Scaling and relations of morphology with locomotor kinematics in the sidewinder rattlesnake Crotalus cerastes.

The movement of limbless terrestrial animals differs fundamentally from that of limbed animals, yet few scaling studies of their locomotor kinematics and morphology are available. We examined scaling and relations of morphology and locomotion in sidewinder rattlesnakes (Crotalus cerastes). During sidewinding locomotion, a snake lifts sections of its body up and forward while other sections maintain static ground contact. We used high-speed video to quantify whole-animal speed and acceleration; the height to which body sections are lifted; and the frequency, wavelength, amplitude and skew angle (degree of tilting) of the body wave. Kinematic variables were not sexually dimorphic, and most did not deviate from isometry, except wave amplitude. Larger sidewinders were not faster, contrary to many results from limbed terrestrial animals. Free from the need to maintain dynamic similarity (because their locomotion is dominated by friction rather than inertia), limbless species may have greater freedom to modulate speed independently of body size. Path analysis supported: (1) a hypothesized relationship between body width and wavelength, indicating that stouter sidewinders form looser curves; (2) a strong relationship between cycle frequency and whole-animal speed; and (3) weaker effects of wavelength (positive) and amplitude (negative) on speed. We suggest that sidewinding snakes may face a limit on stride length (to which amplitude and wavelength both contribute), beyond which they sacrifice stability. Thus, increasing frequency may be the best way to increase speed. Finally, frequency and skew angle were correlated, a result that deserves future study from the standpoint of both kinematics and physiology.

Impact of cannabis legalization on treatment and research priorities for cannabis use disorder.

An increasing proportion of the world has legalized cannabis for medicinal or recreational use. The legalization trend appears to be continuing. These changes in the legislative landscape may have important health, treatment, and research implications. This review discusses public health outcomes that may be impacted by increases in cannabis availability and use. It additionally considers potential research and treatment priorities in the face of widespread cannabis legalization.

Gender differences among treatment-seeking adults with cannabis use disorder: Clinical profiles of women and men enrolled in the achieving cannabis cessation-evaluating N-acetylcysteine treatment (ACCENT) study.

BACKGROUND AND OBJECTIVES: Recent evidence suggests that women may fare worse than men in cannabis trials with pharmacologic interventions. Identifying baseline clinical profiles of treatment-seeking cannabis-dependent adults could inform gender-specific treatment planning and development. METHODS: The current study compared baseline demographic, cannabis use, and psychiatric factors between women (n = 86) and men (n = 216) entering the Achieving Cannabis Cessation-Evaluating N-acetylcysteine Treatment (ACCENT) study, a multi-site, randomized controlled trial conducted within the National Drug Abuse Treatment Clinical Trials Network. RESULTS: Women reported greater withdrawal intensity (p = .001) and negative impact of withdrawal (p = .001), predominantly due to physiological and mood symptoms. Women were more likely to have lifetime panic disorder (p = .038) and current agoraphobia (p = .022), and reported more days of poor physical health (p = .006) and cannabis-related medical problems (p = .023). Women reporting chronic pain had greater mean pain scores than men with chronic pain (p = .006). Men and women did not differ on any measures of baseline cannabis use. DISCUSSION AND CONCLUSIONS: Cannabis-dependent women may present for treatment with more severe and impairing withdrawal symptoms and psychiatric conditions compared to cannabis-dependent men. This might help explain recent evidence suggesting that women fare worse than men in cannabis treatment trials of pharmacologic interventions. Baseline clinical profiles of treatment-seeking adults can inform gender-specific treatment planning and development. SCIENTIFIC SIGNIFICANCE: Cannabis-dependent women may benefit from integrated treatment focusing on co-occurring psychiatric disorders and targeted treatment of cannabis withdrawal syndrome.(Am J Addict 2017;26:136-144).

A preliminary randomized controlled trial of repetitive transcranial magnetic stimulation applied to the left dorsolateral prefrontal cortex in treatment seeking participants with cannabis use disorder.

