Journal of psychopharmacology (Oxford, England)
January 1, 2025
Gianmarco Ingrosso, Anthony J Cleare, Mario F Juruena
20 citations
A review of 16 studies involving 2,174 patients found that addiction phenomena during ketamine treatment for depression are rare. Only four patients showed clear signs of tolerance or dependence, while the vast majority did not. The review included randomized controlled trials and other study designs using various routes of administration, including intravenous and intranasal esketamine. The findings suggest that medically supervised ketamine treatment is relatively safe for adult depression patients, though the authors emphasize the need for vigilant monitoring and careful dosing. Future research using standardized scales could further strengthen evidence for safe use.
Journal of psychopharmacology (Oxford, England)
June 1, 2024
Emily M Gent, Joshua W Bryan, Maisy A Cleary et al.
20 citations
A double-blind pilot study tested whether a single dose of esketamine, combined with two weeks of daily mindfulness-based intervention (MBI), enhances engagement in meditation and improves alcohol-related outcomes among 28 individuals with alcohol problems. Participants received either sublingual esketamine (115.1 mg) or a vitamin C placebo. Esketamine increased psychological engagement with daily MBI and produced transient decreases in alcohol cravings, along with greater mystical experiences and dissociative states compared to placebo. The findings suggest that esketamine may improve treatment outcomes when paired with mindfulness-based therapies by boosting engagement with meditative practice.
Journal of psychopharmacology (Oxford, England)
December 1, 2023
Genís Ona, Ingrid Reverte, Giordano N Rossi et al.
20 citations
Ibogaine and its main metabolite, noribogaine, modulate several brain targets associated with substance use disorders. Rather than having a single key mechanism, their anti-addictive action appears to arise from a complex modulation of multiple receptor systems, creating potential beneficial synergies. This understanding comes from a review of theoretical and experimental studies published up to July 2022. The authors suggest that future research should apply polypharmacology approaches to better describe the multifaceted patterns of this multi-target drug, which could guide both mechanistic and therapeutic studies.
Journal of psychopharmacology (Oxford, England)
June 5, 2025
Ben Beaglehole, Paul Glue, Shona Neehoff et al.
19 citations
In an open-label extension of a prior crossover trial, oral ketamine was given for six weeks to people with treatment-resistant depression, post-traumatic stress disorder, or obsessive-compulsive disorder. Doses started at 1-1.5 mg/kg and increased to 1.5-2.5 mg/kg, taken one to three times per week. Symptom scores remained low throughout the six weeks, and the oral formulation was well tolerated with few side effects. The findings suggest that oral ketamine can sustain improvements in these treatment-resistant conditions and offers a practical alternative for maintenance therapy.
Journal of psychopharmacology (Oxford, England)
March 1, 2023
Takesha Cooper, Michael David Seigler, Stephen Stahl
18 citations
Several new drugs for depression work much faster than traditional antidepressants, sometimes after a single dose. These agents target three different brain systems: NMDA glutamate receptors, GABA A neurosteroid and benzodiazepine sites, and serotonin 2A/2C receptors. Despite their different targets, all trigger rapid neuroplasticity—the brain's ability to reorganize—which correlates with their fast antidepressant effects. Some of these drugs, called neuroplastogens, induce neuroplasticity without altering mental state. Others, called psychoplastogens, cause dissociation or hallucinatory experiences. There is debate whether these mental changes are necessary for the antidepressant effect or are unwanted side effects. These new treatments are expected to transform the management of major depressive disorder.
Journal of psychopharmacology (Oxford, England)
January 1, 2025
Karen P Barrios, Dean J Connolly, Jason A Ferris et al.
17 citations
Ketamine use has increased globally, particularly among young men, yet emergency medical treatment for its toxicity is rare and often linked to other substance use. Analysis of over 130,000 Global Drug Survey responses found that 5.93% had used ketamine in their lifetime, with 57.70% using it in the past year. Past-year users were typically younger (average age 24.84 years), gay, students, and used other drugs. Among 4,477 past-year users, 120 adverse events occurred, with less than 0.10% requiring emergency medical treatment. The findings indicate frequent use but low harm, highlighting the need for tailored harm reduction and comprehensive screening for substance dependence.
Journal of psychopharmacology (Oxford, England)
October 1, 2024
Jessica L Ables, Leah Israel, Olivia Wood et al.
