Psychedelic Research Recap March 2024
Psychedelic Research Recap March 2024
This month’s research highlights the potential of psychedelics in treating a range of mental health conditions, as well as the importance of considering individual factors and safety considerations in different populations.
Three papers on randomized controlled trials (RCTs) have provided valuable insights into the efficacy of psychedelics in treating depression, anxiety, and substance use disorders. These studies have shown promising results, with psychedelics demonstrating rapid and sustained improvements in symptoms compared to placebo or active comparators. Additionally, open-label studies have explored the subjective effects and potential mechanisms of action of psychedelics, contributing to our understanding of how these substances work in the brain.
Safety considerations have also been a key focus of recent research. Studies have investigated the safety profiles of psychedelics in adolescents, healthy participants, and individuals with opioid use disorder. While the findings suggest potential benefits and safety in controlled settings, it is crucial to consider individual factors, such as genetic vulnerability and drug interactions, to minimize risks and optimize treatment outcomes.
Other notable studies published in March 2024 explore topics such as microdosing, mystical experiences, structure-activity relationships, placebo responses, and the role of attachment history in shaping psychedelic experiences. These studies contribute to the growing body of research on psychedelics, addressing a wide range of topics and helping to advance our understanding of these substances.
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Check out the research link overview for all the studies we didn’t add to the database.
Psilocybin Therapy and SSRIs
Recent studies have explored the impact of discontinuing serotonergic antidepressants (SSRIs/SNRIs) before psilocybin therapy for major depressive disorder (MDD) and the potential psychological mechanisms underlying psilocybin’s therapeutic effects compared to escitalopram treatment.
A post hoc analysis of a clinical trial comparing psilocybin with psychological support to escitalopram for MDD found that discontinuing SSRIs/SNRIs prior to psilocybin treatment led to reduced treatment effects on depression severity measures. However, there were no observed effects on the acute psychedelic experience. The study suggests that discontinuing these antidepressants before psilocybin treatment might impact treatment response.
Another reanalysis of the same trial investigated the mechanisms underlying the efficacy of psilocybin therapy versus escitalopram treatment in patients with MDD over a 6-week period. The study found that acute psychological experiences, such as “mystical experience” and “ego dissolution,” mediated the effect of treatment condition on depressive response, suggesting a mechanistic role of these experiences in treating depression via psilocybin therapy. Additionally, higher reported levels of mystical experience, emotional breakthrough, and intense responses to music listening were associated with greater antidepressant response.
Psychedelic Randomized Controlled Trials in March
Recent randomized controlled trials (RCTs) have investigated the therapeutic effects of psilocybin, esketamine, and ketamine in various contexts, including depression treatment and meditation.
A placebo-controlled study with 36 experienced meditators undergoing focused attention and open-monitoring meditation before and after a five-day psilocybin-assisted meditation retreat found that psilocybin-induced positive derealization, coupled with enhanced open-monitoring meditation, correlated with the optimal transport distance between open monitoring and resting state. This suggests that enhanced meta-awareness through meditation combined with psilocybin may mediate insightfulness, offering potential novel brain markers for positive synergistic effects between mindfulness practices and psychedelics.
Another RCT (n=24) for major depressive disorder (MDD) assessed the therapeutic alliance between participants and intervention facilitators in psilocybin-assisted therapy (PAT). The study found that therapeutic alliance significantly increased from the final preparation session to one-week post-intervention, with a stronger alliance predicting depression scores at various post-intervention time points. Stronger alliances were also correlated with peak ratings of mystical experiences and psychological insight, which in turn were correlated with depression scores, highlighting the importance of the therapeutic relationship in PAT.
Two RCTs explored the efficacy of oral esketamine and ketamine formulations in treatment-resistant depression (TRD). A trial(n=111) investigating fixed low-dose oral esketamine found no benefit on depressive symptom severity compared to placebo, but individually titrated higher doses in the open-label extension phase demonstrated potential antidepressant properties. Another double-blind, randomized study (n=27) assessed the antidepressant effects of a novel oral prolonged-release formulation of racemic ketamine (KET01) in TRD patients as add-on therapy, with results suggesting a positive trend towards antidepressant efficacy with 240 mg/day KET01.
