Sex differences in the acute effects of cannabis on human cognition: A systematic review.

Cannabis is among the most consumed psychoactive substances world-wide. Considering changing policy trends regarding the substance, it is crucial to understand more clearly its potential acute and residual adverse effects from a public health viewpoint. Cognitive function is one of the targeted areas with conflicting findings. This meta-review measured the magnitude of acute and residual effects of cannabis on cognition in adolescents and adults provided by meta-analyses and evaluated quality of evidence. A systematic search was performed in PubMed, PsycINFO, Web of Science and Google Scholar. Meta-analyses were included if they quantitatively examined the performances of users from the general population on cognitive tasks. The search retrieved 10 eligible meta-analyses (71 effects sizes, n = 43 761) with evidence ranging from low to moderate quality, which were categorized into domains of cognitive functions: executive functions (k = 7), learning and memory (k = 5), attention (k = 4), processing speed (k = 5), perceptual motor function (k = 2) and language (k = 2). Verbal learning and memory displayed the most robust evidence and were most impaired by acute cannabis intoxication that persisted after intoxication passed. Small-to-moderate acute and residual adverse effects were reported for executive functioning. Cannabis use led to small deficits in inhibitory processes and flexibility, whereas small-to-moderate deficits were reported for working memory and decision-making. Evidence regarding processing speed and attention has shown that cannabis administration induced small-to-moderate adverse effects and residual neurocognitive deficits were observed in heavy cannabis-using youths. Results showed no significant difference between cannabis users and non-users on language, and small-to-moderate effects for simple motor skills. Meta-analytical data on the acute effects of cannabis use on neurocognitive function have shown that cannabis intoxication leads to small to moderate deficits in several cognitive domains. These acute impairments accord with documented residual effects, suggesting that the detrimental effects of cannabis persist beyond acute intake.

Long-term harms of cannabis may be exacerbated in adolescence, but little is known about the acute effects of cannabis in adolescents. We aimed to (i) compare the acute effects of cannabis in adolescent and adult cannabis users and (ii) determine if cannabidiol (CBD) acutely modulates the effects of delta-9-tetrahydocannabinol (THC). Randomised, double-blind, placebo-controlled, crossover experiment. The experiment was registered on ClinicalTrials.gov (NCT04851392). Laboratory in London, United Kingdom. Twenty-four adolescents (12 women, 16- to 17-year-olds) and 24 adults (12 women, 26- to 29-year-olds) who used cannabis 0.5-3days/week and were matched on cannabis use frequency (mean = 1.5days/week). We administered three weight-adjusted vaporised cannabis flower preparations: 'THC' (8mg THC for 75 kg person); 'THC + CBD' (8mg THC and 24 mg CBD for 75 kg person); and 'PLA' (matched placebo). Primary outcomes were (i) subjective 'feel drug effect'; (ii) verbal episodicmemory (delayed prose recall); and (iii) psychotomimetic effect (Psychotomimetic States Inventory). Compared with 'PLA', 'THC' and 'THC + CBD' significantly (P < 0.001) increased 'feel drug effect' (mean difference [MD] = 6.3, 95% CI = 5.3-7.2; MD = 6.8, 95% CI = 6.0-7.7), impaired verbalepisodicmemory (MD = -2.7, 95% CI = -4.1 to -1.4; MD = -2.9, 95% CI = -4.1 to -1.7) and increased psychotomimetic effects (MD = 7.8, 95% CI = 2.8-12.7; MD = 10.8, 95% CI = 6.2-15.4). There was no evidence that adolescents differed from adults in their responses to cannabis (interaction P ≥ 0.4). Bayesian analyses supported equivalent effects of cannabis in adolescents and adults (Bayes factor [BF01 ] >3). There was no evidence that CBD significantly modulated the acute effects of THC. Adolescent cannabis users are neither more resilient nor more vulnerable than adult cannabis users to the acute psychotomimetic, verbalmemory-impairing or subjective effects of cannabis. Furthermore, in adolescents and adults, vaporised cannabidiol does not mitigate the acute harms caused by delta-9-tetrahydocannabinol.

