Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
March 27, 2026
Kade L Huckstep, Billi Newton, Grace Bailey et al.
Post-traumatic stress disorder and alcohol use often co-occur and worsen each other, but no medications specifically target trauma-driven increases in drinking. In rats predisposed to heavy alcohol use (inbred alcohol-preferring rats), a single dose of MDMA given before fear-extinction training prevented the rise in alcohol consumption that normally follows a stressful experience. MDMA did not improve long-term fear extinction memory in any group. The effect on drinking was specific to the genetically vulnerable rats and was not explained by prior alcohol history. MDMA's main benefit in this model was disrupting the link between trauma and escalated alcohol intake, not enhancing fear extinction.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
November 1, 2025
Justin C Strickland, Hayleigh E Tilton, Noah M Patton et al.
Caffeine co-administered with THC produced minimal changes in subjective effects, performance, or metabolism, though signals for perceived driving impairment were observed. In contrast, CBD co-administered with THC and caffeine increased outcomes associated with abuse liability and performance impairment versus THC alone. CBD also increased plasma THC and 11-OH-THC concentrations. These data provide the first direct assessment of pharmacodynamic and pharmacokinetic effects of THC and caffeine co-administered in humans, emphasizing the importance of considering full cannabinoid profiles and drug combinations in regulatory decision-making.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
October 1, 2025
Andrew Jin Soo Byun, Harshawardhan U Deshpande, Jessi Stover et al.
Chronic delta-9-tetrahydrocannabinol (THC) exposure during adolescence alters functional connectivity between the default mode and central executive networks in the adult brain in a dose-dependent manner. In squirrel monkeys given daily low (0.32 mg/kg) or high (3.2 mg/kg) THC injections for six months during adolescence, only the low dose increased connectivity between these networks during the exposure period, an effect that reversed after discontinuation. The high dose and vehicle controls showed no such change. The central executive network appeared to drive this effect. The findings suggest that adolescent THC exposure can produce non-linear, dose-dependent disruptions in large-scale brain networks.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
March 1, 2025
Ella Williams, Ursule Taujanskaite, Sunjeev K Kamboj et al.
Nitrous oxide (N2O), a gas used for sedation and pain relief, shows rapid-acting antidepressant effects in treatment-resistant depression. Subanaesthetic doses (50%) can disrupt the reconsolidation of maladaptive memories in healthy people and across disorders. Negative memory biases contribute to depression, and disrupting affective memory reconsolidation may be how N2O works. This narrative review introduces evidence for N2O's antidepressant profile, evaluates its clinical use versus other treatments, and proposes a memory-based mechanism of action.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
February 1, 2025
Brian D Kangas, Harshawardhan U Deshpande, Sarah L Withey et al.
Chronic exposure to THC during adolescence in squirrel monkeys produces long-lasting changes in brain functional connectivity and motivation that persist into adulthood. Daily treatment with either a low (0.32 mg/kg) or high dose (3.2 mg/kg) of THC for six months during adolescence led to persistent alterations in connectivity of the medial orbitofrontal cortex, caudate, and ventral striatum. In economic demand tests, THC-treated subjects showed dosage-dependent disruption in reward sensitivity and motivation, unlike vehicle-treated subjects who displayed the expected inverse relationship between reward magnitude and effort. The findings indicate that adolescent THC exposure causes enduring neurocognitive abnormalities in reward processing.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
September 1, 2023
H De Wit, M Heilig, A K Bershad
High doses of psychedelic drugs activate autonomic and hormonal stress responses. Acute stress, for evolutionarily adaptive reasons, instills meaning in the immediate context and leads to the formation of salient, lasting memories of surrounding events. The stress-inducing effect of psychedelic drugs may therefore contribute to the reported sense of meaning and the durability of memories from the drug experience. In therapeutic contexts, this could enhance the salience of insights gained and strengthen memories formed. Future empirical studies are needed to determine whether acute stress contributes to the emotional significance and lasting effects of psychedelic-assisted psychotherapy.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
June 1, 2022
Błażej D Pędzich, Sarah Rubens, Mehdi Sekssaoui et al.