Potential and Risks in Observational Studies
Recent observational studies have investigated the therapeutic effects and risks associated with ketamine, psychedelics, and ayahuasca in various contexts, including depression treatment, well-being in older adults, and the impact of childhood trauma.
A longitudinal study (n=71) examining five years of real-world clinical data on the use of IV low-dose ketamine alongside standard care for outpatients with depression (MDD & TRD) found a significant reduction in depressive symptoms and suicide ideation by treatment endpoint, with 55% of patients responding to treatment. Side effects were transient and mild for 78% of patients, with a dropout rate of 11%, suggesting that IV low-dose ketamine treatment is effective, fast-acting, and well-tolerated in naturalistic clinical practice.
A prospective cohort study (n=124) investigated the effects of a guided psychedelic group session on well-being in older adults (OA) compared to younger adults (YA). The study found significant improvements in well-being in both groups, particularly amplified in OA with a history of psychiatric diagnosis. Although acute subjective psychedelic effects were attenuated in OA compared to YA, a psychosocial measure of Communitas emerged as a predictor in OA, indicating the potential value of relational components in psychedelic group settings for this population.
A comparative study in healthy subjects compared the effects of chronic methamphetamine (METH) and MDMA use on conflict control processes in social-affective contexts. The comparative study (n=42 MDMA, n=38 METH, n=83 controls) found that both METH and MDMA users exhibited reduced behavioral effects in cognitive-emotional conflict processing, particularly regarding anger content. These effects were associated with stronger P3 event-related potential modulations, suggesting altered decision-making and stimulus-response mapping. The authors propose that these changes may be linked to noradrenergic dysfunctions, as both MDMA and METH use may be associated with alterations in the noradrenaline system.
Another observational study (n=807) analyzed negative psychological responses to psychedelics, defined as a clinically meaningful decline in mental health four weeks post-use. The study found that 16% of participants experienced negative responses, with a notably higher prevalence (31%) among those with a prior diagnosis of personality disorder, implying that individuals with a history of personality disorder might face elevated risks with psychedelic use and emphasizing the need for enhanced psychological support and therapeutic alliance in this population.
Lastly, a survey study (n=231) examined the relationship between childhood trauma, challenging experiences during acute ayahuasca effects, and posttraumatic growth. Results showed that individuals with histories of childhood trauma were not at higher risk of adverse experiences during ayahuasca use, nor did they exhibit different levels of posttraumatic growth compared to those without such histories. Additionally, experiencing more challenges during acute ayahuasca effects did not correlate with increased posttraumatic growth.
Safety Considerations for Psychedelic Use
Next to the observational study of negative psychological responses to psychedelics, three other studies have investigated the safety aspects of psychedelic use in various populations, including adolescents, healthy participants, and individuals with opioid use disorder (OUD).
An observational study explored the association between naturalistic psychedelic use and self-reported psychotic or manic symptoms in adolescents. The results suggest that, after adjusting for other drug use, psychedelic use may be associated with reduced psychotic symptoms. However, the association between psychedelic use and manic symptoms appears to be linked to genetic vulnerability to schizophrenia or bipolar I disorder. These findings should be interpreted with caution due to the study’s limitations.
A pooled analysis (n=85; doses=113) of three randomized crossover studies evaluated the safety pharmacology of psilocybin (15-30mg) in healthy participants. Psilocybin induced stronger effects at higher doses, with 25 mg and 30 mg doses showing increased anxiety. However, overall, psilocybin was found to be safe in terms of acute psychological and physical harm, with no serious adverse reactions reported, suggesting its potential safety for controlled research settings.
A pharmacokinetic study (n=14) on ibogaine (700mg/70kg) for opioid use disorder (OUD) found significant variability in ibogaine clearance, strongly correlated with CYP2D6 genotype. Ibogaine plasma concentrations were found to correlate with QTc prolongation and cerebellar effects, while neither ibogaine nor noribogaine correlated with the severity of opioid withdrawal symptoms. The study highlights the importance of considering individual genetic factors, such as CYP2D6 genotype, when determining ibogaine dosing.
