Ryan Joseph McLaughlin

People who use cannabis commonly report stress-relieving effects, yet no studies have simultaneously assessed the acute effects of cannabis on multiple stress systems under placebo-controlled conditions. We conducted a randomized, double-blind, placebo-controlled trial in which 120 people (56 men, 52 women, 12 non-binary/transgender) who regularly use cannabis were assigned to vape placebo, a moderate dose (20 mg Δ⁹-tetrahydrocannabinol [THC]), or a high dose (40 mg THC) of cannabis. Stress ratings and salivary cortisol samples were obtained before (T0), 5 minutes (T1), and 60 minutes (T2) after vaping. Participants wore an Embrace wristband continuously measuring electrodermal activity (EDA), heart rate (HR), and heart rate variability (HRV). Stress ratings decreased across all conditions from T0 to T1 (p = 0.01) and T2 (p < 0.001), suggesting expectancy effects rather than cannabis effects. Salivary cortisol concentration decreased from T0 to T1 across all conditions (p < 0.001), with a significantly larger decrease in the high-dose condition (p = 0.03), followed by an increase from T1 to T2 in both cannabis conditions (p = 0.001). Skin conductance response amplitude and area under the curve decreased in both cannabis conditions (p's < 0.01), whereas peaks-per-minute increased in the high-dose condition at T2 (p = 0.01). HR was elevated significantly more in the high-dose than placebo condition during vaping (p = 0.001) and at T1 (p = 0.02). No effects of cannabis on HRV were detected. These findings indicate that cannabis intoxication divergently modulates stress physiology, attenuating neuroendocrine and electrodermal responses while elevating cardiovascular arousal and producing subjective stress reductions comparable to placebo. Thus, common perceptions of stress relief do not reflect uniform suppression of stress-related outcomes. This has important implications for the widespread use of cannabis as a coping strategy.

With approximately 4% of the world’s population using cannabis, there is a need to better understand its physiological effects. Cannabis consumption acutely promotes food intake (“the munchies”) via delta-9-tetrahydrocannabinol-mediated activation of cannabinoid 1 receptors (CB1R); however, these appetitive effects have not been well characterized. We examined effects of cannabis vapor inhalation on energy and macronutrient intake patterns in human participants and then validated these findings in a translational rat model through which we explored behavioral and physiological mechanisms subserving this response. Vaporized cannabis acutely and robustly increased energy intake. In humans, this occurred in the first 30 min of snack and beverage access, irrespective of dose or gender. In rats, these effects were observed in the first 60 min of food access, irrespective of macronutrient content, satiation, or sex, and were a result of cannabis vapor reducing latency to eat and increasing feeding bout number. Also, cannabis vapor did not change the proportion of macronutrients consumed by human participants and abolished preexisting macronutrient-specific food preferences in rats. Our rat data indicate that cannabis vapor may override homeostatic appetite regulation by increasing motivation to eat and reducing food reward devaluation to promote energy intake. Finally, cannabis vapor did not alter circulating appetite-associated hormones, and these feeding effects were mediated by central, but not peripheral, CB1Rs. This study complements and builds upon previous literature to characterize the appetitive effects of vaporized cannabis and uses a translational approach to examine cannabis-driven energy and macronutrient intake patterns in humans and rodents.

The recent wave of recreational cannabis legalization in the US has underscored the importance of identifying predictors of individual variability in cannabis use. While a subset of recreational cannabis users will go on to meet diagnostic criteria for cannabis use disorder, many do not, making it critical to characterize traits that confer both vulnerability and resilience. However, progress in identifying relevant predictors has been hindered by limited mechanistic insight and a lack of translationally relevant animal models of cannabis use. To address this, we employed a rat model of cannabis vapor self-administration that uses whole-plant cannabis extract and mimics the intrapulmonary route of intake typically used in humans. Using this model, we sought to identify behavioral and biological predictors of motivation to self-administer vaporized cannabis. Male and female Long-Evans rats (N = 48) underwent a battery of assays indexing behavioral domains aligned with the NIMH Research Domain Criteria (RDoC) prior to self-administration training. After four weeks of cannabis vapor self-administration (1 h sessions daily), motivation for cannabis vapor was assessed via a 3-h fixed ratio escalation (FRE) procedure. A series of linear regressions revealed that Social Processes, Arousal/Regulatory Systems, Cognition, and Positive Valence domains significantly predicted the number of cannabis vapor deliveries earned during the FRE test. Specifically, higher basal corticosterone (CORT), lower morning anandamide, impaired set-shifting performance, superior visual cue discrimination, and more social grooming during adolescence each predicted responding for cannabis. The Negative Valence domain was not a significant predictor. A multivariate machine learning approach combining principal component analysis and permutation importance further identified basal CORT and set-shifting performance as the strongest predictors of responding for vaporized cannabis. These findings highlight individual differences in stress regulation and cognitive flexibility as possible risk factors for cannabis use propensity and demonstrate the utility of leveraging RDoC framework for identifying relevant phenotypes in rodents that may extend across human psychiatric conditions.

