Journal of psychopharmacology (Oxford, England)
November 19, 2025
Hillary Ung, Gemma Mckeon, Zorica Jokovic et al.
1 citation
A systematic review and meta-analysis examined whether cognitive side effects of recreational MDMA (ecstasy) improve after at least six months of abstinence. Fourteen studies were reviewed; five were included in a meta-analysis of learning and memory. Both current and former MDMA users showed poorer learning and memory than people who never used MDMA (effect sizes of -1.06 and -1.37, respectively). There was no significant difference between current and abstinent users, and longer abstinence did not correlate with cognitive recovery. Evidence for impairments in other cognitive domains was limited. The authors note these conclusions rest on low-quality evidence.
Journal of psychopharmacology (Oxford, England)
July 1, 2025
Julie A Marusich, Cassandra Prioleau, Luli R Akinfiresoye
1 citation
Hexahydrocannabinol (HHC), sold as a legal replacement for Δ9-THC, has two epimers: 9(R)-HHC and 9(S)-HHC. In adult male mice, 9(R)-HHC produced all four cannabimimetic effects (locomotor suppression, antinociception, hypothermia, and catalepsy) and fully substituted for Δ9-THC in drug discrimination, with similar potency except for greater hypothermia. 9(S)-HHC only produced effects in two tetrad measures, was less potent, and partially substituted for Δ9-THC. 9(R)-HHC likely has abuse liability in humans, while 9(S)-HHC may produce weak Δ9-THC-like psychoactivity. The ratio of epimers consumed may influence effects in human users.
Journal of psychopharmacology (Oxford, England)
May 28, 2025
Yana Vella, Kateřina Syrová, Aneta Petrušková et al.
1 citation
Psilocin, the active compound in magic mushrooms, promotes the formation of new synapses in rat brain cells, an effect comparable to ketamine and lithium. In laboratory experiments on rat cortical cultures, psilocin increased the number of synaptic puncta and boosted expression of the immediate early gene Arc after acute treatment. Lysergic acid diethylamide (LSD) and N,N-dimethyltryptamine (DMT) did not produce significant synaptogenic effects. Fluoxetine, a common antidepressant, had no effect on synapse formation but upregulated other immediate early genes. These findings add evidence that psilocin may be a promising therapeutic agent for psychiatric conditions.
Journal of psychopharmacology (Oxford, England)
May 1, 2025
Katherine Cheung, Rebecca Ehrenkranz, Jared T Hinkle et al.
1 citation
A commentary responds to a proposed framework for assessing adverse events in psychedelic-assisted therapies, which includes spiritual, existential, religious, and theological impacts. The authors argue that adverse event assessment in psychedelic clinical trials should match the rigor and standards of other research areas, and emphasize the need for transparency and accessibility in reporting. The commentary discusses the framework's feasibility and various assessment methods, focusing on ensuring systematic and unbiased evaluation of adverse events.
Journal of psychopharmacology (Oxford, England)
May 1, 2025
Niloufar Pouyan, Jacob S Aday, Steven E Harte et al.
1 citation
People with treatment-resistant conditions often see their illness as part of their identity. The pictorial representation of illness and self measure (PRISM) gauges this self-condition enmeshment. In a survey of 297 individuals who used psychedelics therapeutically on their own, most reported symptom improvement: 95.4% with depression, 98.36% with posttraumatic stress disorder, and 94.87% with anxiety. PRISM scores dropped significantly after the most salient psychedelic experience, indicating reduced identification with the condition. The decrease in PRISM scores correlated with symptom improvement across all conditions. PRISM appears useful for tracking how psychedelics affect self-perception across diagnoses, though limitations include convenience sampling, potential positive bias, and retrospective reporting.
Journal of psychopharmacology (Oxford, England)
March 24, 2025
Chung-Feng Kao, Shih-Jen Tsai, Tung-Ping Su et al.
1 citation
Low-dose ketamine, an N-methyl-D-aspartate receptor antagonist, has an antidepressant effect in treatment-resistant depression that may involve multiple monoamine neurotransmitter systems beyond glutamate. In a trial with 65 patients, those receiving 0.5 mg/kg or 0.2 mg/kg ketamine were compared with those receiving normal saline. Genetic analysis of 50 monoamine-related genes found that variants in the cholinergic, dopaminergic, serotonergic, opioid, cannabinoid, and σ1 receptor systems were associated with ketamine's antidepressant effect. The neuroactive ligand-receptor interaction pathway played a key role. The findings suggest that ketamine's effects involve serotonin, dopamine, and other monoamine systems.
