Brazilian Journal of Psychiatry
June 16, 2026
Daniel B.a. Prado, Matheus T. Rossignoli, Rafael N. Ruggiero et al.
In a rat model of schizophrenia-like symptoms induced by ketamine, the combination of cannabidiol and sodium nitroprusside given during brain development prevented hyperactivity and memory problems in both sexes, while each drug alone had limited effects. The model produced different symptoms in males and females: females showed greater hyperactivity and long-term memory deficits, whereas males showed reduced pleasure-seeking and short-term memory impairments. The combined treatment was more effective in females, and distinct behavioral patterns were seen between sexes. This suggests that a combination of these two compounds may offer a sex-specific preventive strategy for schizophrenia symptoms.
Psychoactives
June 8, 2026
Fizza Mitter, Anton Sheptooha, Janni Leung et al.
Post-traumatic stress disorder (PTSD) is often not well treated by current medications or talk therapies, leading to interest in psychedelic-assisted psychotherapy. A systematic review and meta-analysis of 11 randomized controlled trials with 358 participants examined MDMA, ketamine, and cannabidiol. MDMA-assisted psychotherapy produced a moderate-to-large reduction in PTSD symptoms, with more participants achieving clinical response and loss of PTSD diagnosis. Ketamine showed a small, non-significant effect, and one trial of cannabidiol found no clear benefit. All agents were generally well tolerated. The evidence is dominated by MDMA trials, and safety data remain insufficient for strong comparisons. More studies with standardized outcomes and direct comparisons are needed.
Physiological research
May 12, 2026
M Bochin, Č Vejmola, V Koudelka et al.
Acute oral administration of THC (10 mg/kg), CBD (10 mg/kg), or their combination in freely moving rats alters resting-state EEG dynamics. THC and THC+CBD produced the strongest and most spatially extensive increases in low-frequency spectral power, with significant delta-beta clusters in prefrontal, cingulate, hippocampal, and striatal regions. CBD yielded fewer and smaller clusters. Connectivity analyses revealed altered functional coupling within overlapping CB1 receptor-rich regions. The combination treatment closely resembled THC alone, suggesting a dominant THC-driven contribution. These findings identify a cannabinoid-specific EEG signature of enhanced low-frequency oscillatory activity and altered large-scale network organization.
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.
Journal of psychopharmacology (Oxford, England)
March 1, 2026
Eilidh Macnicol, Michelle Kokkinou, Maria Elisa Serrano Navacerrada et al.
2 citations
THC increases brain functional connectivity and blood flow in rats, while CBD decreases connectivity without affecting blood flow. When combined, CBD moderates THC's effects. Adult male rats received THC, CBD, a combination, or a placebo. Brain scans two hours later showed THC raised whole-brain connectivity and blood flow in cortical and subcortical regions. CBD lowered connectivity metrics. The combination produced moderate increases in both measures. THC specifically strengthened connections between the cortex and hippocampus and between the cortex and striatum, an effect reduced when CBD was present. These distinct neurophysiological profiles suggest cannabinoids induce different brain states, supporting the use of functional neuroimaging in developing cannabinoid-based therapies.
Psychoactives
February 3, 2026
Eliana Rodrigues
Interest in psychoactive substances like psychedelics is growing in medicine and academia, but misclassifications of certain plants, animals, fungi, and their substances persist in media and scholarly circles. This opinion piece argues whether cannabidiol (CBD) is a non-psychoactive phytocannabinoid, noting that hundreds of robust studies support its clinical use for seizures, anxiety, psychosis, schizophrenia, post-traumatic stress disorder, and addiction. The text reviews historical classifications of psychoactive substances, reflects on terminology, and proposes a new classification for psychedelics.
Iranian Journal of Chemistry & Chemical Engineering
December 7, 2025
Sajedeh Rabipour, Evan Abdolkareem Mahmood, Abdol Ghaffar Ebadi et al.
