Psychedelic Research Recap September 2023
Psychedelic Research Recap September 2023
In September 2023, the second Phase III study from MAPS was published, showing more than 2/3rd of those treated with MDMA-assisted psychotherapy no longer met DSM-5 criteria for PTSD. With 104 participants, the study complements the first Phase III study and marks the transition to the next step in psychedelic research, the FDA approval process.
Next to MAPS’ landmark study, we were also treated to the largest prospective survey of people using psychedelics outside the clinical setting. In settings outside the lab, respondents generally found benefits such as reduced alcohol misuse, better emotional regulation, and improved spiritual well-being. The data could serve as a counterpoint towards recent negative news around self-experimentation with psychedelics.
September was another productive month for psychedelic research, with 25 articles (and full summaries for paying members) added to the database (nearing 2000 articles). In this recap, we also cover exciting news about psychedelics and our immune system, the surprising similarity between MDMA and methamphetamine, and how to prevent history from repeating itself.
For all the latest papers, check out our database and those that weren’t added in our September Link Overview.
The Final Clinical Step for MDMA-assisted Therapy
The long-awaited second Phase III clinical trial provides further evidence that MDMA-assisted therapy (MDMA-AT) can significantly reduce symptoms of post-traumatic stress disorder (PTSD). The randomized, placebo-controlled trial involved 104 participants with moderate to severe PTSD. After three sessions of MDMA-AT or placebo plus therapy, the MDMA group showed significantly greater reductions in PTSD symptoms on the CAPS-5 scale and functional impairment on the Sheehan Disability Scale.
Remarkably, 86.5% of the MDMA group showed a clinically meaningful response, and 71.2% no longer met diagnostic criteria for PTSD after treatment. MDMA-AT was also well-tolerated, with mostly mild to moderate side effects reported. Though a history of suicide risk was common, suicidal ideation did not increase with MDMA treatment.
The results support and extend previous Phase II and III(a) trials showing MDMA-AT can provide lasting relief for PTSD when combined with therapy. The data from the Phase III trials will now go to the FDA, which is expected to come back with a decision in late 2024. This marks the final clinical step and the start of a thousand more steps between these positive results and MDMA-AT’s eventual (relatively) widespread availability.
Further down the line, MDMA-AT might become an available treatment for adolescents. A focus group study with 19 participants found generally unfavourable attitudes from parents, clinicians, and youth. Still, after explaining the therapy, all but one person supported its potential use. Studies with ketamine and adolescents, of which one was published last month, generally find no unexpected adverse effects (e.g. on cognition).
Naturalistic Psilocybin Use Outcomes
An extensive survey of people using psilocybin mushrooms in naturalistic settings found persisting improvements in symptoms of anxiety, depression, and alcohol misuse after psilocybin use. Participants also reported increased well-being, spirituality, cognitive flexibility, and extraversion after psilocybin. However, a minority (11% in the weeks after) experienced persistent adverse effects like mood fluctuations. This is the most extensive prospective study of naturalistic psilocybin use, adding to evidence of the therapeutic potential while highlighting the importance of safeguards.
A smaller survey and interview study dove into the long-term negative effects of psychedelics. The study identified potential causal factors, such as unsafe or complex environments during or surrounding the experience, prior psychological vulnerabilities, high or unknown drug quantities, and young age.
Other recent psychedelic studies further demonstrate shifting attitudes and insights. A 7-year follow-up survey showed a significant positive change in American psychiatrists’ opinions about psychedelics. In 2016, only 29% expressed belief in the therapeutic potential of psychedelics, but that rose to 81% in 2023. Acceptance is growing, but risks remain.
One survey linked psychedelic use to greater belief in alternative facts, especially around politics, though psychedelic users did not favour intuition over evidence. As we expand access, education on benefits and risks is essential.
This is How the Cookie Crumbles
Doing psychedelic science is hard. Funding is difficult, treatment is intensive, and bias is pervasive. Michiel van Elk and Eiko Fried identify ten pressing problems facing the field, grouped into easy, moderate, and complex issues. Taking a sample from the moderate problems, the researchers talk about – well – sample size (generally relatively small), selection bias, and the lack of long-term follow-up. The checklist provided in the article serves as an excellent summary of their recommendations.
Still, progress has been made in psychedelic research. One helpful set of tools has been the introduction of neuroimaging. An article we previously covered as a pre-print now reviews the landscape and highlights PET and (f)MRI’s contributions to the field. At the same time, much discussion still exists around the exact mechanisms that psychedelics work through.