Journal of psychopharmacology (Oxford, England)
January 1, 2025
Sarah Pereira Gomes, Sofia Rodrigues Lima, Fabio Gomes de Matos Souza et al.
1 citation
A letter critically discusses a previously published study on ketamine for treatment-resistant depression, raising concerns about the methodology, choice of outcome measures, and interpretation of results. The author questions whether the active control and crossover design adequately addressed placebo effects and blinding, and whether the reported improvements reflect genuine antidepressant effects or unblinding and expectation bias. The letter does not present new data but highlights potential limitations in the original study's design and conclusions.
Journal of psychopharmacology (Oxford, England)
July 13, 2026
Todd D Gould, Sanjay J Mathew, Maurizio Fava et al.
A new pharmacological model called event-driven pharmacology (EDP) is described, in which a plastogen—a drug that induces lasting neural plasticity—produces sustained effects after only transient binding, unlike traditional drugs that require continuous receptor occupancy. Plastogens such as ketamine and classical psychedelics can trigger metaplasticity, priming synapses to respond to later stimuli long after the drug has left the body. Dosing such drugs to maintain constant target occupancy may paradoxically reduce benefits and increase side effects. The EDP model calls for new drug development, dosing strategies, and biomarkers to harness the therapeutic potential of plastogens for depression and other synaptic disorders.
Journal of psychopharmacology (Oxford, England)
June 25, 2026
Pavan S Brar, Rebecca B Price, Stephen Ross et al.
Psychedelic compounds like psilocybin and LSD are being studied again as potential treatments, but research usually excludes people at risk for psychosis. This narrative review examines the historical and theoretical links between psychedelics and schizophrenia spectrum disorders (SSDs), including the psychotomimetic hypothesis. The authors compare the phenomenological experiences induced by psychedelics with those of SSDs, finding both overlap and important qualitative differences that challenge a simple equivalence. They review neural mechanisms involving serotonin, dopamine, and glutamate. Clinical evidence shows psychedelics can worsen existing psychotic illness and may trigger psychosis in vulnerable individuals, though the risk magnitude is not well quantified. The authors suggest potential therapeutic applications for carefully selected symptoms in stable patients using low-dose, controlled approaches and provide recommendations for managing psychosis-related risk.
Journal of psychopharmacology (Oxford, England)
June 25, 2026
Joost C Van Mechelen, Tobias A Wieles, Laura G J M Borghans et al.
Oral S-ketamine (S-KETPO) has poor bioavailability (9-12%) and produces much lower peak concentrations of S-ketamine but higher levels of its active metabolites norketamine and hydroxynorketamine compared to intravenous S-ketamine (S-KETIV). In 16 healthy participants, S-KETIV caused sedative, psychomotor, and psychotomimetic effects along with reductions in brain electrical activity, while the higher oral dose (0.45 mg/kg) showed limited psychotomimetic effects and smaller brain activity reductions, and the lower oral dose (0.20 mg/kg) had no effects. Safety was similar across treatments. These pharmacokinetic and pharmacodynamic differences may affect dose selection and therapeutic outcomes in treatment-resistant depression.
Journal of psychopharmacology (Oxford, England)
June 24, 2026
Shreya Vasudeva, Gabrielle F M Lovell, Sabrina Wong et al.
Ketamine and its enantiomer esketamine show low risk of abuse, dependence, or misuse when administered under controlled clinical supervision, based on a systematic review of 30 studies (25 clinical and 5 preclinical). Clinical studies found minimal evidence of craving, dose escalation, or illicit use in monitored settings. Preclinical work indicated that (S)-ketamine produces reward-related behaviors, racemic ketamine shows reinforcing effects at higher doses, and (R)-ketamine has minimal reinforcing effects. Abuse risk was identified mainly in case reports lacking proper monitoring. The findings support safe incorporation of ketamine into mood disorder treatment protocols with structured administration and ongoing monitoring.
Journal of psychopharmacology (Oxford, England)
June 16, 2026
Alice Caulfield, Matthew Butler, Mitul A. Mehta
Psychedelics show promise for treating neuropsychiatric conditions, but their Schedule 1 status creates regulatory and economic hurdles for research. Rigorous human mechanistic studies are needed to understand how psychedelics produce therapeutic effects. This article offers practical guidance on study design, legislation, and drug sourcing, based on the authors' experience setting up non-clinical studies in the UK. The guidance aims to help researchers navigate the complex process of establishing human psychedelic studies, with some content applicable to investigator-initiated studies more broadly.