17 citations
Harmine, a component of the hallucinogenic brew ayahuasca, was tested in a phase 1 clinical trial to determine its safety, tolerability, and psychoactive effects when taken alone. Twenty-five healthy adults received single oral doses of 100 to 500 mg of pharmaceutical-grade harmine hydrochloride. The maximum tolerated dose was between 100 and 200 mg, and doses above 2.7 mg/kg caused vomiting, drowsiness, and limited psychoactive effects in 90% of participants. No serious adverse events occurred. Harmine alone can be safely administered at low doses, but higher doses produce dose-limiting side effects and only mild psychoactivity.
Journal of psychopharmacology (Oxford, England)
October 1, 2024
Valerie Bonnelle, Amanda Feilding, Fernando E Rosas et al.
16 citations
The joint influence of the sympathetic and parasympathetic nervous systems over cardiac activity, known as sympathovagal coactivation, is positively related to ratings of spiritual experience and insightfulness during the DMT-induced peak experience, and also to improved well-being two weeks later. The balance between the two autonomic branches before DMT injection predicted insightfulness scores and subsequent coactivation. These findings demonstrate the autonomic nervous system's involvement in psychedelic-induced peak experiences.
Journal of psychopharmacology (Oxford, England)
May 1, 2025
Sean P Goldy, Benjamin A Du, Julia S Rohde et al.
15 citations
Classic psychedelics carry both greater acute challenging effects and persisting negative effects compared to cannabis, but also produce greater positive acute and persisting effects. In two studies using quota-based sampling to approximate US Census demographics, participants reported on their first or most memorable experiences with either substance. Predictors of psychedelic outcomes—such as dose level, presence of others, religiosity, and personality—explained only a small degree of the variation. The findings offer a more nuanced characterization of the risks and benefits of psychedelic experiences relative to cannabis.
Journal of psychopharmacology (Oxford, England)
July 1, 2024
Mariusz Papp, Piotr Gruca, Ewa Litwa et al.
15 citations
Two compounds that selectively activate serotonin 5-HT1A receptors in a biased manner, NLX-101 and NLX-204, produce rapid antidepressant effects in rats exposed to chronic mild stress, similar to ketamine. When injected directly into the prefrontal cortex, these compounds reversed stress-induced anhedonia, reduced anxiety, and improved working memory deficits. Blocking 5-HT1A receptors in the prefrontal cortex eliminated these benefits, showing that the compounds work specifically through these receptors. The findings suggest that biased agonism at 5-HT1A receptors is a promising strategy for rapid-acting antidepressants that may avoid ketamine's side effects while also addressing cognitive deficits and anxiety.
Journal of psychopharmacology (Oxford, England)
May 1, 2024
Thomas Knuijver, Rob Ter Heine, Arnt F A Schellekens et al.
15 citations
Ibogaine, a hallucinogenic drug being studied for opioid use disorder, shows highly variable pharmacokinetics strongly linked to CYP2D6 genotype. In 14 patients given a single 10 mg/kg dose, ibogaine clearance increased by 30.7 L/h per point of CYP2D6 activity score, from a baseline of 0.82 L/h. Higher ibogaine plasma concentrations correlated significantly with QTc prolongation and cerebellar ataxia, while noribogaine did not. Neither ibogaine nor its metabolite correlated with opioid withdrawal severity. These findings suggest that cardiac and neurological side effects are driven more by ibogaine itself, and that lower or genotype-personalized dosing may improve safety.
Journal of psychopharmacology (Oxford, England)
May 1, 2025
Stephanie Lake, Philippe Lucas
13 citations
Co-use of psychedelics with other psychoactive substances may increase health and social harm. An international survey of 5,370 adults who use psychedelics found that 56.3% typically co-use at least one of 11 psychedelic substances, with rates lowest for ayahuasca (14.8%) and highest for nitrous oxide (54.5%). Cannabis and alcohol were the most common secondary substances. Depressants were the only class whose use increased after psychedelic experiences. Greater psychedelic experience and recreational use were associated with higher co-use, while personal exploration and therapeutic use were negatively associated. Findings suggest harm reduction messaging should target specific psychedelic consumers.
Journal of psychopharmacology (Oxford, England)
February 1, 2021
Dylan Truppman Lattie, Hayley Nehoff, Shona Neehoff et al.
13 citations
Ketamine produced rapid, dose-related reductions in fear and anxiety among patients with treatment-resistant anxiety disorders. In a study of 24 patients receiving short-term ascending subcutaneous doses followed by a 3-month maintenance phase, scores on all three Fear Questionnaire subscales (agoraphobia, social phobia, blood-injury phobia) and the Spielberger State Anxiety Inventory decreased quickly after acute dosing and continued to decline progressively during maintenance therapy. Ketamine appears to have broad, dose-related anti-phobic effects, suggesting potential for treating other phobic conditions.