BACKGROUND: Cannabis use disorder (CUD) is a common and consequential disorder. When applied to the dorsolateral prefrontal cortex (DLPFC), repetitive transcranial magnetic stimulation (rTMS) reduces craving across substance use disorders and may have therapeutic clinical effects when applied in serial-sessions. The present study sought to preliminarily determine whether serial-sessions of rTMS applied to the DLPFC had a therapeutic effect in CUD. METHODS: This study was a two-site, phase-2, double-blind, randomized-controlled-trial. Seventy-two treatment-seeking participants (37.5% Women, mean age 30.2±9.9SD) with ≥moderate-CUD were randomized to active or sham rTMS (Beam-F3, 10Hz, 20-total-sessions, two-sessions-per-visit, two-visits-per-week, with cannabis cues) while undergoing a three-session motivational enhancement therapy intervention. The primary outcome was the change in craving between pre- and post- treatment (Marijuana Craving Questionnaire Short-Form-MCQ-SF). Secondary outcomes included the number of weeks of abstinence and the number of days-per-week of cannabis use during 4-weeks of follow-up. RESULTS: There were no significant differences in craving between conditions. Participants who received active-rTMS reported numerically, but not significantly, more weeks of abstinence in the follow-up period than those who received sham-rTMS (15.5%-Active; 9.3%-Sham; rate ratio = 1.66 [95% CI: 0.84, 3.28]; p=0.14). Participants who received active-rTMS reported fewer days-per-week of cannabis use over the final two-weeks of the follow-up period than those receiving sham-rTMS (Active vs. Sham: -0.72; Z=-2.33, p=0.02). CONCLUSIONS: This trial suggests rTMS is safe and feasible in individuals with CUD and may have a therapeutic effect on frequency of cannabis use, though further study is needed with additional rTMS-sessions and a longer follow-up period.

Is it time for a cannabis harm reduction approach? Commentary on Sherman et al. (2022) and Borodovsky et al. (2022).

OBJECTIVE: Recent research suggests potential therapeutic benefits of cannabis-derived products, a lower risk profile than other illicit substances, and significant functional improvement from reduced use. Likewise, low abstinence rates and low motivation to achieve abstinence among those with cannabis use disorder (CUD) are the norm. As such, the harm reduction model has gained traction among substance use scientists and health care professionals as a viable alternative approach. Yet, to date no formal definition of cannabis harm reduction has been proposed. METHOD: We reviewed the literature, including two recent empirical papers published in the Psychology of Addictive Behaviors, Sherman et al. (2022) and Borodovsky et al. (2022), which demonstrate that harm reduction is sufficient to achieve functional improvement. We then propose and define a harm reduction approach for cannabis use research and treatment, and argue why this approach is a timely, necessary discussion. RESULTS: We suggest that a cannabis harm reduction approach includes treatment, research, and education initiatives that reduce the public health burden of cannabis use. This approach includes interventions that reduce functional impairment and risk from cannabis, reduced or managed use, and sometimes, but not necessarily, abstinence. Psychoeducation for treatment providers, legislative barriers, and research recommendations are also discussed. CONCLUSIONS: Research and treatment for CUD has historically focused on cannabis abstinence. Treatment trials rarely yield durable abstinence rates, and reduction has recently been tied to functional improvement. We comment on Sherman et al. (2022) and Borodovsky et al. (2022) and propose a shift toward a cannabis harm reduction approach. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Locomotor kinematics on sand versus vinyl flooring in the sidewinder rattlesnake Crotalus cerastes.

For terrestrial locomotion of animals and machines, physical characteristics of the substrate can strongly impact kinematics and performance. Snakes are an especially interesting system for studying substrate effects because their gait depends more on the environment than on their speed. We tested sidewinder rattlesnakes (Crotalus cerastes) on two surfaces: sand collected from their natural environment and vinyl tile flooring, an artificial surface often used to elicit sidewinding in laboratory settings. Of ten kinematic variables examined, two differed significantly between the substrates: the body's waveform had an average of ∼17% longer wavelength on vinyl flooring (measured in body lengths), and snakes lifted their bodies an average of ∼40% higher on sand (measured in body lengths). Sidewinding may also differ among substrates in ways we did not measure (e.g. ground reaction forces and energetics), leaving open clear directions for future study.

Restructuring reward: A pilot study to enhance natural reward response in adults with cannabis use disorder.

BACKGROUND: Hedonic dysregulation is a core mechanism of addiction. There is a dearth of research on hedonic dysregulation in cannabis use disorder (CUD). The current study tested whether personalized scripted imagery may be an efficacious approach to remediate reward functioning in adults with CUD. METHODS: Adults with CUD (n=10) and non-CUD controls (n=12) completed a single session personalized scripted imagery procedure. Non-drug (i.e. natural) reward and neutral scripts were transcribed and participants listened to the scripts in counterbalanced order. Primary outcomes included positive affect (PA), galvanic skin response (GSR), and cortisol and were assessed at four timepoints. Mixed effects models were used to compare between and within subject effects. RESULTS: Mixed effects models revealed a Condition (reward vs. neutral) X Group (CUD vs. control) interaction (p=0.01) on PA response, indicating blunted PA response to the neutral script relative to the reward script in CUD participants. Likewise, GSR response in CUD participants was decreased in response to the neutral script relative to the reward script (p=0.034; interaction n.s.). An interaction effect of Group X PA on cortisol response was found (p=.036) indicating that cortisol was positively correlated with PA in healthy control participants, but not CUD participants. CONCLUSIONS: Adults with CUD may demonstrate acute deficits in hedonic tone under neutral conditions relative to healthy controls. Personalized scripted imagery may be an efficacious tool to remediate hedonic dysregulation in CUD. Cortisol may play a role in healthy positive affect regulation warranting further investigation.