One of the proposed mechanisms that psychedelics work through is by improving neuroplasticity. A viewpoint article tries to pinpoint the definition of neuroplasticity. Yet, it shows that it can mean many things, and one should be wary of using it without defining the term. Another commentary takes a different route, investigating the neurobiological mechanisms underlying meaningfulness induced by psychedelics.
The Psychedelic Experiments from September 2023
A double-blind study with 60 healthy volunteers investigated the effects of psilocybin on a range of inflammatory markers associated with stress-related psychiatric disorders. Psilocybin immediately reduced levels of the inflammation-inducing TNF-α while other markers were unchanged. After seven days, TNF-α returned to baseline while levels of IL-6 and CRP were reduced in the psilocybin group, which were associated with more persisting positive mood and social effects.
What is the influence of MDMA on feeling connected with someone else? Researchers found that, versus placebo, there was a stronger connection with MDMA, which correlated with raised oxytocin levels. Interestingly, in another group, the researchers looked at the effects of methamphetamine (meth) versus placebo and also found an increase in connectedness. This time, there was no correlation with oxytocin levels (which were still raised). Though MDMA is currently uniquely being researched as an ’empathogen’, the study shows that other drugs – generally considered the ‘bad’ ones – can also enhance feelings of connectedness.
An open-label study with psilocybin-assisted therapy for alcoholism found that showing a nature-themed video during the sessions was safe and didn’t lead to negative outcomes. The researchers also suggest that it could reduce cardiovascular risks, but with an open-label design and only 20 participants, it’s hard to conclude much from the study.
All Other Psychedelic Studies of September 2023
With 25 articles added (and 76 more in our link overview), there is too much to talk about in detail, so here is a quick primer on the other studies: A study compared ayahuasca users in Sante Daime and neo-shamanic groups and found some participant differences (e.g. on personality).
Treating veterans (SOFV) in Mexico with ibogaine and 5-MeO-DMT is once again shown to be effective in reducing PTSD symptoms and improving quality of life. Another study investigated what factors predicted outcomes in the study group.
Predicting if someone will respond to therapy could be a good way to stop unnecessary future treatments. One study looked at 50 participants being treated with esketamine and found that after two sessions, the depression score (MADRS) predicted the 90-day response with 80% accuracy.
A 7-year follow-up to a survey of psychiatrists’ attitudes towards psychedelics finds them being much more receptive than in 2016.
Experts were consulted about the exclusion of those with psychotic disorders from psychedelic research and generally agreed that without support, it would be unwise to include them. Still, they agreed that PAT might benefit some in this group.
Lately, there haven’t been many developments in the group model of psychedelic-assisted therapies. A study on Indigenous elders and ketamine therapy highlights challenges and possible benefits.
A mice study with DPT finds that it can prevent seizures in a mouse model of Fragile X Syndrome.
Infusing DMT to achieve a certain psychedelic intensity has been recently achieved after years of speculation. The infusion protocol has now been published.
Papers Published in September 2023
28 studies from the Blossom database published this month.
Alternative beliefs in psychedelic drug users
In a sample of 392 participants (233 with lifetime psychedelic use), the study found a moderate positive association between psychedelic use and endorsement of "alternative facts" and the belief that facts are politically influenced, while no link was observed for preferring intuition over evidence and alcohol use was negatively associated with alternative‑fact beliefs. The authors interpret this as evidence that psychedelic use correlates with non‑conformist thinking styles, which may reflect drug effects or pre‑existing unconventional belief traits.
Mechanisms and molecular targets surrounding the potential therapeutic effects of psychedelics
This review (2023) discusses the investigation of psychedelics for their therapeutic potential in neuropsychiatric and substance use disorders. Clinical trials have shown promise in alleviating symptoms of depression, anxiety, and reducing nicotine and alcohol use. The underlying molecular mechanisms for these therapeutic effects are not yet fully understood, with ongoing preclinical studies exploring the role of serotonin 5-HT2A receptors and other pathways.
Neuroimaging in psychedelic drug development: Past, present, and future
This review (2023) discusses the emerging field of psychedelic therapy for psychiatric disorders, emphasizing the potential of classic serotonergic psychedelics like psilocybin and LSD and substances like ketamine, MDMA, and ibogaine. It highlights the role of advanced neuroscientific research methods, particularly neuroimaging using Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI), in advancing the understanding of drug and therapy effects on the brain. The article identifies key knowledge gaps, including the relationship between acute and longer-term effects, the precise characterization of effects at the 5-HT2A receptor, and the impact of these compounds on neuroplasticity, and proposes a roadmap for future research to address these questions through multimodal PET/MRI studies.
