Psychopharmacology
October 31, 2025
Vítor Bruno, Lídia Emmanuela Wiazowski Spelta, Matheus Lujan Pereira et al.
Ayahuasca, a brew containing DMT and β-carbolines used in indigenous rituals, has shown potential for treating substance use disorders. In C57Bl/6 mice, ayahuasca at a high dose (15 mg DMT/kg) induced rewarding effects, but these were weaker than those of cocaine. When mice were conditioned with cocaine and later treated with ayahuasca (12.5 or 15 mg DMT/kg), the brew prevented the reinstatement of cocaine-induced conditioned place preference after a cocaine challenge. The findings suggest ayahuasca may have therapeutic value for cocaine use disorder by reducing relapse to drug-seeking behavior.
Psychopharmacology
October 27, 2025
David A Bender, Sandeep M Nayak, Joshua S Siegel et al.
Providers administering psychedelic drugs in clinical trials report a range of challenges, including intense dysphoria during sessions (42% of respondents), disappointment with the intervention (25%), and re-engaging with traumatic experiences (17%). An anonymous survey of 40 qualified respondents who oversaw 1656 psychedelic sessions identified 11 distinct themes of challenges. 70% of respondents felt that individuals with PTSD or prior trauma need additional psychological support, and they recommended an average of 9.8 hours of total psychological support for first-time recipients with serious mental illness. These findings highlight the need to incorporate potential adverse experiences into psychological support protocols for clinical trials and future guidelines.
Psychopharmacology
October 27, 2025
Nina Gregoire, Ethan Klukas, Kimberley Kaseweter et al.
Three personality profiles—Easygoing Extraverts, Average, and Reserved Introverts—emerged among 184 patients receiving ketamine-assisted therapy at a Canadian clinic. Reserved Introverts had more severe baseline depression and anxiety. All profiles showed improvements in depression and anxiety one week after treatment, but personality did not predict differential symptom change. Patients with a trauma history experienced greater reductions in depression and improvements in physical quality of life than those without. Personality relates to baseline mental health severity but not short-term treatment response, while trauma history may indicate greater benefit from ketamine therapy.
Psychopharmacology
October 11, 2025
Michelle St Pierre, Elena Argento, Jordyn Cates et al.
On days when adults microdose psychedelics, they report higher levels of wellbeing, productivity, creativity, connectedness, contemplation, and focus compared to days they do not microdose. The increase in creativity is especially pronounced among people who have previously used larger doses of psychedelics. These findings come from a large international survey of 1,435 adults who microdose, using daily-level self-reports that reduce reliance on memory. Because the study is observational and exploratory, the results should be interpreted cautiously.
Psychopharmacology
April 22, 2025
Anthony N Nist, Stephen J Walsh, Timothy A Shahan
Adding electric footshock punishment to the probabilistic reversal learning task increased behavioral persistence and cognitive flexibility in rats, but a single dose of ketamine had no effect beyond causing acute impairments. The experiment used 40 rats and compared those receiving footshock for non-rewarded trials with those receiving only timeout periods. The findings suggest that punishment conditions significantly affect task performance and support previous evidence that ketamine may not influence cognitive flexibility or reward processing in healthy rats.
Psychopharmacology
July 1, 2024
Dilan Gokalp, Gunes Unal
Ketamine's antidepressant effect requires suppressed activity of the metabotropic glutamate receptor 5 (mGluR5). In adult male Wistar rats, enhancing mGluR5 activity with the drug CDPPB blocked ketamine's antidepressant effect in the forced swim test without affecting locomotion. Combining a low dose of ketamine (1 mg/kg) with the mGluR5 antagonist MTEP produced a robust synergistic antidepressant effect. However, this combination eliminated the anxiolytic effect seen with either drug alone. The findings indicate that mGluR5 antagonism can boost ketamine's antidepressant effectiveness at low doses, but at the cost of its anxiety-reducing properties.
Psychopharmacology
October 1, 2022
Daiane Momo Daneluz, Jeferson Machado Batista Sohn, Gabriela O Silveira et al.
