Biological psychiatry
February 1, 2023
Friederike Holze, Peter Gasser, Felix Müller et al.
294 citations
LSD-assisted therapy produced long-lasting reductions in anxiety and comorbid depression symptoms up to 16 weeks in patients with anxiety related to a life-threatening illness. In a double-blind, placebo-controlled crossover trial with 42 patients, LSD treatment led to significant decreases in anxiety scores compared to placebo, with a large effect size. Similar improvements were seen in depression ratings. Positive acute subjective drug effects and mystical-type experiences correlated with long-term anxiety reductions. Mild, transient side effects occurred in 19% of patients, and one serious adverse event (acute transient anxiety) was reported.
Biological psychiatry
October 15, 2005
John H Halpern, Andrea R Sherwood, James I Hudson et al.
186 citations
Regular use of peyote, a hallucinogen-containing cactus, in a religious setting among Navajo Native Americans does not appear to cause long-term psychological or cognitive deficits. In a study comparing three groups—61 Native American Church members who regularly ingested peyote, 36 individuals with past alcohol dependence who had been sober for at least two months, and 79 individuals with minimal substance use—the peyote group showed no significant differences on a mental health inventory or ten neuropsychological tests compared to the minimal-use group. In contrast, the former alcoholic group showed significant deficits on all mental health scales and two neuropsychological measures. Total lifetime peyote use was not linked to worse performance. These findings may not apply to illicit hallucinogen users.
Biological psychiatry
April 1, 2016
Mohamed Sherif, Rajiv Radhakrishnan, Deepak Cyril D'Souza et al.
127 citations
Controlled laboratory studies in healthy humans show that cannabinoid agonists—both plant-derived and synthetic—produce positive, negative, and cognitive symptoms resembling schizophrenia. These effects are time-locked to drug administration, dose-related, and transient. The magnitude of effects is similar to ketamine but qualitatively distinct from other psychotomimetic drugs. In individuals with schizophrenia, cannabinoid agonists transiently worsen symptoms despite antipsychotic treatment, and no beneficial effects have been found, challenging the self-medication hypothesis. Genetic polymorphisms in dopamine-related genes (COMT, DAT1, AKT1) may moderate these effects. Cannabinoid-induced dopamine release does not fully account for the psychotomimetic effects; interactions among endocannabinoid, GABA, and glutamate systems affecting neural oscillations offer a plausible mechanism.
Biological psychiatry
November 15, 2012
Mohini Ranganathan, Ashley Schnakenberg, Patrick D Skosnik et al.
125 citations
Inhaled salvinorin A, the active ingredient in Salvia divinorum, produces transient psychotomimetic and perceptual alterations including dissociative and somaesthetic effects, increases plasma cortisol and prolactin, and reduces resting electroencephalogram spectral power. It does not cause euphoria, cognitive deficits, or changes in vital signs, and the effects are not dose-related. The substance is very well-tolerated without acute or delayed adverse effects, and its lack of euphoric effects suggests a low addictive potential similar to other hallucinogens.
Biological psychiatry
February 1, 2008
Daniela Braida, Valeria Limonta, Valeria Capurro et al.
107 citations
Salvinorin A, a drug from the plant Salvia divinorum, produces rewarding effects in rats at low to moderate doses but becomes aversive at the highest doses tested. In conditioned place preference tests, doses between 0.1 and 40 micrograms per kilogram given subcutaneously were rewarding, while 160 micrograms per kilogram was aversive. In self-administration tests, doses of 0.1 to 0.5 micrograms per infusion given intracerebroventricularly were rewarding, but 1 microgram per infusion was aversive. The rewarding effect was blocked by pretreatment with either a cannabinoid CB1 receptor antagonist or a kappa-opioid receptor antagonist. Salvinorin A also increased dopamine levels in the shell of the nucleus accumbens by about 150 percent. These findings indicate that the rewarding effects involve interaction between kappa-opioid and endocannabinoid systems.
Biological psychiatry
September 15, 2023
Robin J Murphy, Rachael Sumner, William Evans et al.
