, and correlated with reported subjective effects.
This in vitro study assessed the effect neuroplastic and inflammatory effects of psilocybin. Findings suggest that psilocybin opens a window of plasticity that rapidly normalises while it reduced levels of tumour necrosis factor-alpha (TNF-α) secretion, demonstrating its anti-inflammatory effects.
This paper provides the first account of the interaction between pharmacological and psychological effects in psychedelic-assisted treatment. The paper builds on the previously proposed REBUS hypothesis and the contextual model of Wampold. It is assumed that psychedelics attenuate the precision of high-level predictions, making them more revisable by bottom-up input, and psychotherapy is an important source of such input.
Review Time
Researchers assess drug-drug interactions between MDMA or psilocybin and conventional psychiatric medications in this review. Publications of studies describe interactions between MDMA (n=24) or psilocybin (n=5) and medications from several psychiatric drug classes: adrenergic agents, antipsychotics, anxiolytics, mood stabilisers, NMDA antagonists, psychostimulants, and several classes of antidepressants.
Sam Gandy examines factors that contribute to the occurrence and intensity of mystical experiences and enhance their long-term benefits, including music, meditation and spiritual practices and nature-based settings. The review provides food for thought on these factors and more, and how they might be optimised to increase the chances of a mystical experience occurring.
A bibliometric review of 15 psychoactive drugs from 1960 to 2018 (956,703 publications) finds heterogeneous patterns of growth for the publications of the selected psychoactive drugs. The literature on legal substances and depressants represented between 60% and 80% throughout the years. Additionally, unexpected regional differences in the scientific output about the selected drugs were found, which might be explained by cultural and political phenomena.
The Costs, The Challenges & The Rest
Researchers at MAPS published two separate cost analyses of their Phase III trials using MDMA-assisted therapy (MDMA-AT) to treat PTSD. While MDMA-AT may have cost $11,537 per patient in the trial, the first publication finds that MDMA-AT generates discounted net health care savings of $132.9 million over 30 years when compared to the standard of care for 1,000 patients.
Their second paper uses a decision-analytic model to assess the cost and health benefits of expanded access to MDMA-AT. Expanding access to MDMA-AT to 25-75% of eligible patients was projected to avert 43,618-106,932 deaths and gain 3.3-8.2 million quality-adjusted life-years (QALYs).
There are a number of challenges inherent in clinical trials with psychedelics. In this paper, researchers discuss a number of these challenges, such as the design of individual research studies such as blinding, expectancy, the use of therapy and sources of bias. The broader researcher environment and issues related to evidence, funding and the current scheduling of psychedelics are just some of the other topics discussed.
At Johns Hopkins, researchers conducted a survey (n=1606) to address whether psychedelics change the attribution of consciousness to a range of living and non-living entities. There were large increases in the attribution of consciousness to various entities, including non-human primates (63–83%), quadrupeds (59–79%), insects (33–57%), fungi (21–56%) and plants (26–61%), to name a few. Higher ratings of mystical experience were associated with greater increases in the attribution of consciousness.
Another survey (n=2,150) assessed the associations between the amount of psychedelic use and behavioural outcomes, as well as the frequency of harms ascribed to psychedelic use. Psychedelic use was associated with significant improvements in depressive and anxious symptoms and with increased emotional well-being, and these improvements increased in magnitude with increasing psychedelic exposure.
In this paper, David Nichols discusses how he coined the term ‘entactogen’ for the pharmacological class of drugs that includes MDMA and other substances with similar psychopharmacological effects. Nichols details the chemistry underlying entactogens and how they differ from classical psychedelics such as psilocybin and LSD, and how the effects of MDMA differ from these psychedelics.
Papers Published in March 2022
36 studies from the Blossom database published this month.
Therapeutic Alliance and Rapport Modulate Responses to Psilocybin Assisted Therapy for Depression
In a randomised trial of psilocybin-assisted therapy for moderate–severe depression, stronger therapeutic alliance and pre-session rapport predicted larger emotional‑breakthrough and mystical‑type experiences and were associated with greater symptom reduction. Emotional breakthrough during the first session and mystical experience during the second differentially contributed to improvement, while alliance before the second session had an additional direct effect on endpoint depression.