The ability to integrate feedback and flexibly adjust behavior under shifting environmental demands is required to optimize decision-making strategies. Clinical and preclinical data indicate that individuals with stress-related disorders and rodents exposed to chronic stress exhibit impaired behavioral flexibility. The lateral habenula (LHb) has emerged as a key brain region contributing to the effects of stress on cognitive performance. However, the extent to which the LHb is recruited to fine-tune decision-making strategies, as well as the impacts of chronic stress on LHb recruitment during task performance, remain largely unknown. To this end, we used a three-week model of chronic unpredictable stress (CUS) and performed in vivo fiber photometry to investigate Ca ²⁺ transients in LHb neurons during an attentional set-shifting task in adult male and female Sprague Dawley rats (n=7-12/sex/group). We found that CUS exposure did not significantly impair behavioral flexibility. Rather, CUS-exposed rats made fewer omissions and exhibited shorter response latencies compared to controls, suggesting enhanced task engagement. We also observed sex differences in LHb Ca ²⁺ activity. In control animals, we found that male rats showed stronger LHb signal prior to decision making, and greater activation following trial outcome than females. These differences were normalized by CUS, resulting in similar signaling patterns across sexes. Altogether, these findings reveal that chronic stress alters LHb activity in a sex-dependent manner without overtly impairing behavioral flexibility, thereby underscoring the importance of the LHb in decision making under stressful conditions. Highlights: Chronic stress decreased response latency without impairing behavioral flexibility Male rats displayed greater inhibition of LHb activity prior to decision making Chronic stress abolished sex differences in LHb activity during decision making

The legalization of cannabis in several states across the United States has increased the need to better understand its effects on the body, brain, and behavior, particularly in different populations. Previous rodent studies have revealed age and sex differences in response to injected Δ ⁹ -tetrahydrocannabinol (THC). However, the pharmacokinetic and pharmacodynamic properties of THC administered through more translationally relevant routes of administration are less well known. Here, we addressed this gap by investigating age and sex differences in pharmacokinetics and the acute behavioral effects of vaporized cannabis e-liquid in mice. Adolescent (postnatal day [P] 35–50) and adult (≥P70) mice of both sexes received noncontingent exposure to vehicle vapor, 150 mg/mL (CAN150), or 300 mg/mL (CAN300) vaporized cannabis extract diluted in either 80% propylene glycol/20% vegetable glycerin (PG/VG) or 100% polyethylene glycol 400 (PEG). Immediately after exposure, body temperature, hot plate withdrawal latency, and locomotion were assessed. Blood was collected at 0, 30, and 60 min after vapor exposure, and plasma THC, 11-hydroxy-THC, and 11-nor-9-carboxy-THC were analyzed. THC concentrations were higher in both the plasma of vapor-exposed mice and the cannabis extract solutions when PEG was the carrier oil compared with PG/VG. Vaporized cannabis (mixed with PEG) at the highest dose tested induced hypothermic, antinociceptive, and locomotor-suppressing effects in all groups of mice. We found a dose-dependent age difference in locomotion, indicating that adolescents were less sensitive to the locomotor-suppressing effects of vaporized cannabis, which may be related to differences in circulating THC levels. Although we found no sex differences in the acute behavioral effects of vaporized cannabis, there were sex differences in plasma THC metabolites, suggesting that female mice may metabolize vaporized cannabis more slowly than male mice. Taken together, these findings add to a growing literature implementing vaporized cannabinoid delivery approaches by revealing PEG as a more effective carrier oil than PG/VG for studies involving cannabis extract.