People with psychosis and those at clinical high risk (CHR) for this syndrome have significantly higher prevalence of cannabis use compared to the general population. Furthermore, cannabis use can negatively impact the course and treatment outcomes in psychosis. Understanding the acute subjective and cognitive effects of cannabis and cannabinoids in this population is necessary if we are to disentangle the reasons for the increased prevalence of use; and also to help design interventions. There is little evidence to support the ’self-medication’ hypothesis, in its original form. Among principal phyto-cannabinoids, while THC exacerbates positive and cognitive symptoms of psychosis, cannabidiol lacks these effects and may even improve these symptoms. With the liberalization of cannabis laws in many countries, cannabis and cannabis-based products will be more accessible to both individuals with psychotic disorders and those at risk for psychosis. This chapter summarizes the literature regarding acute effects of cannabis and cannabinoids in people at CHR and with established psychosis.

Cannabis perturbs dynamic brain states.

Substance abuse has often been associated with alterations in response inhibition in humans. Not much research has examined how the acute effects of drugs modify the neurophysiological correlates of response inhibition, or how these effects interact with individual variation in trait levels of impulsivity and novelty seeking. This study investigated the effects of cocaine and cannabis on behavioural and event-related potential (ERP) correlates of response inhibition in 38 healthy drug using volunteers. A double-blind placebo-controlled randomized three-way crossover design was used. All subjects completed a standard Go/NoGo task after administration of the drugs. Compared with a placebo, cocaine yielded improved accuracy, quicker reaction times and an increased prefrontal NoGo-P3 ERP. Cannabis produced opposing results; slower reaction times, impaired accuracy and a reduction in the amplitude of the prefrontal NoGo-P3. Cannabis in addition decreased the amplitude of the parietally recorded P3, while cocaine did not affect this. Neither drugs specifically affected the N2 component, suggesting that pre-motor response inhibitory processes remain unaffected. Neither trait impulsivity nor novelty seeking interacted with drug-induced effects on measures of response inhibition. We conclude that acute drug effects on response inhibition seem to be specific to the later, evaluative stages of response inhibition. The acute effects of cannabis appeared less specific to response inhibition than those of cocaine. Together, the results show that the behavioural effects on response inhibition are reflected in electrophysiological correlates. This study did not support a substantial role of vulnerability personality traits in the acute intoxication stage.

Policy changes have increased access to cannabis for individuals with little or no prior exposure. Few studies have examined sex differences in cannabis effects among individuals with sporadic cannabis use or for nonsmoked routes of cannabis administration. Data from four double-blind, placebo-controlled studies were pooled to compare the acute pharmacodynamic effects of vaporized and oral cannabis in male (n=27) and female (n=23) participants who used cannabis infrequently (no use ≥30days prior to randomization). Analyses compared peak change-from-baseline scores between male and female participants for subjective drug effects, cognitive/psychomotor performance, cardiovascular effects, and blood concentrations of Δ9-tetrahydrocannabinol (THC) and its primary metabolites (11-OH-THC, THC-COOH) after exposure to placebo cannabis or cannabis containing low-dose (5 or 10mg) or high-dose THC (20 or 25mg). Overall, cannabis elicited dose-orderly increases in subjective effects, impairment of cognitive/psychomotor performance, heart rate, and blood cannabinoid concentrations. Females exhibited greater peak blood 11-OH-THC concentrations and reported greater peak subjective ratings of "drug effect" that remained when controlling for body weight. When controlling for both body weight and peak blood cannabinoid concentrations, ratings of "anxious/nervous," "heart racing," and "restless" were significantly higher for females than males. Although additional research is needed to elucidate sex differences in responses to cannabis at a wider range of THC doses, other routes of administration, and products with diverse chemical composition, the current data indicate that public health messaging and clinical decision making around the use of cannabinoids should recommend lower starting doses for females and warnings about acute anxiogenic reactions.