A Single Belief-Changing Psychedelic Experience Is Associated With Increased Attribution of Consciousness to Living and Non-living Entities
In a retrospective survey of 1,606 respondents who reported a belief-changing psychedelic experience, participants reported large increases in attributing consciousness to a broad range of living and non‑living entities (e.g. non-human primates, plants, fungi, inanimate objects), with greater increases linked to higher ratings of mystical experience and persisting for years. Beliefs in free will and superstitions did not change, and the authors recommend prospective controlled studies to rule out expectancy effects.
Insights for the Use of Ketamine From Randomized Controlled Trials That Compared Ketamine With Electroconvulsive Therapy in Severe Depression
This review (2022) compared the effects of ketamine to electroconvulsive therapy (ECT) in depressed patients who had been initially referred for ECT. In two RCTs, ECT emerged as a clearly superior treatment with regard to response rate, remission rate, time to response, time to remission, and magnitude of improvement at the treatment endpoint. However, relapse rate and time to relapse did not differ between ECT and ketamine groups.
Entactogens: How the Name for a Novel Class of Psychoactive Agents Originated
The paper explains the coining of the term "entactogen" for MDMA-like drugs, arguing they are distinct from classical hallucinogenic phenethylamines by three structural features (an N‑methylated nitrogen, a reversal of stereochemical potency, and tolerance of an alpha‑ethyl substitution) and by a unique psychopharmacology characterised by prosocial, anxiolytic and introspective effects. It further summarises the established mechanism for MDMA as uptake via the neuronal serotonin transporter followed by carrier‑mediated release of stored serotonin.
Nitrous Oxide: an emerging novel treatment for treatment-resistant depression
This review (2021) explores the possibilities of using Nitrous Oxide (NO2) for treating treatment-resistant depression (TRD). The use of NO2 as a psychiatric intervention is discussed along with its possible mechanism of action. Its antidepressant effects are believed to be mediated through the NMDA receptor.
Psilocybin-Assisted Compassion Focused Therapy for Depression
This paper (2022) makes a case for using Compassion Focused Therapy (CFT) in tandem with psilocybin for the treatment of depression. The authors present a framework for using CFT as well as the rationale for selecting CFT, the compatibility of CFT and psilocybin-therapy, an overview of the psilocybin-assisted CFT protocol, the study protocol, and limitations to this approach.
Differential contributions of serotonergic and dopaminergic functional connectivity to the phenomenology of LSD
Using receptor‑enriched analysis of functional connectivity (REACT) on an open dataset (N=15), the study found that LSD alters FC maps associated not only with 5‑HT2A but also with 5‑HT1A, 5‑HT1B, D1 and D2 receptors, and that these changes correlate with distinct subjective components. Serotonergic receptor‑enriched FC related primarily to perceptual and selfhood alterations while dopaminergic receptor‑enriched FC related to cognitive effects, suggesting meaningful non‑5‑HT2A contributions to LSD's phenomenology.
Metabolomics and integrated network analysis reveal roles of endocannabinoids and large neutral amino acid balance in the ayahuasca experience
This study (n=23) assessed the human metabolomics signature after consumption of ayahuasca and its connection with both the psychedelic-induced subjective effects and the plasma concentrations of ayahuasca alkaloids. Compared to baseline, the consumption of ayahuasca increased N-acyl-ethanolamine endocannabinoids, decreased 2-acyl-glycerol endocannabinoids, and altered several large-neutral amino acids (LNAAs). Enrichment analysis confirmed dysregulation in several pathways involved in neurotransmission such as serotonin and dopamine synthesis.
Language as a Window Into the Altered State of Consciousness Elicited by Psychedelic Drugs
This review (2022) explores how the acute effects of psychedelic drugs impact speech organization regardless of its semantic content, and how to characterize the subjective effects of psychedelic drugs by analyzing the semantic content of written retrospective reports. It is suggested that researchers studying psychedelics can considerably expand the range of their potential scientific conclusions by analyzing brief interviews obtained before, during and after the acute effects.
Magic Mushroom Use: A Qualitative Interview Study of Post-Trip Impacts and Strategies for Optimizing Experiences
This study (2022) used interviews to shed light on how people use magic mushrooms, what they perceive the effects of such use to be, and the meanings that users attach to their magic mushroom experiences. Participants associated magic mushroom use with lasting impacts on their lives including transformation and learning experiences. Furthermore, participants described strategies to optimize their magic mushroom experiences, including engaging in research regarding magic mushrooms as well as making use of peer support.