Ayahuasca, a psychedelic brew containing DMT and β-carbolines, impairs fear memory reconsolidation in rats when given 20 minutes before or 3 hours after memory retrieval. A dose of 60 mg/kg was effective at both time points and did not produce an anxiolytic effect. The impairment lasted at least 22 days with no spontaneous recovery or reinstatement of fear. The effect depended on memory retrieval; without retrieval, ayahuasca did not impair reconsolidation. These findings suggest ayahuasca disrupts both early and late stages of memory reconsolidation rather than facilitating fear extinction.
Psychopharmacology
January 1, 1977
Herbert Y. Meltzer, Richard G. Fessler, Miljana Simonovic et al.
Lysergic acid diethylamide (LSD) at doses of 0.05 mg/kg and 0.20 mg/kg significantly lowered plasma prolactin levels in male rats. The higher dose also blocked prolactin increases caused by chlorpromazine and alpha-methylparatyrosine, drugs that reduce dopaminergic inhibition of prolactin secretion. LSD was more potent than methysergide, a serotonin blocker, in lowering prolactin, and more potent than apomorphine, a dopamine agonist, in blocking prolactin rises from quipazine, a serotonin agonist. These results suggest LSD acts as a potent dopamine agonist on pituitary or hypothalamic receptors that inhibit prolactin secretion.
Psychopharmacology
July 17, 2026
Richard Saville-Smith, Sharday Mosurinjohn
The term 'mysticism' in psychedelic research is outdated and misleading, rooted in the flawed and unexamined ideas of Walter Stace and Walter Pahnke. The paper critiques this legacy through an archaeological re-evaluation of foundational texts and a genealogical tracing of how 'mysticism' became normalized in second-generation psychedelic research. It advocates renaming the Mystical Experience Questionnaire (MEQ) to the Psychedelic Experience Questionnaire (PEQ), aligning with Pahnke's later five-part typology of psychedelic experience. This change would free the instrument from a dubious quasi-religious construct that forces therapeutic outcomes into a narrow framework.
Psychopharmacology
July 14, 2026
Kate A Lawson, Stephen V Mahler
Rats can convey information about their internal states through ultrasonic vocalizations (USVs). In male and female TH:cre rats and wildtype littermates, amphetamine (2 mg/kg) elicited high-frequency USVs and increased locomotion, heroin (0.25 mg/kg) elicited low-frequency USVs in some rats without altering high-frequency USVs or locomotion, and ketamine (30 mg/kg) suppressed high-frequency USVs while transiently increasing locomotion. Chemogenetically inhibiting or stimulating ventral tegmental area dopamine neurons suppressed amphetamine- or ketamine-induced locomotion and amphetamine-induced USVs. USVs provide a behavioral readout of drug and brain manipulation effects that locomotion alone cannot capture, potentially helping bridge human and rodent neuroscience.
Psychopharmacology
February 20, 2026
Monica S Carbajal, Rebecca C Crenshaw, Victoria E Williams et al.
Perinatal exposure to THC, the psychoactive component of cannabis, reduces motivation to work for rewards in adult rats, especially males, without affecting impulsive behavior. Rats exposed to 5 mg/kg/day THC from before birth through early nursing showed fewer lever presses and earned fewer reinforcers in tasks requiring high effort. The exposure did not alter baseline dopamine release in brain reward regions but dampened the dopamine response to cocaine in the nucleus accumbens. These findings suggest that prenatal cannabis exposure may produce an amotivational state by devaluing rewards rather than by impairing impulse control, with males more affected.
Psychopharmacology
December 12, 2025
Ilenia Salsano, Giorgia Picci, Nathan M Petro et al.
Chronic cannabis use in middle-aged adults (average age 42) is linked to disrupted resting-state functional connectivity between the cerebellum and prefrontal-temporal brain regions. Using whole-brain analysis, adults with chronic cannabis use showed decreased connectivity between the right cerebellar Crus II and several frontal and temporal areas, and between the right cerebellar Crus I and the left pars triangularis, compared to demographically matched non-users. These findings suggest that sustained cannabis use may alter communication between brain regions rich in cannabinoid receptors, even in midlife, though the behavioral impact remains unknown.
Psychopharmacology
November 1, 2025
Marta De Felice, Hanna J Szkudlarek, Matthew J Jones et al.
