Psychedelic Research Papers

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 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 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 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 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 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 systematic review and meta-analysis (s=87; 2025) finds esketamine's efficacy as an adjunctive therapy for treatment-resistant depression (TRD) to be modest (effect size 0.15-0.23) and comparable to atypical antipsychotics, with no significant effect on suicidality. The review raises concerns about esketamine's abuse potential and unknown long-term effects. It also highlights regulatory issues, including deaths and emerging suicidality during clinical trials.

This secondary analysis of an open-label, single-blind, Phase IIIb trial (n=676) compares esketamine nasal spray plus an SSRI/SNRI versus extended-release quetiapine plus an SSRI/SNRI for treatment-resistant depression (TRD). It finds esketamine to be superior in achieving remission at week 8 (27.1% vs. 17.6%, p=0.003) and preventing relapse through week 32 (21.7% vs. 14.1%). Adverse events align with known safety profiles.

This retrospective cohort study (n=14,912) examines healthcare resource use (HRU) and costs among patients with major depressive disorder (MDD) and acute suicidal ideation or behaviour (SI) initiated on esketamine nasal spray, ECT, SGA augmentation, or antidepressant monotherapy in the U.S. Esketamine-treated patients (n=122) had lower acute care HRU (0.59 days) and costs ($1869/month) compared to ECT (3.17 days, $4624) and SGA augmentation (0.92 days, $2163), but higher than monotherapy (0.32 days, $863). Esketamine reduced HRU (58%) and costs (50%) most significantly from baseline.

This secondary analysis of a Phase III trial (n=174) evaluates the effects of subcutaneous ketamine on anxiety in treatment-resistant depression (TRD). Significant reductions in anxiety (HAM-A scores) were observed in cohort 2 with flexible dosing (35-63mg/70kg) but not in cohort 1 with fixed low dosing (35mg/70kg). These effects, mediated by changes in depression (MADRS), were not sustained 4 weeks post-treatment.

This review (2024) examines the effects of classic psychedelics (e.g., LSD, psilocybin, DMT) and non-classic psychedelics (e.g., ketamine, MDMA) on neuroplasticity. Drawing on preclinical and clinical studies, it discusses molecular, structural, and functional changes induced by these agents, highlighting their potential to re-open developmental windows (hyper-plasticity) and increase nervous system sensitivity to stimuli (meta-plasticity). Translating findings to humans remains challenging, but emerging tools like PET radioligands and multimodal approaches offer promise for future research.

This robustness analysis of the ESCAPE-TRD Phase IIIb trial (n=676) investigates esketamine nasal spray versus quetiapine extended release for treatment-resistant depression (TRD). Esketamine significantly outperformed quetiapine in achieving remission at week 8 (MADRS ≤10) and maintaining relapse-free status through week 32, with hazard ratios favouring esketamine (HR: 1.658–1.711, p < 0.001).

This randomized, double-blind, psychoactive-controlled study (n=12) compared intramuscular ketamine (35-70mg/70kg) to fentanyl (50μg) in treatment-resistant OCD patients, with 10 participants completing the trial. The study found dose-dependent reductions in OCD symptoms (Y-BOCS scores) for ketamine compared to fentanyl, with effects lasting up to 168 hours, though two participants dropped out due to dissociative effects.

This meta-analysis (s=29) examines the effects of psychedelics (including ketamine and MDMA) and two other 'psychoplastogens' on peripheral BDNF levels in humans. It finds no significant changes in BDNF levels post-administration (SMD=0.024, p=0.64), regardless of drug, dose, participant age, or psychiatric condition. Studies with better-controlled designs report smaller effect sizes, and later timepoints show minimal increases in BDNF. The authors conclude that peripheral BDNF is likely not a reliable marker of rapid neuroplasticity and recommend neuroimaging or stimulation-based methods for future research.

This review (2024) highlights preclinical research from the past 15 years showing that ketamine and psychedelics trigger dendritic spine growth in cortical pyramidal neurons, enhancing neural plasticity. It compares the longitudinal effects of psychoactive drugs, emphasizing rapid-onset and sustained structural plasticity as key features of rapid-acting antidepressants, and discusses gaps in understanding and prospects for other interventions like rTMS.

This online survey (n=6,193; 2,488 microdosers) examines differences between exclusive microdosers and those who use both micro and macrodoses of psychedelics. The study finds exclusive microdosers were typically older, more likely to be female and non-Caucasian, with psilocybin (74.5%) and LSD (34.4%) being the most commonly used substances, primarily for general wellbeing (73.0%).

This retrospective analysis (n=841) of the Prehospital Tranexamic Acid Use for Traumatic Brain Injury trial evaluates the effects of ketamine in subjects with traumatic brain injury (TBI). It finds no significant difference in mortality or disability between ketamine-exposed (15.5%) and unexposed subjects, though ketamine exposure was associated with fewer instances of elevated intracranial pressure and a lower increase in TBI protein biomarkers, despite a higher likelihood of seizure activity in the ketamine group.