The Other Psychedelic Studies from March 2024
Next to these RCTs, open-label trials, and safety-focussed studies, several noteworthy psychedelic studies were published recently, covering a range of topics from microdosing to the philosophical implications of mystical experiences. A microdosing study investigated the subjective experiences of individuals engaging in psilocybin microdosing in their daily lives. By combining momentary ecological assessments and retrospective interviews, participants reported varied effects, including loosening of mental structures, increased salience of external stimuli, flexible cognition, and ego-dystonic contents.
A philosophical article (2024) discussed the compatibility of mystical-type experiences induced by psychedelic substances with naturalism. The author suggests that while mystical insights may align with naturalism by considering the ultimate nature of reality as observation-independent, accessing the fundamental nature of all reality remains a challenging “hard problem.” Psychedelics are proposed to enhance awareness of consciousness and the limitations of our reality models, but their ability to provide access to the fundamental nature of all reality remains unclear.
A cell and mice study explored the psychopharmacological profile of amino-substituted 5-MeO-tryptamines, focusing on their interactions with serotonin receptors and transporters, as well as their psychoactive and thermoregulatory properties. The study demonstrated selectivity for 5-HT1AR over 5-HT2AR among the examined compounds and identified 5-MeO-pyr-T as the most potent partial 5-HT release.
A meta-analysis (n=1100; s=14) of clinical trials on patients with depression (MDD) receiving ketamine or esketamine revealed a substantial placebo response, accounting for up to 72% of the overall treatment response. The study emphasizes the importance of considering the placebo response in clinical practice to maximize the benefit to patients.
Finally, a survey (n=185) of an international Jewish sample with psychedelic experience explored the association between attachment-related variables and psychedelic experiences. Findings suggest that perceptions of an insecure attachment history are positively linked to various measures of psychedelic phenomenology, while adult attachment orientations show no significant relationship.
Papers Published in March 2024
20 studies from the Blossom database published this month.
Trauma Under Psychedelics: MDMA Shows Protective Effects During the Peritraumatic Period
In a naturalistic cohort of 772 survivors of the October 7 Supernova festival attack, participants who were under the influence of MDMA during the trauma reported lower psychological distress, fewer PTSD symptoms, greater social interaction and better sleep in the one to four months post-attack compared with those who were sober, whereas cannabis and/or alcohol use was associated with worse outcomes. These novel findings suggest a putative protective role for MDMA during the peritraumatic period and warrant mechanistic and longitudinal investigation.
Methyl transfer in psilocybin biosynthesis
Atomic-resolution (0.9 Å) crystal structures of PsiM at multiple reaction stages reveal the SAM-dependent dimethylation mechanism and show that its substrates physicochemically mimic RNA, while structural and phylogenetic analyses indicate PsiM derives from METTL16-family m6A writers. The study also shows inherent limitations of the ancestral monomethyltransferase scaffold that reduce psilocybin assembly efficiency and prevent trimethylation to aeruginascin, informing bioengineering efforts to create improved psilocybin variants.
Psilocybin enhances insightfulness in meditation: a perspective on the global topology of brain imaging during meditation
Using Mapper-based topological data analysis of fMRI during focused-attention and open-monitoring meditation before and after a five-day psilocybin versus placebo retreat in experienced meditators, the study shows that whole-brain activity topology — quantified by optimal transport distance — differentiates meditation styles and psilocybin-induced changes. Crucially, psilocybin-induced positive derealisation paired with enhanced open-monitoring correlated with increased OT distance between open-monitoring and resting state and with greater reported insightfulness, suggesting potential brain markers of beneficial synergy between mindfulness practice and psilocybin.
Oral esketamine in patients with treatment-resistant depression: a double-blind, randomized, placebo-controlled trial with open-label extension
This randomised placebo-controlled trial (n=111) investigated the efficacy, safety, and tolerability of fixed low-dose oral esketamine (3x p/d 42d; 30-90mg; oral) in patients with treatment-resistant depression (TRD). Results indicate that fixed low-dose oral esketamine did not show benefit on depressive symptom severity compared to placebo, but individually titrated higher doses in the open-label extension phase demonstrated potential antidepressant properties.
