Psychedelic Research Recap April 2025

Psychedelic Research Recap April 2025

Welcome back to our monthly update on psychedelic research!

This month, researchers explored how psychedelics affect self-perception, emotional processing, and memory in ways that could inform future therapeutic approaches. For instance, an ayahuasca-inspired formulation combining DMT and harmine was found to blur the neural boundaries between one’s own face and others, potentially explaining its impact on social anxiety and depression. Another brain imaging study found that LSD-induced ego dissolution involves increased connectivity between the dorsolateral prefrontal cortex, thalamus, and visual processing areas, providing deeper insights into how psychedelics restructure emotional and self-related experiences.

Population studies also offered notable findings: survivors of a terrorist attack who had used classic psychedelics during the trauma reported significantly lower anxiety and PTSD symptoms three weeks later, suggesting psychedelics might protect against lasting trauma responses. Meanwhile, a large cohort study investigating hallucinogen persisting perception disorder (HPPD) found that mild perceptual disturbances were common but rarely distressing, although younger age, female gender, and psychiatric history increased risk. Psilocybin use in the U.S. continues to rise sharply, especially among older adults, prompting researchers to call for better public health monitoring and education.

Finally, preclinical neuroscience studies provided mixed insights: one multi-lab mouse study showed psilocybin reliably produced acute anxiety-related behaviours but questioned its purported lasting therapeutic effects. Another mouse study pinpointed specific brain cells (PT neurons) and serotonin receptors essential for psilocybin’s long-term anti-stress effects, helping clarify the biological pathways behind psychedelic therapy.

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.

Recent Randomised Psychedelic Clinical Trials

Clinical trials are crucial in determining the safety and effectiveness of psychedelic substances. This month saw the publication of two randomised, placebo-controlled trials (and one secondary analysis) that investigated how psychedelics affect mental health, emotional responses, and behaviour. These trials included diverse treatments such as esketamine for smoking cessation, MDMA for emotional regulation, and comparisons between psilocybin and traditional antidepressants.

While earlier research into psychedelic treatments for smoking cessation, such as psilocybin-assisted therapy, has shown promising results, including a notable January 2017 follow-up study that found 67% abstinence at 12 months, data on ketamine-based treatments have been limited. Addressing this, a large first-of-its-kind trial in China tested intranasal esketamine for smokers with lung cancer and major depressive disorder (MDD). The trial included 236 patients and found that eight weekly sessions of intranasal esketamine significantly improved smoking abstinence rates at six-month follow-up (44% self-reported and 29% biologically verified). Additionally, the treatment effectively reduced depression, anxiety, nicotine dependence, and respiratory symptoms. These findings suggest esketamine could become a valuable tool for smoking cessation, particularly among those facing serious health conditions like lung cancer.

MDMA-assisted therapy is gaining attention for treating post-traumatic stress disorder (PTSD), but understanding how it works in the brain remains a challenge. A recent study at Stanford explored the effects of MDMA on emotional brain circuits in people with subthreshold PTSD symptoms (symptoms below clinical diagnosis level) and early life trauma. The trial involved 16 participants, split based on their initial emotional brain activity levels. The study showed that MDMA significantly reduced brain activity associated with negative emotions and enhanced emotional processing in those initially highly reactive to threats. These findings suggest that MDMA therapy might be particularly beneficial for PTSD patients who have heightened emotional reactivity, offering a path towards more personalised treatments.

In the third RCT study (the 14th publication from the same clinical trial), researchers compared psilocybin therapy to escitalopram (a common antidepressant) in patients with depression (MDD). The paper focused on how these treatments affect emotional reactions to unexpected changes in music (musical surprises). Music is particularly informative as it naturally triggers emotional responses and provides insight into reward processing, a common difficulty in depression. Results showed that psilocybin maintained emotional sensitivity to these musical surprises, enhancing brain activity in sensory and prefrontal regions. In contrast, escitalopram appeared to dampen emotional reactions and increased brain activity associated with memory and emotional control. This suggests fundamentally different ways the two treatments affect emotional processing in depression, highlighting psilocybin’s potential to enhance emotional engagement rather than suppressing it.

Psychedelic Therapies in Open-Label and Real-World Settings

Four studies explored psychedelic therapies in open-label settings, offering insights into practical treatment applications and broader clinical implications.

Oral esketamine has been proposed as a simpler, less invasive alternative to intravenous (IV), intramuscular (IM), and intranasal administration routes, though evidence supporting this route has been limited. A large, real-world study from the Netherlands evaluated oral esketamine in 185 adults with severe treatment-resistant depression (TRD) who had exhausted multiple treatment options, including electroconvulsive therapy (ECT). Over a six-week period, patients received clinically supervised, twice-weekly doses of oral esketamine, tailored individually between 35 to 210 mg per 70 kg. This treatment resulted in clinically significant improvements, with depressive symptoms decreasing by approximately 26%. Nearly half of the participants reported meaningful symptom relief, about 27% achieved a notable 50% reduction, and roughly 16% reached full remission. The low dropout rate (8%) indicated strong patient acceptance, suggesting oral esketamine as a practical and patient-friendly alternative.