Acute cannabis administration can produce transient psychotic-like effects in healthy individuals. However, the mechanisms through which this occurs and which factors predict vulnerability remain unclear. We investigate whether cannabis inhalation leads to psychotic-like symptoms and speech illusion; and whether cannabidiol (CBD) blunts such effects (study 1) and adolescence heightens such effects (study 2). Two double-blind placebo-controlled studies, assessing speech illusion in a white noise task, and psychotic-like symptoms on the Psychotomimetic States Inventory (PSI). Study 1 compared effects of Cann-CBD (cannabis containing Δ-9-tetrahydrocannabinol (THC) and negligible levels of CBD) with Cann+CBD (cannabis containing THC and CBD) in 17 adults. Study 2 compared effects of Cann-CBD in 20 adolescents and 20 adults. All participants were healthy individuals who currently used cannabis. In study 1, relative to placebo, both Cann-CBD and Cann+CBD increased PSI scores but not speech illusion. No differences between Cann-CBD and Cann+CBD emerged. In study 2, relative to placebo, Cann-CBD increased PSI scores and incidence of speech illusion, with the odds of experiencing speech illusion 3.1 (95% CIs 1.3-7.2) times higher after Cann-CBD. No age group differences were found for speech illusion, but adults showed heightened effects on the PSI. Inhalation of cannabis reliably increases psychotic-like symptoms in healthy cannabis users and may increase the incidence of speech illusion. CBD did not influence psychotic-like effects of cannabis. Adolescents may be less vulnerable to acute psychotic-like effects of cannabis than adults.

Multiple Sclerosis, Cannabinoids, and Cognition

In the Study Of diabetic Nephropathy with AtRasentan (SONAR), the endothelin receptor antagonist (ERA) atrasentan slowed progression of chronic kidney disease (CKD) in individuals with type 2 diabetes. Pre-clinical research suggests sex-based differences in the endothelin system might influence the efficacy and safety of atrasentan. We therefore assessed the effects of atrasentan in men and women participating in SONAR. SONAR was a double-blind, placebo-controlled trial that compared atrasentan 0.75 mg/day with placebo in individuals with type 2 diabetes and CKD (eGFR 25-75 ml/min per 1.73 m2, urine albumin/creatinine ratio [UACR] 300-5000 mg/g). The primary endpoint was defined as the time from randomisation to the first occurrence of a doubling in serum creatinine or kidney failure (eGFR <15 ml/min per 1.73 m2, chronic dialysis, kidney transplantation or death from kidney failure). Hospitalisation for heart failure was the secondary endpoint. We performed Cox proportional hazards regression analyses to compare the treatment effect of atrasentan between male and female participants on the risk of the composite kidney outcome as well as hospitalisation for heart failure. Additionally, differences between male and female participants in atrasentan plasma exposure and eGFR change were assessed using, respectively, a t test and linear mixed effect model. Among 3668 randomised participants, 946 (25.8%) were female. Atrasentan significantly reduced the risk of the composite kidney outcome in female participants (HR 0.46 [95% CI 0.28, 0.76]) but not in male participants (HR 0.83 [95% CI 0.65, 1.05]; p value for interaction 0.032). Atrasentan compared with placebo reduced eGFR decline to a greater extent in female than in male participants (treatment effect difference between male vs female participants -0.99 ml/min per 1.73 m2, p value for interaction=0.020). The RR for hospitalisation for heart failure with atrasentan vs placebo was 1.14 (95% CI 0.74, 1.76) in male participants and 1.88 (95% CI 0.98, 3.63) in female participants (p value for interaction=0.217). Female participants also had significantly higher atrasentan plasma exposure than male participants (geometric mean AUC 54.5 vs 42.6 ng/ml×h; p<0.001). Atrasentan showed greater kidney protection in female than in male participants but also induced more heart failure events in the female participants. These data suggest that sex-specific dosing regimens may be considered to optimise ERA treatment. ClinicalTrials.gov NCT01858532.

Cannabis is the most common illicit drug used in the USA and its use has been rising over the past decade, while the historical gap in rates of use between men and women has been decreasing. Sex differences in the effects of cannabinoids have been reported in animal models, but human studies are sparse and inconsistent. We investigated the sex differences in the acute subjective, psychotomimetic, cognitive, and physiological effects of intravenous (IV) delta-9 tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis. Healthy male and female individuals, with limited exposure to cannabis, participated in a double blind, placebo-controlled study of intravenous (IV) placebo or THC at two doses (0.015mg/kg and 0.03mg/kg). Visual analog scale (VAS) was used to measure subjective effects, Psychotomimetic States Inventory (PSI) and the Clinician-Administered Dissociative Symptoms Scale (CADSS) were used to assess the psychotomimetic effects and perceptual alterations, respectively, and Rey Auditory Verbal Learning Task (RAVLT) was used to evaluate cognitive effects. Outcome variables were represented as the peak change from baseline for each variable, except RAVLT which was used only once per the test day after the subjective effects. A total of 42 individuals participated in this study. There were no significant differences between male and female participants in background characteristics. There was a significant main effect of sex on the VAS scores for THC-induced "High" (F1,38 = 4.27, p < 0.05) and a significant dose × sex interaction (F2,77 = 3.38, p < 0.05) with female participants having greater "High" scores than male participants at the lower THC dose (0.015mg/kg). No other sex differences were observed in acute subjective, psychotomimetic, cognitive, or physiological effects of THC. There were significant sex differences in subjective effects of feeling "High" at a lower dose of THC. However, there were no other sex-related differences in the subjective, physiological, or cognitive effects of THC.

