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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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.

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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.

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