Psychedelic therapy shows great potential and is reemerging amid social transformations and demands in psychotherapy. An integrative literature review examined articles on psychedelics and cannabinoids published between 2000 and 2021. For psychedelics, 22 articles were analyzed from an initial 77. For cannabinoids, 235 articles were selected from 1,164. The United States produced the most publications, followed by Canada and Australia. The cannabinoid literature addresses beneficial and adverse health effects, consequences of cannabis legislation, and associations with various variables. There is a lack of research on cannabis' medicinal use regarding treatments, diseases, standardization, routes of administration, and doses, highlighting the need for more research.
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.
Human psychopharmacology
September 1, 2025
Renée Martin-Willett, Carillon J Skrzynski, Angela D Bryan et al.
In a randomized trial, people using cannabis with cannabidiol (CBD) experienced greater decreases in symptoms of depression, anxiety, and stress over four weeks compared to those using cannabis with tetrahydrocannabinol (THC). This benefit was most pronounced among participants who reported average or high levels of perceived discrimination. No significant changes in drinking behaviors were observed. The findings suggest that CBD may help reduce negative emotional symptoms in the short term without increasing risk for alcohol misuse, and that perceived discrimination plays an important role in this relationship.
Biological psychiatry global open science
July 1, 2025
Yalin Sun, Meenalochani Sivasubramanian, Marija Milenkovic et al.
Adolescent cannabis use increases risk for neuropsychiatric disorders, possibly through amygdala dysfunction. Chronic THC treatment in male adolescent nonhuman primates and rats disrupted sleep and increased anxiety-related behavior. THC activated proinflammatory glial cells (astrocytes) exclusively in the adolescent amygdala, upregulating GFAP and complement factor-B, effects absent in adults or other brain regions. THC also reduced synaptic plasticity markers stathmin-1 and NrCAM. Co-administered cannabidiol prevented astrocyte inflammation but did not restore plasticity markers. Astrogliosis correlated with fragmented sleep, attenuated plasticity markers with anxiety. Elevated CB1R expression in the maturing brain was astrocyte-localized in the amygdala, linking THC to unique adolescent amygdala vulnerability.
Journal of Translational Medicine
October 2, 2020
Lara Sharpe, Justin Sinclair, Andrew Kramer et al.
122 citations
Acute doses of cannabidiol (CBD) reduce anxiety in both animals and humans without causing anxiety at higher doses, while tetrahydrocannabinol (THC) commonly produces anxiety, especially at higher doses. Epidemiological studies support an anxiolytic effect from CBD, THC, or whole-plant cannabis, but human clinical studies show THC often triggers anxiogenic responses. Cannabinoid therapies containing primarily CBD may be more suitable for people with pre-existing anxiety or as an adjunct for managing anxiety or stress-related disorders. Further research is needed on other cannabis constituents like terpenes, and more clinical trials involving patients with anxiety disorders are warranted.
Psychopharmacology
May 1, 2019
Thomas R. Arkell, Nicholas Lintzeris, Richard C. Kevin et al.
177 citations
Both THC-dominant and THC/CBD equivalent cannabis increased lane weaving during simulated driving but had little effect on other driving measures. Impairment on the Digit Symbol Substitution Task, Divided Attention Task, and Paced Auditory Serial Addition Task occurred with both active cannabis types, with worse performance on the latter two tasks after THC/CBD equivalent cannabis. Subjective feelings of being "stoned" and confidence in driving ability did not differ by CBD content. Peak plasma THC concentrations were higher after THC/CBD equivalent cannabis, suggesting a possible pharmacokinetic interaction. Cannabis with equivalent CBD and THC appears no less impairing than THC-dominant cannabis, and CBD may exacerbate THC-induced impairment in some circumstances.
Pharmacology & Therapeutics
October 20, 2018
Michael Bloomfield, Chandni Hindocha, Sebastian F Green et al.
