Psychedelic Research Papers

This observational study (n=202, 470, and 624) compares ketamine alone (KET) to ketamine combined with psychotherapy (KET+PSY) (35mg x 6) for depression and PTSD. Both treatments led to substantial symptom improvements, but no significant differences were found between groups. Exploratory analyses suggest younger females may benefit more from combined treatment, while older males may do better with ketamine alone.

This trial re-analysis (n=15) found that LSD (75µg) produces significant changes in dorsolateral prefrontal cortex (DLPFC) functional connectivity that correlate with subjective experiences: ego dissolution was associated with increased connectivity between DLPFC, thalamus and visual processing areas, while emotional arousal correlated with connectivity between right DLPFC, intraparietal sulcus and salience network. MEG analysis revealed increased theta-band information flow between thalamus and DLPFC, supporting the theory that disrupted thalamic gating underlies ego dissolution.

This open-label pilot study (n=12) found that psilocybin therapy (10mg followed by 25mg dose with psychotherapy) for Parkinson's disease patients with depression and/or anxiety appeared safe with no serious adverse events, whilst showing promising improvements in motor symptoms, cognitive function, depression and anxiety that persisted at three-month follow-up.

This pre-print multi-laboratory mouse study (n=~200 mice across five sites) demonstrates that psilocybin (2mg/kg) produces robust acute effects in mice including increased anxiety-related behaviours and decreased fear expression. However, it fails to show consistent persistent therapeutic effects 24 hours after administration, suggesting previous claims about psilocybin's lasting benefits may have been overstated.

This mouse study investigates how psilocybin affects different types of brain cells in the medial frontal cortex (mPFC; decision-making processes and judgement). The research finds that psilocybin increases dendritic spine density in both pyramidal tract (PT) and intratelencephalic (IT) neurons, but only PT neurons are essential for psilocybin's anti-stress effects through 5-HT2A receptor activation.

This study presents seven cryo-electron microscopy (cryo-EM) structures showing how different classes of psychedelic and non-psychedelic compounds interact with the serotonin (5-HT) 2A receptor—the primary target for classical psychedelics' therapeutic effects—revealing both shared and distinct binding patterns that could guide the development of new therapeutic compounds with improved side effect profiles.

This double-blind placebo-controlled trial (n=53) testing LSD microdosing (20μg; 2xp/w; 6w) for adults with moderate to severe ADHD found that while the treatment was safe and well-tolerated, it showed no advantage over placebo in reducing ADHD symptoms, with both groups showing similar improvements on standardised symptom measures.

This double-blind randomised clinical trial (n=37) found that a single dose of psilocybin (25mg) with brief psychotherapy did not significantly reduce alcohol relapse rates or consumption compared to placebo in patients with alcohol use disorder (AUD) at 4-week or 6-month follow-up, though psilocybin participants reported additional reductions in craving and temptation to drink, suggesting larger trials are needed to evaluate this approach for severely affected patients.

This open-label, proof-of-concept trial (n=5) of psilocybin-assisted therapy for fibromyalgia finds the treatment to be well-tolerated, with only transient blood pressure elevations and headaches reported. Secondary outcomes show clinically meaningful improvements in pain severity, pain interference, and sleep disturbance one month after treatment, with all participants reporting some degree of symptom improvement.

This secondary analysis of an open-label waitlist-controlled clinical trial (n=27) finds no significant differences in depression, anxiety, and suicidality symptom improvements between treatment-resistant depression (TRD) patients who discontinued antidepressants before psilocybin-assisted psychotherapy (1-3x25mg; PAP/PAT) and those unmedicated at screening.

This systematic review (s=98) examining psychedelic-catalysed insight found that 86% of studies showed insight was linked to therapeutic improvement, with insight being dose-dependent and significantly higher than placebo in 93% of comparative studies, suggesting insight may be a key mechanism in psychedelic therapy.