69 citations
Microdosing LSD (10 μg every three days for six weeks) in healthy adult men produced transient improvements in creativity, connectedness, energy, happiness, irritability, and wellness on dose days compared with nondose days, even after controlling for preintervention expectancy. However, no enduring changes in overall mood or cognition were observed between baseline and six-week assessments. The most notable adverse event was treatment-related anxiety, which led four participants in the LSD group to withdraw. Microdosing appears relatively safe in this population but does not support claims of lasting mood or cognitive benefits.
Biological psychiatry
February 1, 2023
Devon Stoliker, Leonardo Novelli, Franz X Vollenweider et al.
49 citations
Under the peak effect of LSD, the inhibitory influence from the salience network to the default mode network becomes excitatory, and inhibition from the default mode network to the dorsal attention network weakens. These changes in effective connectivity between resting-state networks may reduce their normal anticorrelation, offering a neural mechanism for ego dissolution—the blurring of the boundary between self and world. The findings suggest that alterations in the sense of self across different conscious states depend on the organized balance of effective connectivity among these networks.
Biological psychiatry
November 15, 1990
B R Sitaram, W R Mcleod
29 citations
The psychotomimetic indolealkylamines N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, and 5-hydroxy-N,N-dimethyltryptamine have been found in human body fluids, but their link to psychotic illness is still debated. Studies in rats show these compounds are rapidly metabolized and excreted by the kidneys. This rapid clearance may explain inconsistencies in past clinical research and should inform the design of future studies.
Biological psychiatry
February 1, 2025
Cassiano Ricardo Alves Faria Diniz, Ana Paula Crestani, Plinio Cabrera Casarotto et al.
15 citations
Antidepressants such as fluoxetine and ketamine bind to the p75 neurotrophin receptor (p75NTR) and trigger its proteolysis by α- and γ-secretase, leading to p75NTR nuclear localization. These drugs also enhance brain plasticity and extinction memory in mice and rats, and these effects depend on p75NTR signaling. The authors propose that antidepressants co-opt both the BDNF/TrkB and proBDNF/p75NTR systems to promote activity-dependent synaptic competition and brain remodeling.
Biological psychiatry
March 15, 2025
Anna Onisiforou, Andria Michael, Markos Apostolakis et al.
14 citations
Opioid use disorder (OUD) has reached epidemic levels, and current medications, while lifesaving, fail to address negative affect and cognitive impairment, leading to high relapse rates even years after drug cessation. Ketamine, an anesthetic and rapid-acting antidepressant, shows promise for treating OUD, including managing acute withdrawal symptoms, negative affect during protracted abstinence, and preventing return to opioid use. This review examines preclinical and clinical research on ketamine and its metabolites as novel therapeutic strategies. Evidence demonstrates that ketamine and its metabolites can modulate pathophysiological processes in OUD, suggesting a promising role in treatment and relapse prevention.
Biological psychiatry
February 15, 2025
Jessica L Maples-Keller, Laura Watkins, Natalie Hellman et al.
12 citations
Treatment approaches for posttraumatic stress disorder (PTSD) based on fear conditioning and extinction models are reviewed. Fear extinction provides a translational model linking basic research in nonhuman animals to human treatments such as prolonged exposure therapy. Cognitive aspects of extinction, including consolidation and reconsolidation, are discussed along with behavioral and pharmacological strategies for preventing and treating chronic PTSD. Augmentation strategies reviewed include disrupting noradrenergic processes, NMDA receptor medications, physical exercise, cannabinoids, estradiol, dexamethasone, yohimbine, losartan, dopamine, and MDMA, with evidence for their efficacy in human samples. Limitations and future directions are also addressed.
Biological psychiatry
May 5, 2025
Matthew B Pomrenze, Sam Vaillancourt, Pierre Llorach et al.
11 citations
Ketamine produces a rapid increase in movement (locomotor activation) in mice by acting on mu opioid receptors (MORs) in the central amygdala (CeA). This effect is blocked by the opioid receptor antagonist naltrexone, and the same blockade occurs with a MOR-selective antagonist. Whole-brain imaging showed that naltrexone most strongly altered ketamine-induced cFos expression in the CeA, particularly in neurons that co-express MOR and PKCδ. Interrupting MOR function specifically in the CeA, either with a drug or genetic manipulation, prevented ketamine's locomotor effects. This indicates that ketamine's acute behavioral effects involve opioid signaling in the CeA, which may relate to its antidepressant mechanism in humans.