236 citations
Cannabis and its primary psychoactive component, THC, acutely alter executive, emotional, reward, and memory processing by directly interacting with the endocannabinoid system and indirectly affecting glutamatergic, GABAergic, and dopaminergic systems. Cannabidiol, a non-intoxicating cannabinoid, may offset some of these acute effects. Heavy repeated cannabis use, especially during adolescence, is associated with adverse effects that increase the risk of mental illnesses such as addiction and psychosis. This review synthesizes human neuroimaging research on the acute and chronic neuropsychopharmacology of cannabis, covering effects during development, implications for psychosis and cannabis use disorder, and methodological considerations.
Frontiers in Pharmacology
May 11, 2017
Antônio Waldo Zuardi, Natália Pegoraro Rodrigues, Angélica L. Silva et al.
292 citations
Acute administration of 300 mg of cannabidiol (CBD) reduced subjective anxiety after a public speaking test in healthy adults, while 100 mg and 900 mg did not, confirming an inverted U-shaped dose-response curve similar to that seen in animal studies. Clonazepam (1 mg) also reduced anxiety but caused more sedation and smaller increases in blood pressure compared to CBD 300 mg. The public speaking test itself increased anxiety, heart rate, and blood pressure across all groups.
Psychopharmacology
September 2, 2016
Will Lawn, Tom P. Freeman, Rebecca Pope et al.
177 citations
Cannabis containing only THC reduced the likelihood of choosing high-effort rewards compared to placebo, indicating a transient amotivational state, while adding CBD altered the effect of THC on expected value. Cannabis-dependent individuals showed preserved motivation but impaired reward learning compared to non-dependent controls, though depression may have influenced results.
Journal of Psychopharmacology
October 5, 2012
Amir Englund, Paul D. Morrison, Judith Nottage et al.
463 citations
Pre-treatment with 600 mg of cannabidiol (CBD) reduced the likelihood of clinically significant psychotic symptoms and paranoia caused by intravenous delta-9-tetrahydrocannabinol (THC, 1.5 mg) in healthy volunteers. Participants who received CBD before THC had lower scores on the State Social Paranoia Scale and smaller declines in episodic memory compared with those who received placebo before THC. The odds of experiencing a clinically significant increase in positive psychotic symptoms were about 78% lower in the CBD group. These results support the view that cannabis products high in THC and low in CBD pose greater mental health risks.
Current Pharmaceutical Design
September 12, 2012
Rocío Martín‐Santos, José Alexandre S. Crippa, Albert Batalla et al.
288 citations
Delta-9-tetrahydrocannabinol (THC), but not cannabidiol (CBD), produces marked acute behavioral and physiological effects. In a randomized, double-blind, placebo-controlled trial with 16 healthy male volunteers, oral THC (10 mg) caused anxiety, dysphoria, positive psychotic symptoms, physical and mental sedation, subjective intoxication, and increased heart rate relative to placebo and CBD. CBD (600 mg) showed no differences from placebo on any symptomatic or physiological measure, indicating it is safe and well tolerated. The two main cannabis constituents thus have quite different acute effects.
Psychopharmacology
October 30, 2010
Johannes G. Ramaekers, Eef L. Theunissen, Marjolein de Brouwer et al.
168 citations
Heavy cannabis users develop tolerance to the impairing effects of THC on neurocognitive tasks, but they do not develop cross-tolerance to the impairing effects of alcohol. In a double-blind study, 21 heavy cannabis users received alcohol at three levels (targeting blood alcohol concentrations of 0, 0.5, and 0.7 mg/ml) and smoked a THC cigarette (400 μg/kg) 3 hours after drinking began. Alcohol alone impaired performance on tests of perceptual motor control, divided attention, and motor inhibition, while THC alone generally did not affect performance. However, combining THC and alcohol produced greater impairments in divided attention than alcohol alone, indicating that alcohol can potentiate THC effects in tolerant users.
Brazilian Journal of Psychiatry
March 1, 2010
Jaime E. C. Hallak, João Paulo Machado‐de‐Sousa, José Alexandre S. Crippa et al.