Activation of the serotonin 2A (5-HT2A) receptor suppresses fear expression but does not affect retention of fear extinction. Using the psychedelic DOI in mice, the authors found that 5-HT2A receptor activation reduced anxiety-like avoidance behavior and diminished fear expression in multiple tasks, including passive avoidance and auditory fear conditioning. The effect depended on 5-HT2A receptors in the amygdala: local infusion of a 5-HT2A antagonist into the amygdala reversed the effect, while local DOI infusion into the amygdala was sufficient to suppress fear expression. These findings clarify a neural mechanism by which psychedelics may reduce fear, but provide no evidence that they enhance fear extinction memory.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
June 1, 2022
Conor H Murray, Zhengyi Huang, Royce Lee et al.
Adolescents aged 18-20 are more sensitive than adults aged 30-40 to the performance-impairing effects of THC, the main active component of cannabis. In a double-blind, placebo-controlled study with 12 adolescents and 12 adults who had used THC fewer than 20 times, THC doses of 7.5 and 15 mg impaired reaction time, response accuracy, and time perception more in adolescents. THC also decreased P300 brain-wave amplitude in adolescents but not adults, indicating greater cognitive and brain-function disruption at doses that produced similar subjective intoxication and heart-rate effects in both age groups.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
October 1, 2020
Kirsten C S Adam, Manoj K Doss, Elisa Pabon et al.
THC, the main psychoactive component of cannabis, impairs visual working memory—the ability to temporarily hold information in mind. In two double-blind, randomized crossover experiments, healthy adults performed a visual working memory task after taking oral THC (7.5 or 15 mg) or a placebo. THC reduced working memory performance (effect size d = 0.65), increased self-reported mind wandering, and decreased the accuracy of participants' awareness of their own task performance. The findings suggest that THC disrupts working memory both by increasing mind wandering and by reducing metacognitive monitoring. The study also demonstrated that short task durations and small sample sizes can mask such drug effects.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
December 1, 2015
Michael S Placzek, Genevieve C Van de Bittner, Hsiao-Ying Wey et al.
Kappa opioid receptor (KOR) binding availability in the brain was measured in living rats using positron emission tomography (PET) after administration of the KOR agonist salvinorin A. At lower doses, salvinorin A briefly competed for receptor binding but had no lasting effect. At a dose of 0.60 mg/kg, however, it induced a sustained decrease in KOR binding of 40–49% that persisted for up to 2.5 hours after the drug had left the brain, suggesting an adaptive response by the receptor not previously observed in vivo with PET.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
October 1, 2007
Martina Ballmaier, Marco Bortolato, Cristina Rizzetti et al.
CB1 receptor antagonists rimonabant and AM251 reversed deficits in sensorimotor gating caused by phencyclidine in rats, an effect comparable to the atypical antipsychotic clozapine. Rimonabant also attenuated gating disruptions from dizocilpine and apomorphine. No augmentation was seen when rimonabant and clozapine were given together. The findings suggest that blocking CB1 receptors may help restore disrupted interactions between the endocannabinoid and glutamate systems implicated in schizophrenia.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
June 1, 2004
Janne Damm Andersen, Bruno Pouzet
Perinatal treatment with the NMDA receptor antagonist phencyclidine (PCP) in rats causes lasting cognitive deficits that resemble those seen in schizophrenia. Male rats given PCP on postnatal days 7, 9, and 11 showed slight impairment in spatial reference memory and strong impairment in reversal and spatial working memory tasks as adults. Female rats were not significantly affected. Chronic treatment with D-serine reversed the cognitive deficits in male rats. This neurodevelopmental model may be useful for screening antipsychotic drugs aimed at treating cognitive dysfunction in schizophrenia.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
February 1, 2003
Susan M Cochran, Matthew Kennedy, Clare E McKerchar et al.
Chronic intermittent exposure to phencyclidine (PCP) in rats produces metabolic hypofunction in the prefrontal cortex, reticular nucleus of the thalamus, and auditory system—key brain regions that show similar changes in schizophrenia. PCP also decreases parvalbumin mRNA expression in the prefrontal cortex and reticular nucleus of the thalamus. Co-administration of the antipsychotics haloperidol or clozapine did not reverse PCP-induced metabolic reductions in the prefrontal cortex but did reverse deficits in auditory structures. Clozapine, but not haloperidol, reversed PCP-induced decreases in parvalbumin expression in prefrontal cortex GABAergic interneurons, while both drugs reversed deficits in the reticular nucleus of the thalamus. These findings strengthen the validity of chronic PCP as an animal model of schizophrenia and suggest that reversing prefrontal cortex parvalbumin deficits may be a marker of atypical antipsychotic activity.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
January 1, 2003
Andrea Balla, Henry Sershen, Michael Serra et al.