This meta-analysis (2024, s=31) examines the correlation between subjective effects and therapeutic outcomes for ketamine (s=23, n=471) and psilocybin (s=8, n=183) in depression and substance use disorder (SUD) treatment. It finds modest mediating effects of subjective experiences on therapeutic outcomes, with psilocybin showing a stronger mediating effect (R² = 24%) compared to ketamine (R² = 5-10%), and a greater mediating effect observed in SUD compared to depression regardless of the substance used.

This preprint open-label study (n=20) examines the effects of ketamine infusions (35mg/70kg, 6x) on biological ageing markers in individuals with depression (MDD) or PTSD. It finds reductions in epigenetic age as measured by OMICmAge, GrimAge V2, and PhenoAge biomarkers, as well as significant changes in Epigenetic Biomarker Proxies (EBPs) and surrogate protein markers following a 2-3 week treatment course. The study also reports expected decreases in depression and PTSD scores as measured by PHQ-9 and PCL-5.

This randomized, double-blind, placebo-controlled study (n=68) assesses the prosocial, entactogen effects of ketamine (35mg/70kg) in participants with treatment-resistant depression (TRD). Ketamine increased pleasure from social interactions and helping others, lasting for one week post-treatment. In a rodent experiment, ketamine-treated rats showed increased protective behaviour towards their cage mates, indicating entactogen effects.

This Phase I study evaluates the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of (2R,6R)-Hydroxynorketamine (RR-HNK) in healthy volunteers. It finds that RR-HNK has a minimal adverse event profile, no serious adverse events, and no anaesthetic or dissociative effects at all doses. The study also reports dose-proportional increases in PK parameters and promising PD outcomes, including gamma power increases in some participants and CNS exposure, supporting progression to Phase II.

This double-blind, pilot study (n=28) investigates esketamine combined with mindfulness-based intervention (MBI) for individuals with alcohol misuse problems. Esketamine enhanced psychological engagement in MBI and transiently decreased alcohol cravings, while also resulting in greater mystical experiences and dissociative states compared to placebo.

This secondary analysis of a randomized, double-blind, crossover trial (n=61) evaluates the impact of ketamine on sleep metrics in individuals with treatment-resistant depression (TRD) compared to healthy volunteers (HVs). It finds that while ketamine affects delta and alpha power during sleep, it does not significantly alter sleep macroarchitecture or mediate its antidepressant and anti-suicidal effects through sleep variables.

This open-label pilot study (n=20) investigated the safety and efficacy of intranasal ketamine for treating a single cluster headache (CH) attack. While the primary endpoint of a 50% reduction in pain intensity within 15 minutes was not met, at 30 minutes post-treatment, pain intensity was significantly reduced by 59% on an 11-point scale, with no serious adverse events reported.

This randomized controlled trial (n=116) investigated the psychological mechanisms of ketamine's antidepressant effects. Participants receiving ketamine reported significantly heightened feelings of awe compared to those receiving a placebo. Awe experiences, as measured by the Awe Experience Scale (AWE-S), mediated depression outcomes (% improvement in MADRS scores) at multiple time points (24 hours and 5, 12, 21, and 30 days) post-infusion, indicating a potential role of awe in ketamine's therapeutic efficacy for depression.

This retrospective observational cohort study (n=966 esketamine initiators, n=39,219 controls) examines factors influencing esketamine initiation and continuation for treatment-resistant depression (TRD). Initiators resided closer to treatment centres, with initiation rates decreasing significantly with distance. Factors associated with increased initiation included posttraumatic stress disorder, suicidal ideation, and male sex, while Medicaid, substance use disorder, older age, and greater distance were associated with lower initiation rates.

This single-blind placebo-controlled study (n=40) investigated the neural and behavioral effects of acute ketamine in healthy participants. Results revealed robust inter-individual variability in both neural and behavioral responses to ketamine, with data-driven individual symptom variation mapping onto distinct neural gradients. These findings emphasize the need to consider individual variation in response to ketamine and suggest potential implications for developing precise pharmacological biomarkers in psychiatry.

This pre-print open-label trial (n=117) administered intravenous ketamine in highly supportive environments to outpatients with elevated PTSD symptoms. The protocol included preparatory, integration, sensory immersion, and psychotherapy sessions, resulting in significant reductions in PTSD symptoms. The study highlights the potential of ketamine when delivered in a psychedelic therapy paradigm, suggesting it as a promising option for PTSD treatment resistant to other therapies.

This 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. Patients received either 160 mg/day or 240 mg/day KET01 or placebo for 14 days, with the primary endpoint being the change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to day 15. Results suggest a positive trend towards antidepressant efficacy with 240 mg/day KET01.

This meta-analysis (n=1100; s=14) of clinical trials on patients with depression (MDD) receiving ketamine or esketamine reveals 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.