A suite of engineered mice for interrogating psychedelic drug actions
The authors generated a suite of engineered Htr2a mouse lines—including an Htr2a‑EGFP‑CT‑IRES‑CreERT2 reporter, a humanised Htr2a line and a constitutive Htr2a‑Cre line—that enable independent visualisation of HTR2A receptors and HTR2A‑expressing cells and provide detailed anatomical and cell‑type maps. They validated the lines with psychedelic‑induced behavioural phenotypes and electrophysiology showing extracellular 5‑HT produces an HTR2A‑mediated increase in firing of genetically identified pyramidal neurons, consistent with plasma‑membrane localisation and utility for in vivo studies of psychedelic drug actions.
Ayahuasca, Personality and Acute Psychological Effects in Neo-Shamanic and Religious Settings in Uruguay
This study (n=44) analyzed Uruguayan ayahuasca users in neo-shamanic and Santo Daime groups through chemical tests, ethnography, and psychometrics. Santo Daime participants scored lower in certain personality traits, possibly due to the neo-shamanic group's treatment or Santo Daime's religious framework. The neo-shamanic group had higher scores in Somesthesia and Perception, likely due to their high-arousal rituals.
Case analysis of long-term negative psychological responses to psychedelics
The study documents multiple cases of lasting negative psychological responses (≥72 h) after classic psychedelics or MDMA, finding new or worsened psychiatric symptoms—predominantly anxiety—and, from in‑depth interviews, implicating unsafe/complex settings, unpleasant acute experiences, prior vulnerabilities, high or unknown doses and young age as common contributing factors. These findings corroborate the reality of iatrogenic mental health harms following psychedelic use but, given the selective small sample and study design, cannot be used to estimate prevalence.
History repeating: guidelines to address common problems in psychedelic science
This critical review (2023) examines the challenges currently facing psychedelic research, which has seen a surge of interest in recent years for its potential in treating mental disorders. The paper identifies ten pressing challenges, categorized into easy, moderate, and hard problems, that threaten the validity of key findings in this field. These challenges encompass issues related to internal validity, external validity, construct validity, and statistical conclusion validity, which collectively limit the ability to draw definitive conclusions about the safety and efficacy of psychedelic therapy. The paper also offers a roadmap for addressing these challenges.
Drug-induced social connection: both MDMA and methamphetamine increase feelings of connectedness during controlled dyadic conversations
In controlled semi‑structured dyadic conversations, both MDMA (100 mg) and methamphetamine (20 mg) increased participants' feelings of connectedness relative to placebo. Both drugs elevated oxytocin, but only MDMA's oxytocin increase correlated with subjective closeness, indicating similar behavioural effects may arise from different neuroendocrine mechanisms and demonstrating a sensitive method for measuring pro‑social drug effects in person.
Open-label study of consecutive ibogaine and 5-MeO-DMT assisted-therapy for trauma-exposed male Special Operations Forces Veterans
This open-label study (n=86) examined the effectiveness of psychedelic-assisted therapy (PAT) among trauma-exposed Special Operations Forces Veterans (SOFV) in Mexico. Results indicated significant improvements in self-reported PTSD symptoms, depression, anxiety, insomnia severity, post-concussive symptoms, satisfaction with life, psychological flexibility, and cognitive functioning from baseline to one-month follow-up. The combination of ibogaine and 5-MeO-DMT assisted therapy showed potential for providing rapid and lasting improvements in mental health functioning, with effects observed up to six months after treatment.
Early effects predict trajectories of response to esketamine in treatment-resistant depression
This longitudinal study (n=50, confirmatory sample n=55) investigated the use of esketamine in patients with treatment-resistant depression (TRD) and aimed to define distinct response trajectories. The study identified two classes, one representing response and the other non-response, influenced by factors like concomitant benzodiazepine medication, number of depressive episodes, or polarity. After two esketamine administrations, the depression score (MADRS) predicted the 90-day response trajectory with 80% accuracy, suggesting clinicians could use MADRS scores to decide whether to continue treatment in TRD patients.
Expert Opinion on Psychedelic-Assisted Psychotherapy for People with Psychopathological Psychotic Experiences and Psychotic Disorders
This expert consultation study (n=12) investigated the exclusion of individuals with personal or familial histories of psychopathological experiences from most psychedelic clinical trials and treatment programs. Experts in psychiatry, clinical psychology, medicine, and psychedelics were interviewed, and the findings revealed that exclusion criteria may be justified in studies with minimal psychological support. They agreed that psychedelic-assisted psychotherapy, as well as therapy with MDMA and ketamine, might be beneficial for some individuals within this group.
