Psychedelic Research Papers

This randomised, double-blind, placebo-controlled single ascending dose study (n=29) tested prolonged intravenous DMT administration (30-s bolus (1.5-7.5mg) + 6-h infusion (4.4-33.3nl/ml)) in healthy volunteers. It found the treatment to be safe, with only mild, self-limiting adverse events, and observed mild psychedelic effects, reduced attention and stability, and decreased occipital alpha EEG power at higher doses, supporting further investigation in stroke recovery contexts.

This secondary analysis (n=82) of a Phase III RCT of MDMA-assisted therapy found significant improvements in both uncompassionate self-responding and compassionate self-responding across all six Self-Compassion Scale subscales, most with large effect sizes. Changes in self-compassion fully mediated the reductions in PTSD severity and depressive symptoms observed with MDMA-AT versus placebo plus therapy, though no significant effects were seen for alcohol or substance use outcomes.

This Phase III open-label extension study (n=1148) evaluates the long-term safety and efficacy of esketamine nasal spray combined with oral antidepressants in treatment-resistant depression (TRD) patients who previously participated in other Phase III trials. The study involved flexible dosing of intranasal esketamine (twice-weekly during induction, then weekly to monthly during maintenance) with direct staff supervision, with participants either entering through a 4-week induction phase (n=458) or directly into maintenance (n=690) based on their previous response.

This secondary analysis of an RCT (n=59) investigates the impact of psilocybin-assisted therapy (PAT) and escitalopram (SSRI) on responsiveness to emotional stimuli in patients with moderate-to-severe major depressive disorder over a 6-week trial period. Responses to emotional faces were reduced in the SSRI group, not the psilocybin group at the follow-up.

This secondary analysis of an RCT brain imaging (EEG) study (n=30) examines how DMT/HAR and Harmine alone affect face recognition and self-processing in healthy males using a visual oddball task. It finds DMT/HAR enhanced early visual processing while reducing neural differentiation between self and other faces at posterior sites, suggesting psychedelics reshape rather than erase self-boundaries while preserving socially meaningful representations.

This randomised, double-blind, placebo-controlled clinical trial (n=16) examines MDMA's (80-120mg) effects on neural circuits in individuals with subthreshold PTSD symptoms and early life trauma. The study finds that participants with higher baseline amygdala reactivity (emotional experiences) showed significant reductions in amygdala and sgACC (emotional processing) activity, increased sgACC-amygdala connectivity, and increased likability of threat expressions after 120mg MDMA compared to those with lower baseline reactivity.

This real-world study (n=185) found that oral esketamine (35-210mg/70kg; 6w; 12x) was effective and well-tolerated in severely treatment-resistant depression (TRD) patients, showing significant symptom improvement with minimal dropouts (7.6%), suggesting it could be a viable alternative to intranasal or intravenous administration.

This open-label fixed-order dose-escalation trial (n=14) evaluated inhaled DMT (15mg & 60mg) for treatment-resistant depression (TRD) for the first time. Results showed rapid and sustained antidepressant effects with a 21-point reduction on the Montgomery-Asberg Depression Rating Scale by day 7 (p<0.001), an 86% response rate, and a 57% remission rate lasting up to 3 months, with significant decreases in suicidal ideation (SI).

This multicenter, randomised, placebo-controlled clinical trial (n=236) investigates the efficacy and safety of esketamine (ESK) (8x35mg) for smoking cessation in patients with lung cancer and major depressive disorder (MDD). Eight weekly intranasal ESK sessions significantly improved both self-reported (44.1%) and biologically verified (28.8%) smoking abstinence at 6-month follow-up, alongside reductions in depression, anxiety, nicotine dependence, and respiratory symptoms.

This multi-dataset observational study (n=5 nationally representative surveys) quantifies changes in psilocybin use and healthcare utilisation in the United States between 2014 and 2023. It finds that adult lifetime use increased from 10.0% (25 million) in 2019 to 12.1% (31.3 million) in 2023, while adolescent use rose modestly from 1.1% to 1.3% during the same period.

This secondary analysis of a randomised trial (n=41) found that while psilocybin therapy (2x25 mg, three weeks apart) maintained emotional responses to musical surprises and increased activation in prefrontal and sensory brain regions. Escitalopram reduced surprise-related affective responses and increased activation in memory and emotional processing areas, suggesting distinct neurological mechanisms between these treatments for depression.

This exploratory observational study (n=14) examines the phenomenological and neuronal effects of 5-MeO-DMT through micro-phenomenological interviews, psychometric questionnaires, and EEG recordings in naturalistic ceremonial settings. The findings reveal that 5-MeO-DMT induces variable experiences of visual imagery, bodily and narrative self-disruption, and reduced phenomenal distinctions, with EEG showing alpha and beta power reductions suggesting inhibited top-down processing.

This prospective cohort study (n=654 start, n=212 end) investigated delusional ideation, magical thinking, and HPPD symptoms in participants before and after planned psychedelic use. Results showed reduced delusional ideation after one month, no changes in magical thinking, and HPPD-like effects in 30% of participants (though rarely distressing at <1%), with younger age, female gender, psychiatric history, and baseline trait absorption predicting HPPD-like effects.

This observational study (n=343) of terrorist attack survivors found that those under the influence of classic psychedelics during the traumatic event reported lower anxiety and post-traumatic symptoms compared to MDMA users or non-users, particularly when psychedelics were taken alone.

This re-analysis of a Phase I RCT (n=80) examines the pharmacokinetics (how the body affects a drug) of LSD microdosing (10µg; 14x; 6w) in healthy adult males. The study established a one-compartment pharmacokinetic model showing an elimination half-life of 3.08h, found minimal physiological effects (<15% change in heart rate), noted possible influence of CYP enzymes on drug metabolism, and reported no changes in peripheral BDNF levels.

This re-analysis (n=14) applies a receptor-informed network control theory framework to investigate the effects of DMT on the brain's control energy landscape. It reveals that DMT, like LSD and psilocybin, reduces global control energy, with these trajectories correlating with EEG signal diversity and subjective intensity ratings. Furthermore, the regional effects of DMT correlate with serotonin 2a receptor density, demonstrating a potential proof-of-concept for predicting pharmacological intervention effects on brain dynamics using control models.

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.