Exploring the Utility of a Functional Magnetic Resonance Imaging (fMRI) Cannabis Cue-Reactivity Paradigm in Treatment Seeking Adults with Cannabis Use Disorder.

Introduction: Functional magnetic resonance imaging (fMRI) studies examining cue-reactivity in cannabis use disorder (CUD) to date have either involved non-treatment seeking participants or been small. We addressed this gap by administering an fMRI cue-reactivity task to CUD participants entering two separate clinical trials. Methods: Treatment-seeking participants with moderate or severe CUD had behavioral craving measured at baseline via the Marijuana Craving Questionnaire (MCQ-SF). They additionally completed a visual cannabis cue-reactivity paradigm during fMRI following 24-hours of abstinence from cannabis. During fMRI, the Blood Oxygen Level Dependent (BOLD) signal was acquired while participants viewed cannabis-images or matched-neutral-images. BOLD responses were correlated with the MCQ-SF using a General Linear Model. Results: N=65 participants (32% female; mean age 30.4±9.9SD) averaged 46.3±15.5SD on the MCQ-SF. When contrasting cannabis-images vs. matched-neutral-images, participants showed greater BOLD response in bilateral ventromedial prefrontal, dorsolateral prefrontal, anterior cingulate, and visual cortices, as well as the striatum. Similarly, there was stronger task-based functional-connectivity (tbFC) between the medial prefrontal cortex and both the amygdala and the visual cortex. There were no significant differences in either activation or tbFC between studies or between sexes. Craving negatively correlated with BOLD response in the left ventral striatum (R 2 =-0.25; p =0.01). Conclusions: We found that, among two separate treatment-seeking CUD groups, cannabis cue-reactivity was evidenced by greater activation and tbFC in regions related to executive function and reward processing, and craving was negatively associated with cue-reactivity in the ventral striatum. Future directions include examining if pharmacological, neuromodulatory, or psychosocial interventions can alter corticostriatal cue-reactivity.

A Preliminary Investigation Of Repetitive Transcranial Magnetic Stimulation Applied To The Left Dorsolateral Prefrontal Cortex In Treatment Seeking Participants With Cannabis Use Disorder.

Background: Cannabis use disorder (CUD) is a common and consequential disorder. When applied to the dorsolateral prefrontal cortex (DLPFC), repetitive transcranial magnetic stimulation (rTMS) reduces craving across substance use disorders and may have a therapeutic clinical effect when applied in serial sessions. The present study sought to preliminarily determine whether serial sessions of rTMS applied to the DLPFC had a therapeutic effect in CUD. Methods: This study was a two-site, phase-2, double-blind, randomized-controlled-trial. Seventy-two treatment-seeking participants (37.5% Women, mean age 30.2±9.9SD) with ≥moderate-CUD were randomized to active or sham rTMS (Beam-F3, 10Hz, 20-total-sessions, with cannabis cues) while undergoing a three-session motivational enhancement therapy intervention. The primary outcome was the change in craving between pre- and post-treatment (Marijuana Craving Questionnaire Short-Form-MCQ-SF). Secondary outcomes included the number of weeks of abstinence and the number of days-per-week of cannabis use during 4-weeks of follow-up. Results: There were no significant differences in craving between conditions. Participants who received active rTMS reported numerically, but not significantly, more weeks of abstinence in the follow-up period than those who received sham rTMS (15.5%-Active; 9.3%-Sham; rate ratio = 1.66 [95% CI: 0.84, 3.28]; p=0.14). Participants who received active rTMS reported fewer days-per-week of cannabis use over the final two-weeks of the follow-up period (Active vs. Sham: -0.72; Z=-2.33, p=0.02). Conclusions: This trial suggests rTMS is safe and feasible in individuals with CUD and may have a therapeutic effect on frequency of cannabis use, though further study is needed with additional rTMS-sessions and a longer follow-up period.

Characterizing cannabis use reduction and change in functioning during treatment: Initial steps on the path to new clinical endpoints.