Naturalistic psilocybin use is associated with persisting improvements in mental health and wellbeing: results from a prospective, longitudinal survey
In the largest prospective longitudinal survey to date of naturalistic psilocybin use (n=2,833 baseline; 657 at 2–3 months), participants reported sustained reductions in anxiety, depression and alcohol misuse and increases in cognitive flexibility, emotion regulation, spiritual wellbeing and adaptive personality traits after a planned psilocybin experience. A minority (11% at 2–4 weeks; 7% at 2–3 months) reported persisting negative effects such as mood fluctuations or depressive symptoms.
Dynamic Functional Hyperconnectivity after Psilocybin Intake is Primarily Associated with Oceanic Boundlessness
In healthy volunteers given psilocybin, ultra-high field fMRI revealed a recurrent hyperconnected, low‑BOLD‑amplitude brain state reflecting increased cortical arousal and overall functional connectivity. Transition probabilities into this hyperconnected pattern were linked primarily to feelings of oceanic boundlessness (and secondarily to visionary restructuralization), providing a first direct neurophenomenological association between dynamic brain states and psychedelic experience.
Indigenous Voices in Psychedelic Therapy: Experiential Learnings from a Community-Based Group Psychedelic Therapy Program
This pilot program (n=8, +2 Elders) explored the effectiveness and safety of group-based therapy augmented by three sessions of ketamine at a psychedelic dose for Indigenous participants in partnership with Roots to Thrive and the Snuneymuxw First Nation. Thematic analysis of qualitative interviews and feedback revealed participant motivations, perceived barriers, program benefits, and psychedelic experiences. Participants emphasized the importance of Indigenous team members, incorporating traditional healing approaches, and fostering authentic relationships between participants and facilitators, highlighting both challenges and significant program benefits. The article underscores the need for reconciliation efforts within and beyond psychedelic therapies.
Nature-themed video intervention may improve cardiovascular safety of psilocybin-assisted therapy for alcohol use disorder
In a pilot randomised controlled trial of 20 participants with alcohol use disorder, viewing a nature-themed "Visual Healing" video during preparation and the ascent/descent phases of 25 mg psilocybin sessions was feasible, safe and well tolerated. Compared with standard procedures (eyeshades and music), Visual Healing significantly attenuated peak post‑psilocybin blood pressure increases while producing similar psychedelic effects and reductions in alcohol use.
The Psychedelic N,N-Dipropyltryptamine Prevents Seizures in a Mouse Model of Fragile X Syndrome via a Mechanism that Appears Independent of Serotonin and Sigma1 Receptors
This mouse study investigated the effects of N,N-dipropyltryptamine (DPT), a psychedelic tryptamine, on audiogenic seizures in a mouse model of fragile X syndrome (genetic cause of autism). DPT was found to prevent seizures at a 10 mg/kg dose completely but not at lower doses (3 or 5.6 mg/kg). Despite being a serotonin receptor agonist, the antiepileptic effects of DPT were not mediated through specific serotonin receptor subtypes (5-HT2A, 5-HT1B, or 5-HT1A), nor through sigma1 receptors.
MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial
This multi-site, randomised, double-blind, Phase IIIb trial (n=104) evaluated the efficacy and safety of MDMA-assisted therapy (MDMA-AT) for individuals with moderate to severe PTSD. The study found significant reductions in PTSD severity (CAPS-5 score) and functional impairment (SDS score) for the MDMA-AT group compared to placebo with therapy. Seven participants experienced severe treatment-emergent adverse events, but no deaths or serious adverse events were reported. The treatment was found to be generally well tolerated in a diverse population.
Short-term cognitive effects of repeated-dose esketamine in adolescents with major depressive disorder and suicidal ideation: a randomized controlled trial
In a randomised controlled trial of 51 adolescents with major depressive disorder and suicidal ideation, three subanaesthetic esketamine infusions (0.25 mg/kg) did not impair cognition and were associated with improved processing speed and some improvement in working memory by Day 12. Baseline cognitive performance did not predict antidepressant or antisuicidal response.
Longitudinal and transcultural assessment of the relationship between hallucinogens, well-being, and post-traumatic growth during the COVID-19 pandemic
In a longitudinal, multilingual online study begun during the COVID‑19 peak, regular users of hallucinogens reported higher psychological well‑being, lower psychopathology and greater post‑traumatic growth (even among those with higher distress) than non‑users. Findings were culturally heterogeneous — with more English‑speaking regular users — suggesting further research on hallucinogens’ role in large‑scale catastrophes.