Predictors and potentiators of psychedelic-occasioned mystical experiences
This review (2022) examines factors that contribute to the occurrence and intensity of mystical experiences and enhance their long-term benefits, including music, meditation and spiritual practices and nature-based settings. The review provides food for thought on these factors and more, and how they might be optimised to increase the chances of a mystical experience occurring, while also considering factors that are negatively associated with mystical experiences with suggestions on how these might be mitigated.
Towards psychedelic apprenticeship: Developing a gentle touch for the mediation and validation of psychedelic-induced insights and revelations
The authors argue that psychedelics’ tendency to confer strong noetic feelings can both facilitate therapeutic change and increase risk of iatrogenic harms (e.g. false memories), illustrated across therapeutic, neo‑shamanic and research settings. They propose a pragmatic “psychedelic apprenticeship” framework that emphasises culturally embedded, intersubjective validation and empathic resonance by experienced guides to mediate and validate psychedelic-induced insights.
How Low-Doses Of Psychedelics Compliment High Dose Experiences: Observational Evidence In Naturalistic Settings
This preprint (n=41) explores how people use low doses of psychedelics to complement high-dose therapeutic and spiritual experiences by conducting a secondary analysis of interviews from a private-sector wellness company that provides psychedelics educational materials and coaching. High-dose psychedelics are most often meaningful for belief re-appraisal and acute mental illness, while lose-dose experiences benefit behavioural change, relationship development, and managing episodic stress. Low dosing appears to help users “integrate” the existential and therapeutic insights from high doses by improving in-the-moment mindfulness of everyday challenges.
Reduced precision underwrites ego dissolution and therapeutic outcomes under psychedelics
This preprint (2021) argues that reductions to precision of belief updating underpin ego dissolution and that alterations to consciousness under psychedelics have a common mechanism of reduced precision of Bayesian belief updating. Connectivity changes in the cortex under the influence of psychedelics suggest that precision of Bayesian belief updating may be a mechanism to modify and investigate consciousness.
Repeated lysergic acid diethylamide (LSD) reverses stress-induced anxiety-like behavior, cortical synaptogenesis deficits and serotonergic neurotransmission decline
This rodent study (2022) assessed the effects of LSD administration on anxiety-like behaviour, on the cortical dendritic spines and on the activity of serotonin neurons in mice exposed to chronic restraint stress. LSD dose of 30 µg/kg (daily for 7 days) prevented the stress-induced anxiety-like behaviour and the stress-induced decrease of cortical spine density. LSD acutely decreased the firing activity of serotonin neurons, yet repeated LSD increased their basal firing rate and restored the low serotonin firing induced by stress. Overall, repeated LSD prevents the exacerbation of anxiety-like behaviour following chronic stress exposure, but has no behavioural effects in non-stressed mice.
Effects of Naturalistic Psychedelic Use on Depression, Anxiety, and Well-Being: Associations With Patterns of Use, Reported Harms, and Transformative Mental States
In a cross-sectional online survey of 2,510 adults, naturalistic psychedelic use was associated with significant reductions in depression and anxiety and increased emotional well‑being, with larger (but ceiling‑limited) benefits at greater exposure and detectable improvement after a single use. Thirteen per cent reported at least one harm (those individuals reported smaller benefits), no single psychedelic showed clear superiority, and increases in mystical‑type experiences and prosocial perspective‑taking were linked to better outcomes, suggesting potential real‑world mental health benefits alongside risk for a minority.
Psychedelic Cognition-The Unreached Frontier of Psychedelic Science
This paper (2022) reviews the current state of research regarding the effect psychedelics have on different aspects of cognition. The gaps regarding the acute effects psychedelics have on cognition are discussed as well as the findings related to how psychedelics impact memory, attention, reasoning, social cognition, and creativity.
Disintegrating and Reintegrating the Self - (In)Flexible Self-Models in Depersonalisation and Psychedelic Experiences
Using the Active Inference Framework, the paper argues that controlled alteration of prior expectations (as in psychedelic—and some meditative—states) permits flexible disintegration and reintegration of multisensory self-models, enhancing perceptual and sensorimotor plasticity; by contrast, depersonalisation reflects an uncontrolled, rigid disintegration that leaves individuals "stuck" and risks adverse clinical outcomes.
