Psychedelic Research Recap April 2024

This April, psychedelic research dives deep into the mechanisms by which this group of compounds work their magic. We look at both the psychological level – at cognitive flexibility & the ‘inner healer’ concept – as well as the neurological level – battling it out between the 2a & 1a serotonin receptors.

After mechanisms, we will take a closer look at two articles that look at the challenges that come with psychedelic research. The first explores the side effects seen in psychedelic studies, the second investigates the influence of the placebo effect in ketamine studies for depression. We will then remain in the risky corner when discussing two articles that pit MDMA against another amphetamine (meth).

For the final two sections, we’ll first review the literature on 5-MeO-DMT, maybe the most reality-breaking psychedelic of them all (though your reviewer hasn’t tried salvia, so take my opinion with a grain of salt). After that, we will tackle research in areas where psychedelics are showing promise outside of the well-known indications (PTSD, depression, anxiety). The areas that were researched last month include functional seizures, personality disorders, and chronic cluster headaches.

This month’s recap is made possible by our supporting members.

Check out the research link overview for all the studies we didn’t add to the database.

Exploring the Mechanisms of Psychedelic Therapy

Psychedelic therapy is showing promise for treating a range of mental health conditions, but the mechanisms behind its therapeutic effects are still being unravelled. Several recent studies shed light on potential pathways, including changes in psychological flexibility, the interplay of serotonin receptors, and modulation of visual processing.

A re-analysis of a placebo-controlled trial found that psilocybin, when combined with Acceptance and Commitment Therapy (ACT), improved psychological flexibility, mindfulness, and values-based living in people with major depression. These changes persisted for the 16-week study period. Greater psychological flexibility and experiential acceptance were also linked to lower depression scores after psilocybin treatment. This suggests that increasing psychological flexibility may be a key mechanism underlying psilocybin’s antidepressant effects when paired with psychotherapy.

An exploratory re-analysis of a psilocybin depression trial investigates the concept of an ‘inner healer’ effect associated with psychedelics. Participants receiving a high dose of psilocybin reported stronger experiences of inner healing compared to those on placebo, and higher ‘inner healer’ scores predicted greater reductions in depressive symptoms. While preliminary, this hints at a potential belief-updating mechanism where psychedelics enhance psychological self-healing capacities.

Looking at receptor-level effects, a computational model based on hierarchical predictive processing proposes that the therapeutic benefits of serotonergic psychedelics arise from a combination of 5-HT2a and 5-HT1a receptor agonism. The simulations indicate that 5-HT2a agonism introduces stochastic perturbations that relax overly rigid beliefs, while 5-HT1a agonism smooths the brain’s internal models. Mixed 5-HT2a/1a agonists like LSD, psilocybin and DMT may strike an optimal balance of therapeutic efficacy and tolerability compared to pure 5-HT2a or 5-HT1a agonists alone. This dual-receptor model aligns with the clinical success of these “classic” psychedelics.

Visual distortions and hallucinations are a hallmark of the psychedelic experience. A novel theory proposes that psychedelic modulation may begin earlier in the visual pathway than previously thought, in retinal interneurons called amacrine cells. These cells express serotonin receptors and shape visual signals travelling from the retina to the brain. Disrupted communication between visual cortical and subcortical regions, influenced by psychedelics (serotonergic drugs), could contribute to perceptual alterations. The retinofugal pathway may play an underappreciated role in the subjective effects of psychedelics, akin to rare conditions like Charles Bonnet syndrome that cause visual hallucinations.

Together, these studies paint a picture of psychedelic therapy invoking multiple levels of changes – from receptor binding to visual processing to meta-cognitive beliefs. Flexibility emerges as a common theme, whether in one’s relationship to thoughts and feelings, the brain’s neural dynamics, or the revision of entrenched worldviews. As psychedelic research progresses, integrating these multilevel insights may help optimize therapeutic protocols and identify new targets for drug development.

Understanding the Hurdles in Psychedelic Clinical Trials

Psychedelic clinical trials face unique methodological challenges that need to be carefully considered as research in this field progresses. Two recent studies highlight important issues: the need for rigorous safety monitoring and reporting of side effects in MDMA-assisted psychotherapy trials, and the substantial placebo response observed in ketamine and esketamine trials for depression. These findings underscore the importance of refining clinical trial methods to ensure the safety and efficacy of psychedelic-based treatments.