Journal of psychopharmacology (Oxford, England)
May 31, 2026
Anna Beatriz Vicentini, Caio César De Paula, José Augusto Silva Reis et al.
A systematic review of 48 studies (14 experimental, 34 observational) covering 2016–2024 found that classic psychedelics—such as psilocybin and ayahuasca—most consistently increase the personality trait Openness and reduce Neuroticism. Changes in Extraversion, Agreeableness, and Conscientiousness were more variable. Microdosing was linked to modest reductions in Neuroticism and higher Absorption. Most studies used the Five-Factor Model. The findings suggest psychedelics can promote lasting personality changes, but contradictory results remain, and future research should combine experimental and naturalistic designs with longer follow-ups.
Journal of psychopharmacology (Oxford, England)
May 29, 2026
Kristoffer Brendstrup-Brix, Brice Ozenne, Patrick M Fisher et al.
Patients with chronic cluster headache (CCH) suffer from poor sleep, which may affect brain microstructure and waste clearance. In 11 CCH patients, subjective sleep quality—measured by the Pittsburgh Sleep Quality Index—improved one week after three doses of psilocybin (0.14 mg/kg) given one week apart, with a mean PSQI change of -2.50 points. Before treatment, CCH patients had poorer sleep and differences in brain microstructure and water diffusivity compared to 24 healthy controls, primarily in grey matter. Psilocybin intervention was not associated with statistically significant changes in brain microstructure or water diffusivity on average, though most patients showed lower white matter diffusivity and neurite volume. Subjective sleep quality showed borderline significant correlations of moderate effect size with brain microstructure and water diffusivity.
Journal of psychopharmacology (Oxford, England)
May 29, 2026
Elliot Hampsey, Kirsty Martin, Michail Kalfas et al.
A systematic review of 32 trials in healthy adults found that LSD and psilocybin show dose-proportional peak concentrations (Cmax), while DMT's oral and intravenous formulations differ in ways that may be clinically significant. LSD was the most studied psychedelic, followed by DMT and psilocybin; mescaline appeared in only two trials. Single studies examined intravenous LSD, intravenous psilocybin, inhaled 5-MEO-DMT, and intranasal 5-MEO-DMT. Variations in absorption, distribution, and elimination among the compounds may have important implications for clinical and research settings.
Journal of psychopharmacology (Oxford, England)
May 23, 2026
Joanna Kuc, Rosalind G McAlpine, Amelia Sellers et al.
A short-acting psychedelic, 5-MeO-DMT, shifts speech from external focus to introspection. In 29 participants who kept daily voice journals two weeks before and after a single 12 mg dose, language analysis showed increased cognitive words and fewer social words, while vocal quality changed with more jitter and shimmer. Baseline speech patterns predicted how prepared people felt, the intensity of emotional breakthrough, and later well-being. This is the first longitudinal study showing that vocal journaling can track and predict psychological transformation around a psychedelic retreat, offering a framework for monitoring preparation and integration periods.
Journal of psychopharmacology (Oxford, England)
May 2, 2026
Zarmeen Zahid, Rick J Strassman, Clifford R Qualls et al.
Blocking the 5-HT1A receptor with pindolol before giving a low dose of DMT to experienced hallucinogen users intensified the drug's subjective effects, with a moderate effect size. Blood pressure also increased shortly after DMT administration, while heart rate was unchanged. The findings suggest that 5-HT1A receptor activity normally dampens the subjective effects of psychedelics, pointing to a functional role for this receptor in shaping the psychedelic experience.
Journal of psychopharmacology (Oxford, England)
May 1, 2026
Vincent J Diehl, Abigail E Calder, Gregor Hasler
A new questionnaire, the Helioscope Questionnaire, measures how psychedelics such as psilocybin and MDMA alter the processing of traumatic memories during an experience, a process called the helioscope effect. In an online survey of 468 people who had used psychedelics or MDMA, the 21-item scale captured three factors: protection, exposure, and avoidant-distress. A composite score from protection and exposure subscales predicted positive changes in mood and attitude afterward, while avoidant-distress predicted negative changes. Having a trip sitter was linked to stronger protection and exposure scores, and MDMA use was linked to less avoidant-distress. The scale adds a new way to assess therapeutic mechanisms beyond existing measures.
Journal of psychopharmacology (Oxford, England)
May 1, 2026
Brian O'Mahony, Colm Harrington, Andrew Harkin et al.