Psilocybin-Induced Mystical-Type Experiences are Related to Persisting Positive Effects: A Quantitative and Qualitative Report
In healthy volunteers given medium–high doses of psilocybin, greater acute mystical-type experiences (MEQ total score)—notably the Positive Mood and Mysticality subscales—were associated with persisting positive psychological effects at three months, whereas Transcendence of Time and Space and Ineffability were not. The paper also provides the first qualitative descriptions of complete mystical experiences after oral psilocybin, emphasising themes of cosmic connection, familial love and profound beauty.
How Psychedelic-Assisted Treatment Works in the Bayesian Brain
The paper proposes that psychedelics attenuate the precision of high-level predictions (REBUS), thereby amplifying psychotherapy’s common factors (set and setting) so that bottom-up input more readily revises maladaptive beliefs, accelerating therapeutic change and symptom relief.
Psilocybin Combines Rapid Synaptogenic And Anti-Inflammatory Effects In Vitro
In vitro, psilocybin rapidly induces synaptogenic changes in cultured mouse hippocampal neurons—upregulating Piccolo and Homer1 within 1–3 h and Synapsin‑1 peaking at 72 h—thereby opening a transient window of plasticity, and it also exerts anti‑inflammatory effects by reducing LPS‑induced TNF‑α secretion from microglial cells.
Drug-drug interactions between psychiatric medications and MDMA or psilocybin: a systematic review
This review (2022) explores the drug-drug interactions between MDMA or psilocybin and conventional psychiatric medications. Publications of studies describe interactions between MDMA (n=24) or psilocybin (n=5) and medications from several psychiatric drug classes: adrenergic agents, antipsychotics, anxiolytics, mood stabilizers, NMDA antagonists, psychostimulants, and several classes of antidepressants.
Perceptions of safety, subjective effects, and beliefs about the clinical utility of lysergic acid diethylamide in healthy participants within a novel intervention paradigm: Qualitative results from a proof-of-concept study
In a proof-of-concept study of 31 healthy participants given 50–100 µg LSD in a novel, more scalable intervention paradigm, most reported feeling safe, experienced transcendent/mystical-type effects—often enhanced by music—and credited the study structure and attendant support for their sense of safety. Participants broadly endorsed LSD’s clinical utility in controlled settings, providing preliminary evidence that this scalable approach is feasible and warrants further research in clinical populations.
Prospective examination of the therapeutic role of psychological flexibility and cognitive reappraisal in the ceremonial use of ayahuasca
In a prospective study of 261 participants at Shipibo ayahuasca retreats, ceremonial ayahuasca use produced significant reductions in negative mood and sustained increases in positive mood and psychological flexibility at three months, with acute in‑ceremony cognitive reappraisal exerting the strongest moderating effect. Increases in psychological flexibility statistically mediated the link between acute reappraisal and improved positive mood, suggesting acute reappraisal and post‑acute flexibility are putative mechanisms and supporting integration of third‑wave and mindfulness‑based approaches with psychedelic‑assisted interventions.
Role of 5-HT2A receptors in the effects of ayahuasca on ethanol self-administration using a two-bottle choice paradigm in male mice
This rodent study (2022) assessed the effects of ayahuasca on the expression of ethanol self-administration using a two-bottle choice test. Treatment with ayahuasca blocked the expression of ethanol self-administration, decreasing ethanol intake and preference during re-exposure tests. Pretreatment with the 5-HT2A receptor antagonist M100907 blocked the effects of ayahuasca on ethanol drinking without significantly attenuating ethanol self-administration.
Safety, tolerability, pharmacokinetics, and subjective effects of 50, 75, and 100 µg LSD in healthy participants within a novel intervention paradigm: A proof-of-concept study
This trial (n=32) assessed the safety, tolerability, pharmacokinetics, and subjective effects of 50, 75, and 100 µg LSD in healthy adults within a novel intervention paradigm. Participants received 50 (n = 3), 75 (n = 7), 100 (n = 3) LSD, 50 µg followed by 75 µg LSD (n = 9) 1 week apart, or placebo followed by a 75 µg LSD (n = 10) 1 week apart. No serious adverse events were reported, This data indicates that LSD is safe and well-tolerated with mild adverse events reported.