Adolescent female rats exposed to THC gained weight slower than controls during treatment. In adulthood, they showed no behavioral abnormalities in tests of locomotion, sensorimotor gating, memory, or anxiety. However, long-lasting molecular adaptations occurred: altered expression of estrogen receptor-α and fatty acid amid hydrolase in the hypothalamus and hippocampus, along with enduring changes in hippocampal oscillatory patterns. These sex-specific adaptations may protect females against the long-term behavioral abnormalities consistently seen in male cohorts.
Psychopharmacology
February 7, 2025
S. Zequeira, E. Gazarov, A. A. Güvenli et al.
Cannabis and its psychoactive component Δ9-tetrahydrocannabinol (THC) can improve working memory in aged rats, depending on sex and route of administration. Acute cannabis smoke enhanced working memory accuracy in aged male rats but impaired it in aged females, with no effect on young adults. Chronic oral THC improved working memory in aged rats of both sexes, again with no effect on young adults. Neither cannabis smoke nor oral THC affected hippocampus-dependent memory tasks in any age group. The findings suggest that cannabis may attenuate some age-related working memory deficits without worsening other cognitive impairments, though effects vary by sex and administration route.
Psychopharmacology
February 1, 2025
Maricela X Martinez, Vanessa Alizo Vera, Christina M Ruiz et al.
Adolescent THC exposure in rats leads to sex-dependent effects on learning to seek rewards guided by cues, but has minimal impact on cognitive flexibility or decision-making under uncertainty. Adult rats treated with THC during adolescence showed reduced discounting of improbable reward options when given amphetamine, indicating heightened sensitivity to dopamine augmentation. Direct chemogenetic stimulation of dopamine neurons in the ventral tegmental area or their projections to the medial prefrontal cortex did not alter decision-making in control rats, but slightly disrupted choices in THC-exposed rats. These findings suggest that adolescent THC exposure produces specific, persistent cognitive changes that may alter responses to amphetamine through mechanisms independent of the VTA-mPFC dopamine pathway.
Psychopharmacology
October 1, 2023
Ana Carolina Dutra-Tavares, Thainá P Souza, Juliana O Silva et al.
Sex differences in schizophrenia may originate early in life. Mice given phencyclidine (PCP) on postnatal days 7, 9, and 11 showed dose-dependent deficits in open field, social interaction, and prepulse inhibition tests during late adolescence (PN48-50). Males were more susceptible to these behavioral deficits and had reduced GluN1 subunit expression in the frontal cortex at early adolescence (PN30). By late adolescence (PN50), cortical GluN1 was increased in both sexes, while PCP increased cortical and decreased hippocampal PSD-95 in females. The antipsychotic olanzapine failed to mitigate most PCP-evoked alterations and sometimes worsened deficits, suggesting its use during adolescence needs further evaluation.
Psychopharmacology
October 1, 2023
Youjia Qiu, Longyuan Li, Aojie Duan et al.
A meta-analysis of four clinical trials involving 133 patients with major depressive disorder found that 50% nitrous oxide produces a rapid and lasting antidepressant effect. Depression severity scores improved significantly at 2 hours, 24 hours, and 2 weeks or more compared with placebo. Response and remission rates were also significantly higher with nitrous oxide. However, patients receiving nitrous oxide had a substantially higher risk of nausea or vomiting. The authors call for further research on lower or titrated concentrations.
Psychopharmacology
September 1, 2022
Camila Sanz, Federico Cavanna, Stephanie Müller et al.
Natural speech can reveal whether someone has taken a microdose of psilocybin. In a double-blind, placebo-controlled experiment, 34 healthy adults provided speech samples after consuming either 0.5 grams of psilocybin mushrooms or a placebo. Machine learning classifiers distinguished between the two conditions with high accuracy (AUC ~0.8), based on features such as verbosity and sentiment scores, though semantic variability did not differ significantly. This suggests that low doses of serotonergic psychedelics leave detectable signatures in unconstrained speech, offering a potential low-cost, non-invasive method for monitoring microdosing regimens.
Psychopharmacology
January 1, 2022
Nina Schimmers, Joost J Breeksema, Sanne Y Smith-Apeldoorn et al.
Both classical psychedelics (DPT, LSD, psilocybin) and atypical psychedelics (MDMA, ketamine) show promise for reducing anxiety, depression, and existential distress in terminally ill patients, with recent controlled trials indicating positive effects on existential and spiritual well-being, quality of life, and acceptance while causing few adverse and no serious adverse effects. Early studies had serious methodological flaws, but newer trials are of higher quality. Larger high-quality studies are still needed for classical psychedelics and MDMA, and ketamine research should better address existential well-being and psychotherapeutic context.