Biological psychiatry
January 1, 2024
Elizabeth A Hoge, Caroline H Armstrong, Mihriye Mete et al.
10 citations
Anxiety disorders are linked to heightened startle responses during unpredictable threat, a physiological marker called anxiety-potentiated startle (APS). In a study of 93 individuals with anxiety disorders and 66 healthy controls, APS was higher in the anxious group at baseline. After eight weeks of treatment with either escitalopram or mindfulness-based stress reduction, both treatment groups showed significantly greater reductions in APS compared to controls, with patients' APS levels falling into the range of healthy individuals. Fear-potentiated startle (FPS), a response to predictable threat, did not differ between groups at baseline nor change with treatment. These results validate APS as a biological correlate of pathological anxiety and provide evidence that mindfulness-based stress reduction can alter anxiety-related neurocircuitry similarly to medication.
Biological psychiatry
July 7, 2025
Cory B Langreck, Briana Chen, Victor M Luna et al.
9 citations
Mu opioid receptor (MOR) activation is required for the antidepressant-like effects of both (R,S)-ketamine and the selective NMDAR antagonist fluoroethylnormemantine (FENM) against stress-induced maladaptive behaviors. (R,S)-ketamine and its enantiomers showed weak partial agonism of MOR, while FENM had negligible direct MOR activity. Despite these differences, the long-acting MOR antagonist methocinnamox (MCAM) blocked the behavioral effects of both compounds when given before or after stress. The antinociceptive effect of (R,S)-ketamine was more potent and more sensitive to MCAM blockade than that of FENM. These findings suggest that NMDAR antagonists function indirectly through endogenous opioid signaling to produce their effects.
Biological psychiatry
May 1, 2025
Alessia Mastrodonato, Michelle Jin, Noelle Kee et al.
5 citations
A single injection of (R,S)-ketamine or its metabolite (2S,6S)-hydroxynorketamine (HNK) given one week before stress attenuated learned fear in male mice. The drugs altered neural activity in distinct and overlapping brain regions: (2S,6S)-HNK affected dorsal CA3, while both drugs changed activity in ventral CA3, CA1, infralimbic and prelimbic cortex, insular cortex, retrosplenial cortex, piriform cortex, nucleus reuniens, and periaqueductal gray. (R,S)-ketamine uniquely affected the paraventricular nucleus of the thalamus. (R,S)-ketamine increased connectivity between cortical and subcortical regions, whereas (2S,6S)-HNK increased connectivity within those regions. The findings identify novel fear network nodes that could be targeted to treat fear-induced disorders.
Biological psychiatry
May 15, 2025
Anya K. Bershad, Harriet de Wit
3 citations
Disrupted social homeostasis underlies many behavioral disorders, including problematic drug use. This narrative review examines whether single doses of psychoactive drugs can relieve the discomfort of social isolation and promote social connection. For opioid drugs, mu opioid agonists and kappa opioid antagonists reduce distress from social isolation, and mu opioid agonists enhance social reward. Amphetamine-like stimulant drugs, including MDMA, do not reduce the distress of social isolation but increase motivation for social contact and the pleasure derived from social interaction. Many questions remain, including whether these effects contribute to problematic drug use and the effects of drug withdrawal or dependence on social function.
Biological psychiatry
June 25, 2025
Kevin G Mulvihill, Gemma J Cockcroft, Angela C Roberts
2 citations
Different types of anxiety, arising from distinct forms of prefrontal cortex dysregulation, respond differently to different classes of anxiolytic drugs. In marmoset monkeys, heightened threat reactivity caused by overactivation of the ventromedial prefrontal cortex (vmPFC-14) was reduced by the SSRI citalopram, given either peripherally or directly into vmPFC-14, but inconsistently by ketamine. In contrast, heightened threat reactivity caused by inactivation of the orbitofrontal cortex (OFC-11) was reduced by central ketamine but not by citalopram. This suggests that matching anxiolytic treatment to the specific neural basis of a patient's anxiety could improve treatment success.