Presence, Trust, and Empathy: Preferred Characteristics of Psychedelic Carers
Analysing 403 forum posts, the study found that people who use psychedelics outside clinical settings prefer carers who demonstrate presence, trust and empathy. These user-derived insights largely support existing PAP guidelines but highlight “holding space” as a central practice and suggest nonclinical experience can help triangulate and extend treatment principles.
The challenges ahead for psychedelic ‘medicine’
This paper (2022) discusess a number of challenges inherent to psychedelic medicine including the challenges related to the design of individual research studies such as blinding, expectancy, the use of therapy and sources of bias. The broader researcher environment and issues related to evidence, funding and the current scheduling of psychedelics are just some of the other topic discussed.
The Costs and Health Benefits of Expanded Access to MDMA-assisted Therapy for Chronic and Severe PTSD in the USA: A Modeling Study
This study (2022) uses a decision-analytic model to assess the cost and health benefits of expanded access to MDMA-assisted therapy (MDMA-AT) in the phase III clinical trials from MAPS. Expanding access to MDMA-AT to 25-75% of eligible patients was projected to avert 43,618-106,932 deaths and gain 3.3-8.2 million quality-adjusted life-years (QALYs).
Virtual Reality as a Moderator of Psychedelic-Assisted Psychotherapy
The paper proposes virtual reality (VR) as a full‑spectrum adjunct to psychedelic‑assisted psychotherapy, arguing VR can catalyse and shape altered states of consciousness—supporting relaxation, sensory modulation, mystical‑type experiences and therapeutic alliance—and outlines specific VR models for integration. The authors caution the idea is currently speculative, list potential harms (sensory overstimulation, cyber‑sickness, retraumatisation, distraction) and call for rigorous, evidence‑based evaluation before clinical adoption.
Psilocybin induces spatially constrained alterations in thalamic functional organization and connectivity
Using a novel data-sparing ICA to subdivide the thalamus in resting-state fMRI, the study found that psilocybin produces spatially localised alterations in intrathalamic organisation—principally in the mediodorsal and pulvinar nuclei—that alter thalamocortical connectivity with visual and default-mode networks and correlate with subjective effects. These focal decreases, which may offset modest widespread increases detected by whole-thalamus analyses, were not apparent when the thalamus was treated as a single unit.
A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings
This retrospective analysis (n=537) assessed the effectiveness of intravenous ketamine therapy in community-based practices i.e real-world care settings. Over half of the participants showed a response at 14-31 days post-infusion and 28.9% remitted while 73% exhibited a reduction in suicidal ideation. However, remission status was weakly inversely correlated with depression severity.
Beating Pain with Psychedelics: Matter over Mind?
This review (2021) makes the case for using psychedelics to treat pain. Key areas discussed include studies that have directly used psychedelics to treat pain, potential neuro-restorative effects of psychedelics in pain-related states of consciousness, anti-neuroinflammatory and pro-immunomodulatory actions of psychedelics and the safety, legal, and ethical consideration inherent in psychedelics’ pharmacotherapy. Psychedelics could also help to elucidate the mechanism of pain syndromes.
Comparative effectiveness of repeated ketamine infusions in treating anhedonia in bipolar and unipolar depression
This open-label study (n=97) investigated the effects of six intravenous ketamine infusions (35mg/70kg) on anhedonia (the inability to feel pleasure) in patients with major depressive disorder (MDD) (n=77) or bipolar depression (BD) (n=20). A significant reduction in the MADRS anhedonia subscale score was observed at 4hrs after the first infusion and was maintained with repeated infusions. Reductions were similar in both MDD and BD groups.
Ketamine Modulates the Neural Correlates of Reward Processing in Unmedicated Patients in Remission from Depression
This double-blind, placebo-controlled study (n=37) found that ketamine improved responses to rewards two hours after depressed patients had received ketamine (35mg/70kg) treatment. This correlated with neurological observations (increases in activation of NAc, the putamen, the insula, and the caudate).
Oral ketamine reduces the experience of stress in people with chronic suicidality
This open-label study (n=32) investigated the efficacy of weekly oral ketamine (35-210 mg/70 kg) for reducing stress in adults with chronic suicidality. Results indicate that ketamine produced a robust and clinically significant reduction in self-reported stress, which was sustained in a subgroup of participants during the four-week follow-up.