Effects of discontinuation of serotonergic antidepressants prior to psilocybin therapy versus escitalopram for major depression
Exploratory post hoc analyses of a trial comparing psilocybin-assisted therapy with escitalopram found that participants who discontinued SSRIs/SNRIs before receiving psilocybin showed reduced treatment effects on depression and wellbeing measures compared with unmedicated participants, despite no differences in the acute psychedelic experience. These hypothesis-generating results suggest pre-treatment antidepressant discontinuation might diminish response to psilocybin and indicate the need for controlled trials comparing SSRI/SNRI continuation versus discontinuation.
The pharmacokinetics and pharmacodynamics of ibogaine in opioid use disorder patients
This pharmacokinetic study (n=14) on ibogaine (700mg/70kg) for opioid use disorder (OUD) finds significant variability in ibogaine clearance, strongly correlated with CYP2D6 genotype. Ibogaine plasma concentrations correlate with QTc prolongation and cerebellar effects, while neither ibogaine nor noribogaine correlate with the severity of opioid withdrawal symptoms.
Childhood trauma, challenging experiences, and posttraumatic growth in ayahuasca use
In an online survey of 231 ayahuasca users, self‑reported childhood trauma was not associated with greater challenging experiences during acute ayahuasca effects nor with differences in posttraumatic growth, and acute challenging experiences were not linked to increased posttraumatic growth; this suggests childhood trauma may not predict poorer response to ayahuasca as it does for some other interventions.
Salience, Sensemaking, and Setting in Psilocybin Microdosing: Methodological Lessons and Preliminary Findings of a Mixed Method Qualitative Study
Using momentary ecological assessment and retrospective interviews, the study found psilocybin microdosing was associated with loosening of mental structures, increased salience of external stimuli, greater cognitive flexibility but reduced cognitive stability and occasional ego-dystonic content, with highly structured environments tending to produce more positive appraisals. Crucially, momentary and retrospective reports were often diametrically opposed, highlighting methodological biases and the need for systematic mixed-methods studies to accurately characterise the lived experience of microdosing.
IV low dose ketamine infusions for treatment resistant depression: Results from a five-year study at a free public clinic in an academic hospital
This longitudinal study (n=71) examines five years of real-world clinical data on the use of IV low-dose ketamine alongside standard care for outpatients with depression (MDD & TRD). Results indicate a significant reduction in depressive symptoms and suicide ideation by treatment endpoint, with 55% of patients responding to treatment. Side effects were transient and mild for 78% of patients, with a dropout rate of 11%. Multivariate analysis suggests that demographic variables did not impact treatment efficacy or tolerability.
Naturalism and the hard problem of mysticism in psychedelic science
This philosophical article (2024) discusses the compatibility of mystical-type experiences induced by psychedelic substances with naturalism. The author suggests that while mystical insights may align with naturalism by considering the ultimate nature of reality as observation-independent, accessing the fundamental nature of all reality remains a challenging hard problem. Psychedelics are proposed to enhance awareness of consciousness and the limitations of our reality models, but it is unclear if they provide access to the fundamental nature of all reality. In conclusion, the author contends that mystical-type conceptions about reality may coexist with naturalism but are generally unverifiable, similar to many metaphysical theses.
Structure-activity relationships of serotonergic 5-MeO-DMT derivatives: insights into psychoactive and thermoregulatory properties
This cell & mice study explores the psychopharmacological profile of amino-substituted 5-MeO-tryptamines, focusing on their interactions with serotonin receptors and transporters, as well as their psychoactive and thermoregulatory properties. The study demonstrates selectivity for 5-HT1AR over 5-HT2AR among examined compounds using radioligand binding methodologies and computational docking analyses, and 5-MeO-pyr-T was identified as the most potent partial 5-HT releaser.
The therapeutic alliance between study participants and intervention facilitators is associated with acute effects and clinical outcomes in a psilocybin-assisted therapy trial for major depressive disorder
In a randomised, waiting‑list‑controlled psilocybin‑assisted therapy trial for major depressive disorder (N = 24), therapeutic alliance strengthened over time and higher alliance ratings before and shortly after dosing predicted stronger acute mystical and psychological‑insight experiences and significantly greater reductions in depressive symptoms up to 12 months. These results highlight the therapeutic relationship as an important predictor of both acute psychedelic experiences and long‑term clinical outcomes.