This pre-print qualitative study (n=18) explores therapeutic touch in psychedelic-assisted therapy (PAT) for Generalised Anxiety Disorder (GAD). It finds that most participants valued touch during psilocybin dosing sessions, feeling it provided connection and helped manage intense emotional experiences, with some attributing therapeutic effects to it. The study emphasises the importance of a strong therapeutic relationship and recommends individualised use of touch, alongside further research on safety and therapist training.

This double-blind Phase IIb trial (n=147) evaluated the efficacy, safety, and tolerability of esketamine nasal spray versus midazolam in reducing depressive (MDD) symptoms in adolescents at imminent risk for suicide (SI). The study finds that pooled doses of esketamine (56 and 84 mg) significantly reduce depressive symptoms at 24 hours, with common side effects including dizziness, nausea, and dissociation.

This systematic review (s=31) examines the side effects of microdosing LSD and psilocybin, finding that adverse effects are typically dose-dependent, mild, and short-lived. Common side effects include increased blood pressure, anxiety, and cognitive impairment. The review highlights the lack of standardised reporting on side effects and calls for future studies to provide more systematic and transparent assessments.

This neuroimaging study (n=62) investigates how psilocybin (19mg) reorganises brain connectivity in different contexts using fMRI and EEG. Participants were scanned before and after ingestion during rest and naturalistic stimuli (meditation, music, and visual). Under psilocybin, brain activity in eyes-closed states became more similar to eyes-open states, with increased connectivity in associative regions and decreased connectivity in sensory areas. The findings suggest that psilocybin induces a state of "embeddedness," reducing distinctions between self and environment, which may underlie both its subjective and therapeutic effects.

This computational fMRI study (n=15) examines brain dynamics after DMT (iv; 20mg) administration, focusing on the onset of the psychedelic state. It reveals a peak destabilization of brain dynamics around 5 minutes post-administration and identifies a heightened reactivity phase, primarily affecting fronto-parietal and visual regions. The study links these changes to serotonin 5HT2a receptor density, suggesting these dynamics underpin the psychedelic state's complexity and flexibility.

This randomized, double-blind, cross-over study (n=23) investigates LSD (100μg) effects after daily paroxetine (SSRI) or placebo administration in healthy participants. It finds paroxetine reduced negative LSD effects ("bad drug effect," "anxiety," "nausea") while maintaining pleasant effects, and caused higher LSD concentrations (1.4-1.5x) due to CYP2D6 inhibition, suggesting no LSD dose adjustment is needed when combined with CYP2D6-inhibiting SSRIs.

This one-year observational follow-up study (n=66) examined the long-term outcomes of psilocybin (25 mg, 10 mg, 1 mg; COMP360) in treatment-resistant depression (TRD). Median time to depressive relapse was longest in the 25 mg group (92 days) compared to 10 mg (83 days) and 1 mg (62 days), with most participants relapsing by week 12. A post hoc analysis of those entering the follow-up study (n=58) found a more pronounced difference, with the 25 mg group maintaining benefits for 189 days. Adverse events were minimal, with one case of mild suicidal ideation in the 1 mg group.

This systematic review (s=8) analyses completed controlled trials of psychedelics for depression, including psilocybin, LSD, ayahuasca, and DMT, all in Phase II or I/II. It evaluates methodological patterns against the draft European Medicines Agency guideline revision, highlighting challenges such as unblinding, expectancy, and adverse event characterisation, while calling for larger studies to assess long-term efficacy and safety.

This naturalistic longitudinal study (n=66) investigates the long-term effects of ayahuasca on mental health in adults with no prior exposure. Participants attending neo-shamanic ceremonies reported sustained improvements in depression, anxiety, stress, affect, personality traits, spirituality, and relationships up to 12 months. Individuals with depression or anxiety experienced lasting symptom reductions, while those without a diagnosis had short-term benefits. Alcohol and cannabis use decreased only at one month. Findings suggest ayahuasca's mental health benefits persist, with varying trajectories of change over time.

This open-label study (n=10) investigates the effects of single-dose psilocybin (25mg) therapy in adults with severe alcohol use disorder (AUD). It finds significant reductions in alcohol consumption, craving, and increases in self-efficacy over 12 weeks following treatment despite notable between-participant pharmacokinetic variations.