A systematic review and meta-analysis looked at the side effects of MDMA-assisted psychotherapy across multiple Phase II and III studies. The analysis found an increased likelihood of side effects during MDMA sessions and in the week following treatment compared to control conditions. However, the overall quality of evidence was low to moderate, and side effect reporting in the included trials was often inadequate. This highlights the need for more rigorous safety monitoring and reporting standards in future MDMA therapy trials to fully understand the treatment’s risk profile.

Another major hurdle in psychedelic research is accounting for the placebo response. A meta-analysis of ketamine and esketamine trials for depression revealed that the placebo effect was responsible for up to 72% of the overall treatment response. While ketamine still showed strong antidepressant effects, the sizable placebo component emphasizes the importance of well-controlled study designs. Researchers need to carefully consider placebo effects when interpreting trial results and find ways to optimize these effects in clinical practice for the benefit of patients.

Prioritizing participant safety, maintaining high reporting standards, and accounting for the complex interplay of specific and non-specific treatment factors are crucial steps in refining clinical trial methods in the growing field of psychedelic medicine. As the studies on MDMA-assisted psychotherapy and ketamine trials demonstrate, addressing these methodological challenges head-on is essential for ensuring the translation of psychedelic research into meaningful clinical applications. By tackling these issues, investigators can pave the way for more robust and reliable evidence on the safety and efficacy of psychedelic-based treatments.

The Unique Effects of MDMA (Versus its Chemical Cousins)

MDMA is on the brink of becoming an approved medicine for PTSD (as soon as August this year). In research, it’s often classified as an ’empathogen’ or ‘entactogen’ (when comparing it against ‘classical’ psychedelics). But, it might be just as right to group MDMA under the amphetamines group. So, what is different between this ‘medicine’ and its chemical cousins?

A comparative study evaluated social cognitive functions and behaviours in chronic methamphetamine (METH) users, chronic MDMA users, and stimulant-naïve controls. The results revealed that METH users showed reduced cognitive and emotional empathy, increased aggressive behaviour, and heightened trait anger. In contrast, MDMA users only displayed more impulsive aggression when provoked. These findings suggest that MDMA and METH have different impacts on social cognition and behaviour, despite their chemical similarities.

An EEG study investigated the effects of MDMA and METH on early visual processing of socio-emotional stimuli. MDMA was found to enhance the N170 component, which is sensitive to detecting faces, particularly for happy and angry expressions. Methamphetamine did not show similar effects. These results provide insights into the neural mechanisms underlying MDMA’s effects on socio-emotional processing, which could inform its therapeutic use in treating social anxiety and other psychiatric disorders.

A retrospective cohort study (which was pre-published in March, but we missed it at the time) examined the acute experiences and peritraumatic processing of survivors from a high-casualty terror attack (October 7th), with many under the influence of psychoactive substances. Interestingly, those who experienced the trauma under MDMA showed improved intermediate outcomes, including increased social support, more interactions, better sleep quality, and reduced mental distress and PTSD symptom severity. These findings suggest that MDMA may have a protective effect during trauma, possibly mediated by its ability to reduce negative emotions and increase prosocial behaviour.

Finally, a literature review addressed the importance of studying touch in MDMA-assisted therapy (MDMA-AT). The article introduced 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. With the increasing likelihood of MDMA-AT becoming a widely used therapy, understanding the impact of therapeutic touch on clients is crucial for ensuring safe and effective treatment.

Reviewing & Developing 5-MeO-DMT

5-MeO-DMT, a short-acting psychedelic substance, shows promise for therapeutic applications, particularly in the treatment of alcohol use disorder (AUD). Two studies last month investigated the safety, pharmacokinetics, and pharmacodynamics of 5-MeO-DMT, as well as its possible mechanisms of action in treating AUD.

A double-blind, placebo-controlled study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of BPL-003, a novel intranasal benzoate salt formulation of 5-MeO-DMT, in healthy participants. The study found that BPL-003 was well tolerated at doses up to 12 mg, with no serious adverse events reported. The substance was rapidly absorbed and eliminated, and its systemic exposure increased approximately dose-proportionally. The intensity of subjective drug effects was associated with plasma 5-MeO-DMT concentrations, and participants reported profound and highly emotional consciousness-altering effects with a rapid onset and short duration.