Introduction Sex disparities in both insomnia and perceived pain have been demonstrated, where female patients tend to report greater insomnia symptoms, pain sensitivity and higher prevalence to insomnia disorder and chronic pain conditions compared to male patients. The present trial examined the sex differences in response to cognitive behavioral therapy for insomnia (CBT-I) in patients with insomnia disorder undergoing hip or knee joint arthroplasty. Methods Participants (N=69; 68% Female; Mean age=67.3 years) were randomly assigned to receive CBT-I (n=23 female; n=11 male) or Health Education Control (HEC; n=24 female, n=11 Male). The Insomnia Severity Index (ISI), PROMIS Pain, and Hip/Knee Osteoarthritis Outcome Score (HOOS/KOOS) were administered at baseline and post-intervention. Generalized linear models were performed to detect sex and treatment group differences and sub-group analysis by sex. Results There were no significant differences between male versus female participants for pre-post intervention changes in ISI, PROMIS pain intensity or pain interference. In female participants, change in ISI from baseline to post-treatment was significantly lower in the CBTI group than the HEC group (-8.5±6.4 vs -2.1±7.6; P=0.02), but not in male participants (P=0.21). In female participants, there was a significant correlation in pre-post change in ISI with pre-post change in PROMIS pain intensity (r=0.5, P=0.03), pain interference (r=0.6, P=0.01), HOOS/KOOS activities of daily living (r=-0.4, P=0.04) and quality of life (r=-0.5, P=0.01). No significant associations between insomnia and pain were observed in male participants. Conclusion Among individuals with insomnia recovering from hip or knee joint arthroplasty, there was a greater decrease in insomnia severity following CBT-I compared to HEC in female participants but not male participants. Pain outcomes improved across both treatment conditions for male and female participants and no significant group differences were found. Regardless of treatment group of the female participants, improvements in insomnia severity were associated with improvements in pain intensity, pain interference, activities of daily living, and quality of life. Support (if any) This work is supported by NIH Grant #s R01NR018342 (PI Nowakowski) and IQUEST Center (CIN 13-413).

While the acute effects of cannabis are relatively benign for most users, some individuals experience significant adverse effects. This study aimed to identify whether variation in schizotypal personality traits and frequency of cannabis use influence the acute effects of delta-9-tetrahydrocannabinol (THC). Individual participant data from four double-blind, randomised, placebo-controlled, acute crossover studies involving 128 cannabis users were combined for a mega-analysis. Using multilevel linear models and moderation analyses, frequency of cannabis use and schizotypal personality traits were investigated as potential moderators of the subjective, cognitive and psychotomimetic effects of acute THC. There was evidence of a moderating effect where increased frequency of cannabis use was associated with reduced intensity of subjective (changes in alertness and feeling stoned) and psychosis-like effects following THC when compared with placebo. Moderating effects of cannabis use frequency on acute memory impairment were weak. Trait schizotypy did not moderate the acute psychosis-like effects of THC compared with placebo. Our results suggest that a pattern of domain-specific tolerance develops to the acute effects of THC. Tolerance to the alertness-reducing effects occurred more readily than tolerance to psychotomimetic effects. Only partial tolerance to feeling stoned was found, and there was weak evidence for tolerance to memory impairment. Trait schizotypy did not moderate THC's effects on psychotomimetic symptoms.