Biological psychiatry
March 28, 2025
Astrid M Cardona-Acosta, Lyonna F Parise, Carlos A Bolaños-Guzmán et al.
2 citations
Stress-induced disorders such as depression, anxiety, PTSD, and postpartum depression are increasingly common, yet current treatments are limited. This review examines ketamine as a potential preventive treatment, summarizing preclinical and clinical findings on (R,S)-ketamine and its metabolites (2R,6R)- and (2S,6S)-hydroxynorketamine. It explores underlying mechanisms involving brain regions, circuits, and glutamatergic, dopaminergic, serotonergic, and inflammatory processes. The review also notes limitations including age- and sex-specific efficacy, adverse effects, and legal and ethical concerns. Future research directions and clinical integration are discussed. The literature underscores the need for further study to weigh ketamine's benefits and risks as a prophylactic.
Biological psychiatry
June 13, 2025
Shaoqiang Han, Ya Tian, Huiting Yang et al.
1 citation
A systematic review of 18 multimodal neuroimaging studies (440 depressed individuals, 174 healthy controls) mapped brain locations linked to ketamine's antidepressant effects onto a functional brain network. The network primarily involved regions of the default mode, ventral attention, and frontoparietal networks. This network was robust under parameter perturbations and leave-one-study-out validation, and was specific to depression compared to other mental disorders. A ketamine-specific circuit, including the subgenual cingulate cortex and dorsolateral prefrontal cortex, overlapped with optimal brain stimulation sites for depression. These findings reconcile inconsistent results and suggest a network-level mechanism for ketamine's therapeutic effects.
Biological psychiatry
April 15, 2025
Mary L Woody, Rebecca Rohac, Iya Cooper et al.
1 citation
A single intravenous dose of ketamine (0.5 mg/kg over 40 minutes) rapidly reduces attentional bias toward sad stimuli in adults with moderate-to-severe depression. A novel dual-probe video task measuring attentional bias showed good test-retest reliability at one week and one month before treatment. In two studies totaling 83 participants, attentional bias decreased from before to 24 hours after ketamine infusion. In the first study, attentional bias correlated with clinician-rated depressive symptoms at each pretreatment assessment. In the second study, reductions in attentional bias correlated with symptom improvement. The findings suggest that reducing attentional bias may be a cognitive mechanism underlying ketamine's rapid antidepressant effects.
Biological psychiatry
March 16, 2026
Xianglian Wang, Jing Xia, Heyi Luo et al.
Ketamine produces rapid antidepressant effects but also causes hyperlocomotion, a side effect linked to increased dopamine activity in the ventral tegmental area (VTA). Cannabidiol (CBD) blocked ketamine-induced hyperlocomotion in mice when given systemically (30 mg/kg) or directly into the VTA (10 μg per mouse). Whole-brain imaging showed that ketamine increased neuronal activity in the VTA, prefrontal cortex, and nucleus accumbens, which CBD reduced. Electrophysiology revealed that ketamine suppressed glycine receptor (GlyR) function, while CBD reversed this dysfunction by antagonizing ketamine-driven delays in GlyR activation. In GlyRα1S296A mice, CBD's effect on hyperlocomotion was abolished, indicating that VTA GlyRα1 signaling, particularly the S296 residue, is essential for CBD's dissociation of ketamine's therapeutic and adverse effects.
Biological psychiatry
February 3, 2026
Mehmet Bostancıklıoğlu, Davut Sinan Kaplan, Ramazan Bal et al.
Psilocybin and MDMA reduce anxiety-like behaviors in a rat model of fear conditioning, and these effects depend on myelin plasticity in the dentate gyrus. Both drugs triggered oligodendroglial changes and multi-omic signatures of myelin remodeling, though mean myelin thickness (g-ratio) did not differ significantly between treated and untreated fear-conditioned animals. Disrupting myelin abolished the anxiolytic effects. Psilocybin preferentially activated early oligodendroglial gene programs, while MDMA enhanced markers of mature myelin. Blocking the 5-HT2A receptor completely eliminated both the myelin and behavioral enhancements. Enhancing myelination may be a viable strategy to sustain therapeutic effects of psychedelic-assisted treatments for PTSD.