Journal of psychopharmacology (Oxford, England)
April 1, 2025
Leor Roseman
12 citations
The FDA's rejection of MDMA-assisted therapy highlights a fundamental clash between two paradigms in psychopharmacology. The dominant paradigm treats drugs as having purely biological effects, with context treated as noise to be controlled. An emerging paradigm sees therapeutic effects as interactive with context. Psychedelics challenge the dominant model because researchers insist they are drugs combined with psychotherapy. The FDA's critique of the studies partly concerns experiential and psychotherapeutic elements, which the FDA claims not to regulate, creating paradoxes that suggest a need for regulatory and research shifts to integrate a new paradigm where drugs and psychotherapy interact.
Journal of psychopharmacology (Oxford, England)
January 1, 2025
Ben Beaglehole, Paul Glue, Shona Neehoff et al.
12 citations
Ketamine reduces obsessive-compulsive symptoms more than a psychoactive control (fentanyl) in people with severe, treatment-resistant OCD. In a small double-blind trial, participants received a single intramuscular dose of either 0.5 mg/kg ketamine, 1.0 mg/kg ketamine, or 50 µg fentanyl. Both ketamine doses produced greater and dose-related reductions on the Yale-Brown Obsessive-Compulsive Scale, with effects separating from fentanyl within 1–2 hours and persisting for up to 168 hours. Ketamine caused short-term dissociative and cardiovascular effects; two of twelve participants dropped out due to not tolerating dissociation. The findings provide preliminary evidence for ketamine's efficacy and tolerability in an outpatient cohort.
Journal of psychopharmacology (Oxford, England)
April 1, 2024
Nelson B Rodrigues, David Chen-Li, Joshua D Di Vincenzo et al.
12 citations
Ketamine is a rapid antidepressant for people with treatment-resistant depression, but no reliable predictors of response have been identified. This study examined whether variants in the Val66Met and CYP2B6 genes predicted treatment outcomes in 85 participants with major depressive disorder who received four intravenous ketamine infusions. Participants showed significant overall reductions in depression, suicide, and anxiety, with 25% meeting response criteria and 15% meeting remission criteria. However, neither Val66Met nor CYP2B6 genotypes significantly predicted changes in depressive symptoms, suicidality, anxiety, or dissociation. The findings suggest that single-gene predictors are unlikely to be useful and that a broader genetic approach may be needed.
Journal of psychopharmacology (Oxford, England)
December 1, 2023
Brian J Gully, Erica Eaton, Christy Capone et al.
12 citations
PTSD and alcohol use disorder often co-occur in trauma-exposed patients, creating a cycle where PTSD symptoms drive heavy drinking and vice versa. No FDA-approved medications exist specifically for this comorbidity; patients receive treatments approved for each disorder separately or off-label, which have limited efficacy. Emerging research suggests the psychedelic drug MDMA, used with psychotherapy, may be effective. This review examines current pharmacotherapies and MDMA-integrative psychotherapy for PTSD and AUD both individually and together, and discusses future directions for psychedelic-integrative therapy in treating this comorbidity.
Journal of psychopharmacology (Oxford, England)
March 1, 2022
Harriet de Wit, Anya K Bershad, Charles Grob
11 citations
The psychological processes by which mind-altering drugs improve mood or behavior remain poorly understood. Controlled laboratory studies using well-defined psychological constructs can help reveal how these drugs produce therapeutic benefits, but substantial methodological differences exist between clinical studies of therapeutic outcomes and laboratory studies of underlying mechanisms. Using MDMA as an example, this review examines differences in expectancies, social and physical context, participant characteristics, pharmacological factors, and outcome measures between studies with and without psychiatric participants. It describes challenges and opportunities in translating laboratory findings to clinical settings and identifies ways to bridge the gap between these research approaches.
Journal of psychopharmacology (Oxford, England)
April 1, 2016
Matthew W Johnson, Katherine A Maclean, Michael J Caspers et al.
11 citations
After inhaling a high dose of vaporized salvinorin A (18–21 mcg/kg), plasma levels of the compound peak at 2 minutes and then rapidly decline. Higher drug levels are strongly linked to stronger subjective and observer-rated drug effects. Prolactin rises significantly from 5 minutes onward, peaking at 15 minutes, while cortisol increases are inconsistent across participants. Hormonal changes do not closely track drug levels. This work demonstrates a direct relationship between salvinorin A plasma concentrations and drug effects in humans, validating an efficient inhalation method.