Building upon earlier preliminary results discussed in January 2024, a Phase IIb clinical trial explored the antidepressant potential of inhaled DMT for TRD. Despite the small sample size (n=14), vaporized DMT showed rapid and sustained antidepressant effects, achieving a remarkable 21-point reduction on the Montgomery-Asberg Depression Rating Scale by day 7. This rapid response, with an 86% response rate and a 57% remission rate lasting up to three months, points to inhaled DMT as a promising fast-acting therapeutic option, though further studies with larger groups are essential.

An open-label pilot trial examined psilocybin therapy specifically for mood dysfunction in Parkinson’s disease patients experiencing depression and anxiety, conditions notoriously difficult to treat in this population. Involving 12 participants, the study demonstrated safety and tolerability with no serious adverse events. Moreover, participants experienced meaningful improvements in mood, anxiety, cognitive function, and even motor symptoms that persisted at a three-month follow-up. These findings represent the first data on psilocybin’s potential in treating psychiatric symptoms within neurodegenerative diseases, suggesting promising avenues for future research.

Finally, an observational study evaluated whether adding psychotherapy to ketamine treatment enhances outcomes for depression and PTSD compared to ketamine alone. While ketamine is widely recognized for rapidly reducing symptoms, the assumption has been that psychotherapy could extend or deepen its benefits through neuroplasticity. Analyzing overlapping samples of hundreds of patients, the study found significant symptom improvements in both groups, but notably no statistical advantage from adding psychotherapy. Exploratory subgroup analyses hinted that younger females might benefit slightly more from combined treatment, while older males showed better outcomes with ketamine alone. Although observational limitations apply (e.g., patients could have received therapy outside of the study), these findings prompt important considerations for clinical practice regarding the optimal use of therapist resources alongside rapid-acting medications.

Neural Changes Under Psychedelic States

In this third section, we’re looking at recent studies that use advanced neuroimaging methods (EEG, fMRI, and MEG) to understand better how psychedelics influence brain function, self-perception, and subjective experiences. By investigating how psychedelics alter neural connectivity, brainwave activity, and cognitive processing, these studies provide valuable insights into the neural basis of psychedelic experiences, from subtle self-boundary changes to profound states of ego dissolution.

The first study (which is a secondary analysis of the data from this trial) investigates how an ayahuasca-inspired combination of DMT and harmine (HAR) affects face perception and self-recognition in healthy male participants. Using EEG recordings during a visual oddball task, researchers found that DMT/HAR enhanced early-stage visual processing (measured by increased P1 amplitude) but weakened structural face encoding (N170 component). Importantly, the drug significantly reduced the brain’s differentiation between one’s own face and other faces (P300 amplitude), particularly in posterior brain areas involved in visual and self-referential processing. These findings suggest psychedelics do not simply erase the boundaries between self and others but dynamically reshape these boundaries by redistributing neural resources, possibly offering therapeutic benefits in disorders involving overly rigid self-perception, like depression or social anxiety.

A second study explored the pharmacokinetics (how the drug moves through the body) and pharmacodynamics (the effects of the drug) of a low, sublingual (under the tongue) microdose of LSD (10µg) in 80 healthy adult males. Researchers found that LSD reached peak plasma concentrations quickly (~1.5 hours) and was eliminated with a half-life of approximately three hours. Despite measurable LSD plasma levels, participants showed minimal physiological changes, with heart rates increasing less than 15% from baseline. Two participants who withdrew due to anxiety had reduced activity of certain liver enzymes (CYP2D6), suggesting individual differences in drug metabolism could affect tolerance to LSD microdosing. No changes were observed in peripheral brain-derived neurotrophic factor (BDNF), a biomarker sometimes linked to neuroplasticity, challenging assumptions that microdosing significantly alters this protein at low doses.

A third neuroimaging study using both fMRI and MEG investigated the role of the dorsolateral prefrontal cortex (DLPFC), a key brain region involved in mood regulation and cognitive control, in LSD-induced experiences of ego dissolution and emotional arousal. The researchers observed increased functional connectivity between the DLPFC, thalamus, and visual processing regions (like the fusiform face area) during ego dissolution experiences. Emotional arousal correlated with heightened connectivity between the right DLPFC and brain areas involved in attention and emotional salience. MEG analyses further showed increased theta-band information flow from the thalamus to the DLPFC, supporting theories that ego dissolution under psychedelics may result from disrupted sensory gating, allowing more sensory and emotional signals to reach higher cognitive regions.