Dopaminergic hyperactivity in the prefrontal cortex (PFC) may contribute to cognitive dysfunction in schizophrenia. In rats, subchronic treatment with phencyclidine (PCP) at doses of 10 mg/kg/day or higher produced serum concentrations associated with PCP psychosis in humans. PCP-treated rats showed a significant, dose-dependent enhancement in amphetamine-induced dopamine release in the PFC but not in the nucleus accumbens (NAc), along with increased locomotor activity. This enhanced response appeared after 3 days of treatment, persisted through 14 days, and resolved within 4 days of withdrawal. The findings suggest that NMDA receptor dysfunction could underlie the dopaminergic abnormalities seen in schizophrenia and that even short-term PCP abuse may potentiate the effects of psychostimulants.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
October 1, 2001
A C Lahti, M A Weiler, B A Tamara Michaelidis et al.
Ketamine produces a short-lived (<30 minutes) increase in psychotic symptoms in both healthy volunteers and people with schizophrenia, with the magnitude of positive-symptom change similar across groups despite different baselines. In healthy volunteers, ketamine raised scores on both the psychosis and withdrawal subscales of the Brief Psychiatric Rating Scale, whereas in schizophrenic volunteers only positive symptoms increased. Seventy percent of patients reported an exacerbation of previously experienced positive symptoms. The similarity between ketamine-induced symptoms and patients' own positive symptoms suggests ketamine offers a unique human psychosis model, potentially more valid than the amphetamine model for studying schizophrenia.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
July 1, 2001
E J Duncan, S H Madonick, A Parwani et al.
Ketamine, a drug that blocks NMDA receptors, produces schizophrenia-like symptoms in healthy people but does not disrupt sensory gating in the same way schizophrenia does. In a randomized double-blind crossover study, 16 healthy men received a 60-minute infusion of either ketamine (0.5 mg/kg) or saline. Ketamine caused robust dissociative and negative symptoms, but it did not impair prepulse inhibition (PPI) of the startle reflex; instead, it significantly enhanced PPI in the first block. These results indicate that ketamine's clinical effects are not coupled with the PPI disruption seen in schizophrenia.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
July 1, 1999
Z A Martinez, G D Ellison, M A Geyer et al.
Phencyclidine (PCP) can cause acute and lasting psychoses in humans and is used in animal models of psychosis. In rats, acute PCP disrupts prepulse inhibition (PPI) of the startle reflex, similar to deficits seen in schizophrenia. It was unclear whether sustained PCP exposure also disrupts PPI. This study gave rats PCP for 5 days via osmotic minipumps or for 14 days via repeated injections. PPI was disrupted only during drug administration, not after it stopped. PPI does not appear sensitive to the neuropathological effects of sustained PCP exposure.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
July 1, 1999
J Väisänen, A M Lindén, M Lakso et al.
Non-competitive NMDA receptor antagonists MK-801, PCP, and ketamine strongly and dose-dependently increase expression of the immediate early gene c-fos in neurons of layer III of the rat caudal entorhinal cortex. This induction is delayed and blocked by antipsychotic drugs. In cultured primary entorhinal neurons, high doses of MK-801 and PCP kill the cells without inducing c-fos, showing that the in vitro model does not fully replicate in vivo effects. These excitatory effects may be linked to the psychotropic side effects of these drugs and could serve as a model system for studying psychosis neurobiology.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
July 1, 1998
F Sams-Dodd
In rats, continuous administration of D-amphetamine and phencyclidine both induced stereotyped behavior and locomotor hyperactivity, behaviors thought to correspond to positive symptoms of schizophrenia. However, only phencyclidine caused social withdrawal, which models negative symptoms. This finding confirms earlier work showing that amphetamine does not produce social deficits in rats, even when given at high doses over five days.