Cannabis remains the most frequently used illicit drug worldwide. It produces a broad range of acute effects, such as euphoria, increased heart rate and perceptual alterations. Over the last few decades, a substantial number of experiments have been conducted to provide insight into the acute effects of cannabis on cognition. Here, we systematically review studies that investigated the impact of administration of cannabis or [INCREMENT]-tetrahydrocannabinol, the main psychoactive constituent of cannabis, on human executive function, in particular, on the three principal domains of inhibition, working memory and reasoning/association. Our findings suggest that cannabis use results in acute impairment of inhibition, with the strongest effects after pulmonary administration of higher doses of [INCREMENT]-tetrahydrocannabinol. Results from neuroimaging studies indicate that these effects are predominantly modulated through neural processes in the inferior frontal gyrus. Working memory and reasoning/association are less clearly affected by cannabis administration, possibly because of compensational neural mechanisms to overcome the effects of cannabis intoxication on performance accuracy. Factors that may account for the variation in results are the extent to which a paradigm involves attentional processes, differences between studies in administration methods and variation in the patients' history of cannabis use.

Background: Few studies have systematically evaluated whether adaptations to endurance training differ by sex. We assessed sex differences in cardiopulmonary, body composition, and metabolic adaptations among male and female sedentary adults following a 20-week endurance training program. Hypothesis: Male and female participants will demonstrate equal cardiovascular and metabolic adaptations in response to an identical dose of supervised endurance training. Methods: HERITAGE Family Study participants (56% female, mean age: 34 years) completed a supervised endurance training program, with cardiopulmonary exercise tests, body composition, and metabolic assessments performed at baseline (n=834) and after the training period (n=720). Two-sample t-tests were used to compare exercise responses among male and female participants. An external exercise training intervention study involving 149 individuals with abdominal adiposity (63% female, mean age: 52 years) was used for validation of training-related adaptations. Results: We observed sex differences in several (18/65) training-related adaptations in HERITAGE. Notably, while male participants exhibited higher VO2max at baseline (36 vs 27 ml/kg/min, p=5x10-49), female participants demonstrated greater improvements following the training intervention (+20 vs +16%, p=2x10-7). From a body composition and metabolic standpoint, male participants exhibited greater reductions in body fat percentage (-4 vs -2%, p=0.004) and visceral fat (-6 vs -2%, p=0.002), and a three-fold greater increase in insulin sensitivity (+17 vs +6%, p=0.009) compared to female participants. In the validation cohort, male participants also demonstrated greater training-related improvements in body mass index, waist circumference, and insulin/glucose responses to an oral glucose tolerance test. Conclusions: This study highlights important sex differences in adaptations to endurance training. Specifically, while female individuals demonstrated greater trainability in VO2max, male individuals exhibited larger improvements in body composition and glucose/insulin metabolism.

Objective: Amidst the evolving policy surrounding cannabis legalization in the United States, cannabis use is becoming increasingly prevalent as perceptions of harm decrease, particularly among adolescents. Cannabis and alcohol are commonly used by adolescents and are often used together. However, developmental research has historically taken a “single substance” approach to examine the association of substance use and adolescent brain and behavior rather than examining co-(or poly-substance) use of multiple substances, such as cannabis and alcohol. Thus, the acute effects of cannabis and alcohol, and the impact of co-use of cannabis and alcohol on the adolescent brain, cognitive function and subsequent psychosocial outcomes remains understudied. This narrative review aims to examine the effects of cannabis and alcohol on adolescents across a number of behavioral and neurobiological outcomes. Methods: The PubMed and Google Scholar databases were searched for the last 10 years to identify articles reporting on acute effects of cannabis and alcohol administration, and the effects of cannabis and alcohol on neuropsychological, neurodevelopmental, neural (e.g., structural and functional neuroimaging), and psychosocial outcomes in adolescents. When adolescent data were not available, adult studies were included as support for potential areas of future direction in adolescent work. Results: Current studies of the impact of cannabis and alcohol on adolescent brain and behavior have yielded a complicated pattern. Some suggest that the use of cannabis in addition to alcohol during adolescence may have a “protective” effect, yielding neuropsychological and structural brain outcomes that are better than those for adolescents who use only alcohol. However, other adolescent studies suggest that cannabis and alcohol co-use is associated with negative health and social outcomes such as poorer academic performance and impaired driving. Conclusion: Variation in study methodologies, policy-level limitations and our limited understanding of the developmental neurobiological effects of cannabis preclude the straightforward interpretation of the existing data on adolescent cannabis and alcohol use. Further research on this topic is requisite to inform the development of effective intervention and prevention programs for adolescent substance users, which hinge on a more comprehensive understanding of how cannabis—and its intersection with alcohol—impacts the developing brain and behavior.