A review examined the potential therapeutic mechanisms of action of 5-MeO-DMT in the treatment of AUD. The paper highlights that 5-MeO-DMT can induce mystical experiences and ego-dissolution, leading to increased psychological flexibility and mindfulness (also see our first section on psychological flexibility), which may help alleviate AUD symptoms by addressing psychiatric mood-related comorbidities. Additionally, preliminary evidence suggests that 5-MeO-DMT modulates neural oscillations, exhibits neuroplasticity, and has anti-inflammatory properties, indicating its potential clinical implications for AUD and related psychiatric conditions.

Emerging Therapeutic Potential of Psychedelics

For the final section, we look at studies that have explored the therapeutic potential of psychedelics in treating various neurological and psychiatric conditions, such as functional seizures (FS), personality disorders (PDs), and chronic cluster headaches (CCH). These studies highlight the growing interest in psychedelic-assisted therapy (PAT) as a novel treatment approach for conditions that are often challenging to treat with existing interventions.

A conceptual synthesis proposes PAT as a potential treatment for FS, a subtype of functional neurological disorder (FND). The synthesis draws on empirical evidence and complexity science to construct an argument for the potential efficacy of PAT in treating FS. It also highlights FS as a cohort to investigate the neural mechanisms of PAT and outlines a novel analytic roadmap to identify markers of FS diagnostic specificity and treatment success. This work aims to bridge clinical neurology with psychedelic medicine and establish a new field of psychedelic neurology.

Two prospective observational studies investigated the effects of psychedelic use on individuals with PDs. The first study (n=21) followed participants before, 2 weeks, and 4 weeks after psychedelic use, while the second study (n=55) observed participants before, 2-4 weeks, and 2-3 months after psychedelic use. The results indicate reductions in suicidal ideation and improvements in anxiety and depression symptoms. However, some participants experienced increased anxiety and depression severity. The studies also found transient increases in cognitive flexibility (again, see the first section) and sustained increases in cognitive reappraisal, which were associated with reductions in anxiety and depression.

A double-blind, placebo-controlled study (n=10) assessed the safety and efficacy of repeated pulse administration of psilocybin (10mg/70kg, 3x in 15 days) in cluster headache patients. Following an initial trial, eligible participants received a psilocybin pulse at least 6 months later and kept headache diaries for 8 weeks. The results indicate a significant reduction in cluster attack frequency following the psilocybin pulse, suggesting potential therapeutic benefits.

These studies provide promising evidence for the therapeutic potential of psychedelics in treating indications beyond those that we’ve all heard so much about. However, further research with larger, more representative samples and longer follow-up periods is needed to establish the safety, efficacy, and mechanisms of action of psychedelic-assisted therapies in these populations.

The Other Psychedelic Studies from April 2024

Next to the mechanisms of psychedelics, the challenges in psychedelic research, the potential of MDMA, a closer look at 5-MeO-DMT, and psychedelics for novel indications, here are the other studies that we’ve covered this month.

• A single-blind placebo-controlled study (n=40) investigated the neural and behavioural effects of acute ketamine in healthy participants, revealing robust inter-individual variability in both neural and behavioural responses, with data-driven individual symptom variation mapping onto distinct neural gradients.
• An open-label trial (n=117) administered intravenous ketamine in highly supportive environments to outpatients with elevated PTSD symptoms, resulting in significant reductions in PTSD symptoms when the protocol included preparatory, integration, sensory immersion, and psychotherapy sessions.
• A structural study delved into the mechanism of PsiM, the enzyme responsible for the final step in psilocybin biosynthesis. It presented high-resolution crystal structures and proposed evolutionary origins shared with N6-methyladenosine writers, highlighting its potential for bioengineering to enhance psilocybin’s therapeutic benefits.
• A cross-sectional study (n=113) compared experienced psychedelic users (n=56) to nonusers (n=57) regarding neural responses to Self-name stimuli. It found no difference in P300 amplitude for Self- or Target-names but increased P300 amplitude for Other Names in users, suggesting potential alterations in attentional resource allocation rather than prolonged changes in self-representation due to psychedelic use.

What you can find on Blossom

Last month, we added 18 studies to the database of over 2000 research publications.

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