122 citations
A single dose of cannabidiol (CBD) does not improve selective attention in people with schizophrenia, and higher doses may worsen performance. In a study of 28 patients, those given 600 mg of CBD performed worse on the Stroop Color Word Test than those given 300 mg or placebo, while all groups showed some improvement from practice. No differences were found in electrodermal responses to sounds. The authors suggest that chronic CBD administration might still be beneficial, but acute treatment appears ineffective for cognitive symptoms.
The International Journal of Neuropsychopharmacology
September 24, 2009
Paolo Fusar‐poli, Paul Allen, Sagnik Bhattacharyya et al.
165 citations
Cannabidiol (CBD), but not delta-9-tetrahydrocannabinol (THC), disrupts forward connectivity between the amygdala and the anterior cingulate cortex during the neural response to fearful faces. This disruption may represent a neurophysiological correlate of CBD's anxiolytic properties. The study used dynamic causal modelling and Bayesian model selection to analyze effective connectivity in 15 healthy subjects under a double-blind, randomized, placebo-controlled fMRI paradigm while they viewed faces eliciting different levels of anxiety.
Psychological Medicine
July 23, 2009
R. Martín-Santos, Ana B. Fagundo, José Alexandre S. Crippa et al.
207 citations
A systematic review of neuroimaging studies published up to January 2009 assessed evidence for cannabis effects on brain structure and function. Among 41 included studies, functional imaging indicated that resting global and prefrontal blood flow are lower in cannabis users than in controls. Activation studies during cognitive tasks produced inconsistent results. Acute administration of THC or marijuana increased resting activity and activation of the frontal and anterior cingulate cortex during cognitive tasks. Only three of eight structural imaging studies found differences between users and controls, providing minimal evidence of major effects of cannabis on brain structure.
Archives of General Psychiatry
April 1, 2009
Sagnik Bhattacharyya, Paolo Fusar‐poli, Stefan Borgwardt et al.
250 citations
Delta9-tetrahydrocannabinol (THC), a psychoactive constituent of cannabis, increased psychotic symptoms, anxiety, intoxication, and sedation in healthy men with minimal prior cannabis use, while cannabidiol had no significant effect on these measures. Verbal learning performance was not significantly affected by either drug. THC altered brain activation in the parahippocampal gyrus during encoding and in the ventrostriatum during retrieval, with the ventrostriatal change directly correlating with induced psychotic symptoms. These findings suggest THC modulates mediotemporal and ventrostriatal function, potentially underlying cannabis's effects on verbal learning and psychosis.
Archives of General Psychiatry
January 1, 2009
Paolo Fusar‐poli, José A. Crippa, Sagnik Bhattacharyya et al.
461 citations
In healthy men with minimal prior cannabis use, the two main psychoactive compounds in cannabis had opposite effects on anxiety and brain activity. Delta9-tetrahydrocannabinol (THC) increased anxiety, intoxication, sedation, and psychotic symptoms, while cannabidiol (CBD) showed a trend toward reducing anxiety. When participants viewed intensely fearful faces, THC increased skin conductance fluctuations (a measure of autonomic arousal), whereas CBD decreased them. CBD also dampened brain activation in the amygdala and anterior and posterior cingulate cortex, and this suppression correlated with reduced arousal. THC mainly altered activation in frontal and parietal areas. These distinct neural effects may explain why cannabis can both relieve and provoke anxiety.
Brazilian Journal of Medical and Biological Research
April 1, 2006
Antônio Waldo Zuardi, J.a.s. Crippa, Jaime E. C. Hallak et al.
411 citations
A high dose of delta9-tetrahydrocannabinol, the main psychoactive component of cannabis, induces anxiety and psychotic-like symptoms in healthy volunteers, and these effects are significantly reduced by cannabidiol (CBD), a cannabis constituent without typical cannabis effects. Studies in animal models and healthy volunteers suggest an anxiolytic-like effect of CBD. Its antipsychotic-like properties have been investigated in animal models and supported by studies on healthy volunteers using binocular depth inversion and ketamine-induced psychotic symptoms. Open case reports and a preliminary controlled clinical trial indicate that CBD may be a safe, well-tolerated alternative treatment for schizophrenia. Future studies in other psychotic conditions are indicated.