Psychedelic drugs are being studied as treatments for mental health conditions and used recreationally, but they can cause intense psychological distress known as a "bad trip," which may lead to emergency care or psychiatric hospitalization. Managing these episodes should prioritize non-pharmacological strategies, but when those are insufficient, medications that can safely end the psychedelic state are needed. This review systematically evaluates candidate abortive agents, including serotonin antagonists, antipsychotics, and certain anxiety and depression drugs, considering their mechanisms, safety, and suitability for acute care. The authors propose a provisional framework for pharmacological management and identify priorities for future research.
Journal of psychopharmacology (Oxford, England)
May 1, 2026
Otto Simonsson, Taylor Lyons, Joseph Marks et al.
Across three studies—a naturalistic observation, a single-arm psilocybin trial with healthy volunteers, and a randomized controlled trial comparing psilocybin to escitalopram in depressed patients—psychedelic use did not produce significant changes in authoritarian attitudes. Contrary to earlier suggestions, the evidence does not reliably show that psychedelics decrease authoritarian attitudes. Future work should use larger, more diverse samples and examine other political outcomes.
Journal of psychopharmacology (Oxford, England)
May 1, 2026
Otto Simonsson, Sunjuri Sun, Laura W Wesseldijk et al.
In a large twin study using the Swedish Twin Registry, people who reported using psychedelics had lower odds of having a history of migraine. Among identical twins, the twin who used psychedelics was less likely to have migraine than their co-twin who did not. The association was significant in males but not in females. These results suggest a possible link between psychedelic use and reduced migraine likelihood, with sex differences that need further study.
Journal of psychopharmacology (Oxford, England)
May 1, 2026
Guy Simon, Maya Gal-Birman, Nir Tadmor et al.
In the October 7, 2023, attack at the Nova rave, 45 survivors were interviewed using a mixed-methods phenomenological design. Participants used classic psychedelics (24), empathogens (19), or ketamine (2). A dissociative phenomenon termed "adaptive psychedelic dissociation" emerged, combining emotional detachment, derealization, depersonalization, automatic behaviors, and preserved functionality. Participants' awareness of their substance use created an "epistemic container" that helped contain traumatic input in real time but complicated later meaning-making. Psychedelic effects appeared suppressed during acute trauma and resurged afterward. Substance use had a predominantly positive impact on immediate survival (75%-79%) and emotional coping (83%-84%), but mixed outcomes in aftermath processing (42%-53% positive, 25%-26% negative). This paradox suggests acute adaptive benefits with integration challenges.
Journal of psychopharmacology (Oxford, England)
May 1, 2026
Bonnie Brusky, Katia M'Bailara, François Alla et al.
In most clinical trials of psychedelic-assisted treatments, the psychological support provided meets accepted definitions of psychotherapy. A systematic review of 29 trials (449 patients) using a four-item common factors framework found that 69% of all trials satisfied all four criteria. Among trials that explicitly labeled their support as psychotherapy, 84% met all four factors; among those that did not use the label, 40% still met all four. The findings suggest that psychological interventions in these trials are not merely for risk minimization but function as active therapeutic components. This has implications for clinician training, treatment duration, and the ethical need to measure and address the complexity of these interventions to improve outcomes and protect patients.
Journal of psychopharmacology (Oxford, England)
April 24, 2026
Marco Colizzi, Elisa Morandin, Veronica Croccia et al.
In adults with treatment-resistant depression, higher baseline levels of the inflammatory marker interleukin-6 (IL-6) were associated with more rapid symptom reduction after intranasal esketamine treatment, while lower IL-6 predicted greater symptom severity and higher disability. IL-6 levels themselves did not change over the 24-week open-label phase 2 trial. The finding suggests that inflammation may play a role in treatment resistance and that baseline IL-6 could help guide personalized treatment decisions.
Journal of psychopharmacology (Oxford, England)
April 16, 2026
Minna Chang, Allan H Young, Mario F Juruena
Both electroconvulsive therapy (ECT) and ketamine show sustained therapeutic potential for treatment-resistant depression, with ECT possibly associated with longer remission. Higher doses, more frequent administration, and maintenance ECT or ketamine appear to prolong remission, and continuing oral antidepressants may extend it further. This systematic review of 13 studies found no direct head-to-head comparisons of time-to-relapse between the two treatments that met inclusion criteria, preventing formal statistical analysis. The review excluded studies involving psychotic depression, limiting generalizability to those populations.