This single-blind, cross-over study (n=28) using MRI in healthy participants found that psilocybin (18.2mg/70kg) significantly decreased cerebral blood flow (CBF) and internal carotid artery (ICA) diameter. In contrast, ketanserin (20mg) had no significant effect. This finding suggests an asymmetric 5-HT2AR modulatory effect on CBF and provides the first in vivo human evidence of psilocybin-induced ICA constriction.

This pre-print, multimodal study (n=18) investigates psilocybin’s (5mg and 10mg) effects on perception and brain dynamics using psychophysics, ultra-high field fMRI, and computational modelling. It finds that psilocybin alters contextual perception in the Ebbinghaus illusion, modifies cortical responses to visual stimuli, and proposes a computational model linking these changes, suggesting altered contextual computations as a potential general mechanism of psychedelic action.

This theory-building paper proposes the ALBUS (Altered Beliefs Under Psychedelics) model as an extension of the REBUS hypothesis, suggesting that 5-HT2A receptor activation can lead to both relaxation (REBUS) and strengthening (SEBUS) of beliefs depending on dosage and context. The authors draw parallels between psychedelic states and lucid dreaming, focusing on mechanisms of conscious perception, dreaming, and memory.

This pre-print neuroimaging study (n=38) investigates the effects of MDMA and LSD on striatal connectivity (brain area, movement, and reward systems) using resting-state fMRI. The study finds that while neither drug significantly altered within-network connectivity of the striatum, both substances caused significant changes in connectivity with other brain regions, such as MDMA reducing connectivity between the limbic striatum and the amygdala and LSD increasing connectivity between the associative striatum and the frontal, sensorimotor, and visual cortices.

This survey (n=30) of psychedelic researchers identifies key research gaps in psychedelic harm and safety. It highlights the need to define types of harm, their predictors, and effective treatments. It also calls for better post-psychedelic support, including online resources, peer support, therapy, and psychiatric care. The authors advocate for increased funding, suggesting that psychedelic investors and companies allocate 1% of their investments to safety measures.

This qualitative analysis of Erowid.org experience reports (n=279) examines the temporal structure (organisation of time) of psilocybin experiences, focusing on the 'come-up' and 'come-down' phases. The study finds that the onset phase typically resembles an acute stress reaction with negative feelings. In contrast, the descending phase is characterised by positive feelings similar to post-stress recovery, suggesting a potentially important therapeutic mechanism.

This single-blind, randomized, two-arm, factorial, dose-finding study (n=16) investigates the pharmacokinetic and pharmacodynamic interactions between DMT and harmine in an ayahuasca-inspired ('pharmahuasca') formulation. Participants received six dose combinations (0–120 mg DMT, 0–180 mg harmine) via a transmucosal delivery system. Results show dose-dependent subjective effects lasting 4–5 hours, with peak plasma levels (Cmax) of 33 ng/mL for DMT and 49 ng/mL for harmine. Harmine increased DMT bioavailability and plasma half-life while altering its metabolism. The formulation demonstrated a favourable safety profile, supporting its potential for further clinical testing in affective disorders.

This secondary analysis (n=321) of the ESCAPE-TRD trial compared work productivity loss (WPL) and related costs in patients with treatment-resistant depression (TRD) receiving esketamine nasal spray (56mg or 84mg) versus quetiapine (atypical antipsychotic) extended release, both combined with an oral antidepressant. By week 8, WPL decreased by 30.3% with esketamine and 17.3% with quetiapine, leading to a cost savings difference of $156 per week. By week 32, WPL reductions were 45.3% (esketamine) and 32.5% (quetiapine), with a weekly cost savings difference of $153.

This prospective, longitudinal study (n=679) examined the effects of psilocybin use on emotional experiences, particularly feelings of shame and guilt. The study found that while most participants had positive experiences with psilocybin, acute feelings of shame or guilt were common (68%), and the ability to work through these feelings positively correlated with well-being in the weeks following use. On average, psilocybin resulted in a small but significant decrease in trait shame, which was maintained for 2-3 months after use, though in a minority of participants (30%), trait shame increased.