Getting in Touch with Touch: The Importance of Studying Touch in MDMA-Assisted Therapy and the Development of a New Self-Report Measure
This literature review examines the role of therapeutic touch in MDMA-assisted therapy (MDMA-AT), addressing concerns about power imbalances and ethical boundaries. It introduces the Touch Outcomes Measurement Inventory (TOMI) to assess client perceptions of touch in MDMA-AT, emphasizing the need for evidence-based and ethical guidelines in psychedelic-assisted therapy.
Hype or hope? High placebo response in major depression treatment with ketamine and esketamine: a systematic review and meta-analysis
This meta-analysis (n=1100; s=14) of clinical trials on patients with depression (MDD) receiving ketamine or esketamine reveals a substantial placebo response, accounting for up to 72% of the overall treatment response. The study emphasizes the importance of considering the placebo response in clinical practice to maximize the benefit to patients.
Unique Psychological Mechanisms Underlying Psilocybin Therapy Versus Escitalopram Treatment in the Treatment of Major Depressive Disorder
In a phase 2 double‑blind randomized trial comparing psilocybin therapy with escitalopram for moderate‑to‑severe major depressive disorder, acute subjective experiences—particularly mystical experiences and ego dissolution—uniquely mediated the superior antidepressant response to psilocybin over a six‑week period. Emotional breakthrough and intense music‑evoked responses were also associated with greater symptom improvement, providing qualified support that acute psychological experiences may be causal mechanisms in psilocybin’s antidepressant effects.
Psychiatric risks for worsened mental health after psychedelic use
In a pooled analysis of 807 naturalistic prospective studies, 16% of participants experienced a clinically meaningful decline in mental health four weeks after psychedelic use, with those reporting a prior personality disorder showing a disproportionate prevalence (31%) and a greater-than-fourfold elevated risk of adverse response. The authors conclude that personality disorder may be an important risk factor for psychedelic-related psychological harm, indicating a need for enhanced psychological support and therapeutic alliance for this group.
American Psychiatrists' Opinions About Classic Hallucinogens and Their Potential Therapeutic Applications: A 7-Year Follow-Up Survey
This survey (n=131) conducted among American psychiatrists, aimed to assess their opinions about psychedelics & PAT in 2023, comparing the results with a similar study conducted in 2016. The findings revealed a significant positive shift in attitudes among American psychiatrists since 2016, with a majority expressing moderate to strong belief in the therapeutic potential of psychedelics for treating psychiatric conditions (81%) and substance use disorders (61%).
Psilocybin-assisted psychotherapy for treatment resistant depression: A randomized clinical trial evaluating repeated doses of psilocybin
This open-label waitlist trial (n=30) assessed the feasibility of psilocybin-assisted psychotherapy (PAP/PAT) in a complex population with treatment-resistant depression (TRD), including major depressive and bipolar II disorders, baseline suicidality, and significant comorbidity. Participants received one, two, or three sessions of PAP with psilocybin (25mg), accompanied by preparation and integration psychotherapy sessions. Immediate treatment showed greater reductions in depression severity (MADRS) compared to the waitlist period, with a large effect size (g = 1.07, p < 0.01). Repeated doses were associated with further reductions in depression severity. Adverse events were transient, and the study demonstrated feasibility, preliminary antidepressant efficacy, safety, and tolerability in this population.
Safety and tolerability of inhaled N,N-Dimethyltryptamine (BMND01 candidate): A phase I clinical trial
This open-label, single-ascending, fixed-order dose-response study (n=27) investigates the safety and tolerability of inhaled DMT. The healthy volunteers received varying doses of inhaled DMT (5-60mg). Preliminary findings indicate dose-dependent increases in intensity, valence, and perceptual ratings, with no significant safety concerns, suggesting inhaled DMT as a potentially efficient and safe administration method.
Treatment with psychedelics is psychotherapy: beyond reductionism
This opinion piece (2023) challenges the traditional conceptualization of psychedelic-assisted psychotherapy (PAP/PAT), emphasizing that the therapeutic effects of psychedelics should not be solely attributed to the substance itself but also to the importance of psychotherapy. The authors argue against reducing the role of psychotherapy to mere psychological support for safety, advocating for a more integrated approach to understanding and studying the therapeutic potential of psychedelics in treating psychiatric disorders.