The fourth study examined 5-MeO-DMT’s effects on consciousness in naturalistic settings using EEG and detailed micro-phenomenological interviews. Participants described experiences ranging from mild perceptual changes to total loss of self-awareness (“ego dissolution”). EEG recordings revealed significant reductions in alpha and beta wave activity, particularly in posterior brain areas, which aligns with decreased cognitive control and self-referential processing. These findings support 5-MeO-DMT as a potent pharmacological tool for investigating the neurobiology of minimal or “nondual” states of consciousness, where awareness remains despite the absence of specific perceptual or self-related content.

Finally, researchers used advanced network control theory to understand how intravenous DMT affects the brain’s energy landscape, connectivity, and subjective intensity of experiences. Using simultaneous EEG-fMRI data, they found that DMT reduces the overall “control energy” required for the brain to transition between different states. These reductions correlated strongly with increased EEG signal diversity (a marker of complexity and consciousness) and subjective ratings of psychedelic intensity. Additionally, regional changes in brain activity under DMT closely mirrored the distribution of serotonin 2a receptors, providing a proof-of-concept that computational models informed by receptor density maps can effectively predict psychedelic-induced brain changes.

Real-world Patterns and Risks of Psychedelic Use

We’re now leaving the lab and taking a closer look at recent population-level studies that shed light on how psychedelic use affects mental health in naturalistic settings, track emerging patterns of psilocybin use, and identify factors associated with psychedelic-related side effects.

One observational study of survivors from a large-scale terrorist attack found that the use of classic psychedelics (such as LSD or psilocybin) during/around (peri) trauma was associated with significantly lower anxiety and post-traumatic stress symptoms three weeks later, compared to individuals who took MDMA or no psychedelics at all. This protective effect appeared strongest when classic psychedelics were consumed without other substances. These findings suggest that the pharmacological action of psychedelics on serotonin receptors involved in memory formation may modulate traumatic memory encoding, potentially offering acute protective benefits against PTSD and anxiety development immediately following trauma.

A prospective cohort study (which we covered as a pre-print in November 2022) explored delusional ideation, magical thinking, and hallucinogen persisting perception disorder (HPPD)-like symptoms in a self-selected sample before and after psychedelic use. Contrary to fears about psychedelics triggering psychosis, delusional ideation decreased after psychedelic experiences. However, approximately 30% of users reported HPPD-like perceptual changes four weeks later, though fewer than 1% found these symptoms distressing. Younger age, female gender, history of psychiatric diagnoses, and higher baseline trait absorption were predictive of experiencing these visual disturbances. The study highlights the importance of identifying individual risk factors better to inform harm reduction practices and personalized psychedelic treatments.

Finally, a multi-dataset observational study in the United States revealed that psilocybin use among adults has notably increased since its initial decriminalization in 2019, with lifetime use rising from 10% (25 million people) in 2019 to 12% (31.3 million) in 2023. Past-year psilocybin use also increased markedly among adults, with especially pronounced growth among individuals aged 30 and above. Reports to poison control centres involving psilocybin increased substantially, although recorded hospital encounters remained rare, indicating potential underreporting or misclassification in healthcare settings. The study emphasizes the need for improved surveillance methods, clearer healthcare coding, and targeted education to manage potential risks associated with increasing psilocybin use.

Neural Mechanisms Underpinning Psychedelic Effects

This final section examines two recent animal studies elucidating the cellular and neural mechanisms through which psychedelics exert acute and potentially lasting behavioural effects.

A comprehensive multi-laboratory mouse study found consistent acute behavioural effects following psilocybin administration, including increased anxiety-related behaviours and reduced fear expression. Surprisingly, however, previously reported lasting therapeutic effects were not reliably replicated 24 hours post-administration across multiple behavioural assays. This finding suggests that earlier claims regarding robust and long-lasting therapeutic benefits of psilocybin in rodent models may have been overstated. The study underscores the importance of coordinated, multi-site research in identifying reliable and reproducible psychedelic effects.

Another mouse study focused on the cellular and neural circuitry underlying psilocybin’s therapeutic effects, specifically examining two types of cortical pyramidal neurons (PT and IT neurons) within the medial frontal cortex. Researchers found that a single psilocybin dose significantly increased dendritic spine density in both neuron types. However, only PT neurons, which project to subcortical areas, were crucial for psilocybin’s anti-stress behavioural effects. Furthermore, these beneficial effects required activation of the serotonin 5-HT2A receptor specifically in PT neurons, highlighting a precise cellular pathway critical for psilocybin’s sustained behavioural changes and therapeutic potential.