The use of cannabis during pregnancy and nursing is a growing public health concern, and the multigenerational impacts of perinatal cannabis exposure remain largely unknown. To address this knowledge gap, we sought to examine the long-term consequences of perinatal cannabis use on reproductive function and how it might impact subsequent generations. Pregnant female mice were exposed to control vehicle or cannabis extract [25, 100, or 200 mg/ml Δ9-tetrahydrocannabinol (THC) in the cannabis extract] from gestational day 1 to postnatal day 21 (twice/day), encompassing the duration of pregnancy through weaning. Based on plasma THC concentrations in F0 females, we chose 100 and 200 mg/ml THC in the cannabis extract for subsequent studies. The selected doses and exposure conditions did not disrupt pregnancy or nursing in F0 females. Pregnancy and neonatal outcomes, including gestational length, litter size, and sexual ratio, were not affected by cannabis exposure. However, cannabis-exposed neonatal F1 pups were smaller. Cannabis exposure delayed vaginal opening as a sign of puberty onset and disrupted estrous cyclicity in F1 females. However, its effects were minor in F2 and F3 females. F1-F3 females showed no abnormal ovarian and uterine histology or plasma estradiol-17β levels and could produce normal offspring without pregnancy issues. These results suggest that the hypothalamus and pituitary are likely perturbed by perinatal cannabis exposure, and the early hypothalamus-pituitary-ovarian axis is disrupted in F1 females. However, they are not sufficient to compromise adult reproductive function. The present results indicate limited transgenerational effects of perinatal cannabis exposure on female reproductive parameters.

Wearable sensor systems have demonstrated great potential for real-time, objective monitoring of physiological health to support behavioral interventions. However, obtaining accurate labels in free-living environments remains challenging due to limited human supervision and reliance on self-labeling by patients, complicating data collection and supervised learning. To address this, we introduce CUDLE (Cannabis Use Detection with Label Efficiency), a novel framework that leverages self-supervised learning with real-world wearable sensor data to automatically detect cannabis consumption in free-living environments. CUDLE identifies consumption moments using sensor-derived data through a contrastive learning framework, first learning robust representations via a self-supervised pretext task with data augmentation. These representations are then fine-tuned in a downstream task with a shallow classifier, allowing CUDLE to outperform traditional supervised methods, especially with limited labeled data. To evaluate our approach, we conducted a clinical study with 20 cannabis users, collecting over 500 hours of wearable sensor data and user-reported cannabis use moments through Ecological Momentary Assessment (EMA) methods. Our analysis shows that CUDLE achieves a higher accuracy of 73.4% compared to 71.1% for the supervised approach, with the performance gap widening as the number of labels decreases. Notably, CUDLE not only surpasses the supervised model while using 75% less labels, but also reaches peak performance with far fewer subjects, indicating its efficiency in learning from both limited labels and data. These findings have significant implications for real-world applications, where data collection and annotation are labor-intensive, offering a path to more scalable and practical solutions in computational health.

The legalization of cannabis in several states across the US has increased the need to better understand its effects on the body, brain, and behavior, particularly in different populations. Rodent models are particularly valuable in this respect because they provide precise control over external variables. Previous rodent studies have found age and sex differences in response to injected Δ ⁹ -tetrahydrocannabinol (THC), the major psychoactive component of cannabis. However, this route of administration does not mimic the most common way humans consume cannabis, i.e. through inhalation. Here, we sought to address this gap by investigating age and sex differences in pharmacokinetics and the acute behavioral effects of vaporized cannabis extract in mice. Adolescent (postnatal day [P] 35-50) and adult (≥ P70) mice of both sexes received noncontingent exposure to 0 mg/ml, 150 mg/ml, or 300 mg/ml vaporized cannabis extract diluted in either 80% propylene glycol/20% vegetable glycerol (PG/VG) or 100% polyethylene glycol 400 (PEG). Immediately after exposure, body temperature, hot plate withdrawal latency, and locomotion were assessed. Blood was collected at 0, 30, and 60 min after vapor exposure, and plasma THC and its metabolites were analyzed. Measured THC levels were higher in both the plasma of vapor-exposed mice and the cannabis extract solutions themselves when PEG was the solvent compared to PG/VG. Vaporized cannabis (dissolved in PEG) at the highest dose tested induced hypothermic, antinociceptive, and locomotor-suppressing effects in all groups of mice. We found a dose-dependent age difference in locomotion, indicating that adolescents were less sensitive to the locomotor-suppressing effects of vaporized cannabis, which may be related to the plasma THC levels achieved. Although we found no significant sex differences in the acute behavioral effects of vaporized cannabis, there were significant sex differences in plasma THC metabolites indicating that female mice may metabolize vaporized cannabis more slowly than male mice. Taken together, the current findings add to a growing number of studies implementing vaporized cannabinoid delivery approaches by revealing PEG as the superior solvent for studies involving cannabis extract.