Psychopharmacology
May 1, 2020
Toby Lea, Nicole Amada, Henrik Jungaberle et al.
An international online survey of 1102 people who had microdosed psychedelics found that 21% did so primarily for depression, 7% for anxiety, 9% for other mental disorders, and 2% to reduce or stop substance use. Forty-four percent perceived their mental health as "much better" as a result. Perceived improvements were associated with gender, education, microdosing duration and motivations, and recent use of larger psychedelic doses. The authors call for clinical trials to determine microdosing's potential role in psychiatric treatment and for further social research on its use as a self-managed therapy.
Psychopharmacology
March 1, 2020
Arvie Abiero, Chrislean Jun Botanas, Raly James Custodio et al.
Two synthetic dissociative drugs, 4-MeO-PCP and 3-MeO-PCMo, produce rewarding and reinforcing effects in rats, indicating potential for abuse in humans. Both drugs induced conditioned place preference and self-administration, but only 4-MeO-PCP caused locomotor sensitization. Blocking dopamine D1 or D2 receptors prevented the drugs' rewarding effects. The drugs altered dopamine-related proteins and increased delta and gamma brain wave activity, effects also blocked by dopamine antagonists. These findings suggest the drugs' abuse potential is mediated through the mesolimbic dopamine system.
Psychopharmacology
September 1, 2019
Swapnil Gupta, Joao P De Aquino, Deepak C D'Souza et al.
In healthy individuals who respond to THC, pre-treatment with the antipsychotic haloperidol reduces the psychosis-like effects of THC. Among 10 THC responders, THC-induced increases in positive symptoms (measured by the PANSS) were lower after haloperidol (average increase of 1.1 points) than after placebo (average increase of 2.9 points). This suggests that dopamine signaling may play a role in the psychosis-like effects of cannabinoids.
Psychopharmacology
July 1, 2019
Shiho Ito, Satoshi Deyama, Masaki Domoto et al.
The synthetic cannabinoid 5F-AMB, when injected into the brain of mice, reduces anxiety and impairs the acquisition of recognition memory by activating CB1 receptors. Systemic injection severely reduces movement, an effect partially blocked by a CB1 antagonist. Infusion into the medial prefrontal cortex impairs memory acquisition but does not affect anxiety, suggesting other brain regions mediate the anxiolytic effect.
Psychopharmacology
March 19, 2019
L. Sayson, Chrislean Jun Botanas, Raly James Perez Custodio et al.
Three novel analogs of methoxetamine (MXE), an NMDA receptor antagonist related to ketamine, showed antidepressant-like effects in mice. The compounds—NENK, 2-MeO-NEK, and 4-MeO-NEK—reduced immobility time in the forced swimming and tail suspension tests, indicating reduced behavioral despair. Their effects were blocked by an AMPA receptor antagonist (NBQX) and a 5-HT2 receptor antagonist (ketanserin), suggesting involvement of both glutamatergic and serotonergic systems. The analogs also altered mRNA levels of AMPA receptor subunits and brain-derived neurotrophic factor in the hippocampus and prefrontal cortex. These findings suggest the compounds may offer rapid antidepressant effects, though further research is needed.
Psychopharmacology
March 1, 2019
A. Halberstadt, S. Brandt, D. Walther et al.
A class of designer drugs derived from 2-aminoindan (2-AI) interacts with monoamine transporters in ways that predict distinct psychoactive effects. 2-AI itself acts as a selective substrate for norepinephrine and dopamine transporters, suggesting (+)-amphetamine-like effects and abuse potential. Adding ring substitutions increases potency at the serotonin transporter while reducing potency at dopamine and norepinephrine transporters. Among the derivatives, MMAI is highly selective for the serotonin transporter, with 100-fold lower potency at norepinephrine and dopamine transporters, while MDAI and 5-MeO-AI show moderate serotonin selectivity. The compounds also bind to α2-adrenoceptor subtypes, with 2-AI having highest affinity for α2C receptors (Ki = 41 nM). Ring-substituted derivatives may produce MDMA-like effects with less abuse liability.