Neuroplasticity: The Continuum of Change
This viewpoint (2023) explores the concept of neuroplasticity, which is increasingly used in mainstream discourse to describe how the brain responds to various stimuli. Neuroplasticity is a complex concept encompassing molecular, cellular, and circuit-level changes and their impact on human behaviour. The article aims to comprehensively understand neuroplasticity by engaging experts from various scientific disciplines. It emphasizes its relevance in healthy and diseased conditions, highlighting its importance in chemical neuroscience.
Optimized infusion rates for N,N-dimethyltryptamine to achieve a target psychedelic intensity based on a modeling and simulation framework
This study designed an infusion protocol for DMT using pharmacokinetic/pharmacodynamic modelling. Comparing a continuous variable model to two bounded integer models, optimal doses for desired psychedelic intensity were identified. However, achieving consistent target intensity was challenging across models, indicating individual dose adjustments might be needed. Differences between models were especially notable at the scale's boundaries.
Predictors of psychedelic treatment outcomes among special operations forces veterans
This prospective study (n=86) examined the effects of ibogaine and 5-MeO-DMT treatment on U.S. Special Operations Forces Veterans with trauma exposure. Younger age and higher baseline levels of depression and anxiety were correlated with significant improvements in mental and psychosocial outcomes from baseline to 1-month follow-up. Greater intensity of changes in consciousness was linked to improved long-term mental health and psychosocial outcomes up to 6 months post-treatment.
Pharmacokinetics, pharmacodynamics and urinary recovery of oral lysergic acid diethylamide (LSD) administration in healthy participants
In 28 healthy volunteers given 85 or 170 μg oral LSD, pharmacokinetic–pharmacodynamic modelling showed dose‑proportional pharmacokinetics with mean Cmax 1.8 and 3.4 ng/mL at ~1.7 h, elimination half‑lives of ~3.7–4.0 h, and dose‑dependent subjective effects lasting ~9–11 h. The drug was extensively metabolised with only ~1% recovered unchanged and ~16% as 2‑oxo‑3‑hydroxy‑LSD in urine over 24 h, validating prior findings and providing the first detailed urinary recovery data.
Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial
In a randomised, double‑blind phase 2 trial of 104 adults with moderate-to-severe major depressive disorder, a single 25 mg dose of psilocybin with psychological support produced significantly greater and sustained reductions in depressive symptoms (MADRS mean difference −12.3 at day 43) and functional disability versus niacin placebo. No serious treatment‑emergent adverse events were reported, although psilocybin was associated with higher overall and severe adverse event rates.
Acute mood-elevating properties of microdosed LSD in healthy volunteers: a home-administered randomised controlled trial
This placebo-controlled, randomised, naturalistic study (n=80) of repeated microdoses of LSD (10μg, 14x, 6w) finds improved ratings, on dosing days, on creativity, connectedness, energy, and other wellness ratings. Though these transient changes were found, no enduring changes to mood and cognition were observed.
HOPE: A Pilot Study of Psilocybin Enhanced Group Psychotherapy in Patients with Cancer
This open-label study (n=12) investigates the potential of psilocybin-assisted group therapy (PAT) in cancer patients suffering from depression. Participants underwent preparatory sessions, a high-dose (25mg) psilocybin group session, and integration sessions over three weeks, with clinical outcomes measured at baseline, two weeks, and 26 weeks post-intervention. Results show significant decreases in depression symptoms and no serious adverse events, suggesting safety, feasibility, and possible efficacy of the therapy.
MDMA-assisted psychotherapy with adolescents suffering from PTSD: Do or don’t? a qualitative study with youth, parents, and clinicians
This focus group study (n=19) investigated the perspectives of adolescents, parents, and clinicians on MDMA-assisted psychotherapy for adolescents with PTSD. Initial attitudes towards MDMA were mainly unfavourable, but after an explanation of the therapy, all but one participant supported its potential use, emphasizing the importance of research.
Psilocybin intoxication did not affect daytime or sleep-related declarative memory consolidation in a small sample exploratory analysis
This re-analysis of an RCT (n=20) investigated the effects of psilocybin on memory consolidation in healthy volunteers. The study specifically examined the impact of psilocybin on memory consolidation of material learned just after the psilocybin session and on overnight memory consolidation. The results showed that psilocybin did not improve memory consolidation, but importantly, it also did not negatively affect memory consolidation.