Journal of psychopharmacology (Oxford, England)
March 1, 2024
Anya K Bershad, David T Hsu, Harriet de Wit
9 citations
MDMA, a compound being studied for treating PTSD, increases positive feelings in response to social feedback, such as receiving likes or rejections in a dating-app-like task. In a double-blind, placebo-controlled trial with 36 healthy adults aged 18-40, a high dose of MDMA (1.5 mg/kg) boosted positive affective responses to both positive and negative social feedback, compared to placebo and methamphetamine. This suggests MDMA may enhance social connection by making social interactions feel more rewarding, which could explain its therapeutic benefits. Further research is needed to test these effects in clinical populations and with different types of social feedback.
Journal of psychopharmacology (Oxford, England)
January 1, 2025
Luis Gutiérrez-Rojas, Julia Vendrell-Serres, J Antoni Ramos-Quiroga et al.
8 citations
Intranasal esketamine, combined with an antidepressant, significantly reduced depressive symptoms in patients with severe treatment-resistant depression. In a retrospective study of 71 patients (70% women, 85% with work disability), Montgomery-Asberg depression rating scale scores dropped from a mean baseline of 38.27 at 28, 90, and 180 days. Side effects were common but mostly mild and temporary. Patients who also received psychotherapy had lower depression scores at 90 and 180 days than those who did not. The authors argue that pharmacological treatment for treatment-resistant depression should be integrated with psychotherapy, social support, and family interventions to optimize outcomes.
Journal of psychopharmacology (Oxford, England)
April 21, 2025
Einat Karp Barnir, Zohar Rubinstein, Rany Abend et al.
7 citations
Among 343 adult survivors of a single large-scale terrorist attack at a festival, those who had consumed classic psychedelics during the attack reported significantly lower levels of anxiety and post-traumatic symptoms three weeks later, compared to those who took 3,4-methylenedioxymethamphetamine (MDMA) or no psychedelics. The protective effect against post-traumatic responses was stronger for participants who did not use other recreational substances alongside the psychedelics. These findings suggest that classic psychedelics may modulate the formation of enduring trauma memories and confer a protective effect against the development of post-traumatic stress and anxiety.
Journal of psychopharmacology (Oxford, England)
June 30, 2025
Jess Kerr-Gaffney, Anna Tröger, Alice Caulfield et al.
6 citations
Ketamine, a rapid-acting treatment for depression and other psychiatric conditions, has raised safety concerns because chronic recreational use can damage the bladder and urinary tract. This systematic review of 27 clinical studies, mostly in people with depression, found that 0% to 24.5% of patients receiving ketamine reported urological symptoms, which were usually mild or moderate. Objective measures of bladder and kidney function showed no significant changes from before to after treatment. The evidence suggests that therapeutic ketamine does not appear to increase the risk of urological problems, but most studies were short-term and did not systematically monitor symptoms, so more long-term research is needed.
Journal of psychopharmacology (Oxford, England)
June 28, 2025
Rafael S Rodrigues, Isabel Wießner, Dimitri Daldegan-Bueno et al.
6 citations
Two scales that measure altered states of consciousness—the OAV and the 5D-ASC—were adapted and validated for Brazilian Portuguese through expert review and back-translation. In an online survey of 3762 people recounting their psychedelic experiences, factor analyses confirmed an 11-factor structure for the OAV and a 6-factor structure for the 5D-ASC, both with strong internal consistency (α > 0.76). Convergent validity was supported by significant correlations with the Mystical Experience Questionnaire and Ego Dissolution Inventory. Factor scores differed by substance, setting, and meditation frequency; ayahuasca and DMT experiences produced higher oceanic boundlessness and anxious ego-dissolution scores. The scales show reliable psychometric properties for Brazil, though sample homogeneity and recall bias are limitations.
Journal of psychopharmacology (Oxford, England)
April 25, 2025
Jolien Ke Veraart, Sanne Y Smith-Apeldoorn, Annemarie van der Meij et al.
6 citations
Oral esketamine, taken twice weekly for six weeks at doses from 0.5 to 3 mg/kg, reduced depressive symptom severity in adults with severe treatment-resistant depression who had not benefited from an average of 8.1 prior antidepressant trials and, in 63% of cases, electroconvulsive therapy. Hamilton Depression Rating Scale scores dropped from 21.2 to 15.8. Nearly half of participants achieved a clinically meaningful improvement, 26.8% responded, and 15.6% remitted. Side effects were common but well tolerated, with a 7.6% dropout rate and no significant urinary or cognitive adverse effects. Treatment continued beyond six weeks in 45.9% of participants to maintain gains.