Reduction-based cannabis use endpoints are needed to better evaluate treatments for cannabis use disorder (CUD). This exploratory, secondary analysis aimed to characterize cannabis frequency and quantity reduction patterns and corresponding changes in psychosocial functioning during treatment. We analyzed 16 weeks (4 prerandomization, 12 postrandomization) of data (n = 302) from both arms of a randomized clinical trial assessing pharmacotherapy for CUD. Cannabis consumption pattern classes were extracted with latent profile modeling using self-reported (a) past-week days used (i.e., frequency) and (b) past-week average grams used per using day (i.e., quantity). Changes in mean Marijuana Problem Scale (MPS) and Hospital Anxiety and Depression Scale (HADS) scores were examined among classes. Urine cannabinoid levels were examined in relation to self-reported consumption as a validity check. Two-, three-, four-, and five-class solutions each provided potentially useful conceptualizations of associations between frequency and quantity. Regardless of solution, reductions in MPS scores varied in magnitude across classes and closely tracked class-specific reductions in consumption (e.g., larger MPS reduction corresponded to larger frequency/quantity reductions). Changes in HADS scores were less pronounced and less consistent with consumption patterns. Urine cannabinoid levels closely matched class-specific self-reported consumption frequency. Findings illustrate that frequency and quantity can be used in tandem within mixture model frameworks to summarize heterogeneous cannabis use reduction patterns that may correspond to improved psychosocial functioning. Going forward, similar analytic strategies applied to alternative metrics of cannabis consumption may facilitate construction of useful reduction-based clinical endpoints. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Evaluating cannabis use risk reduction as an alternative clinical outcome for cannabis use disorder.

OBJECTIVE: Abstinence is rarely achieved in clinical trials for cannabis use disorder (CUD). Cannabis reduction is associated with functional improvement, but reduction endpoints have not been established, indicating a need to identify and validate clinically meaningful reduction endpoints for assessing treatment efficacy. METHOD: Data from a 12-week double-blind randomized placebo-controlled medication trial for cannabis cessation (NCT01675661) were analyzed. Participants (N = 225) were treatment-seeking adults, M = 30.6 (8.9) years old, 70.2% male, and 42.2% Non-White, with CUD who completed 12 weeks of treatment. Frequency (days of use per week) and quantity (grams per using day) were used to define high-, medium-, and low-risk levels. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale and cannabis-related problems were assessed using the Marijuana Problems Scale. General linear models for repeated measures tested associations between the magnitude of risk reduction and functional outcomes from baseline (BL) to end-of-treatment (EOT). RESULTS: Cannabis risk levels were sensitive to reductions in use from BL to EOT for frequency- (χ² = 19.35, p = .004) and quantity-based (χ² = 52.06, p < .001) metrics. Magnitude reduction in frequency-based risk level was associated with magnitude decrease in depression (F = 2.76, p = .043, ηp² = .04), anxiety (F = 3.70, p = .013, ηp² = .05), and cannabis-related problems (F = 8.95, p < .001, ηp² = .12). Magnitude reduction in quantity-based risk level was associated with magnitude decrease in anxiety (F = 3.02, p = .031, ηp² = .04) and cannabis-related problems (F = 3.24, p = .023, ηp² = .05). CONCLUSIONS: Cannabis use risk levels, as operationalized in this study, captured reductions in use during a clinical trial. Risk level reduction was associated with functional improvement suggesting that identifying risk levels and measuring the change in levels over time may be a viable and clinically meaningful endpoint for determining treatment efficacy. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Varenicline as a treatment for cannabis use disorder: A placebo-controlled pilot trial.

BACKGROUND: An efficacious pharmacotherapy for cannabis use disorder (CUD) has yet to be established. This study preliminarily evaluated the safety and efficacy of varenicline for CUD in a proof-of-concept clinical trial. METHODS: Participants in this 6-week randomized, placebo-controlled pilot trial received either varenicline (n = 35) or placebo (n = 37), added to a brief motivational enhancement therapy intervention. Outcomes included cannabis withdrawal, cannabis abstinence, urine cannabinoid levels, percent cannabis use days, and cannabis sessions per day. RESULTS: Both treatment groups noted significant decreases in self-reported cannabis withdrawal, percentage of days used, and use sessions per day during treatment compared to baseline. While this pilot trial was not powered to detect statistically significant between-group differences, participants randomized to varenicline evidenced numerically greater rates of self-reported abstinence at the final study visit [Week 6 intent-to-treat (ITT): Varenicline: 17.1% vs. Placebo: 5.4%; RR = 3.2 (95% CI: 0.7,14.7)]. End-of-treatment urine creatinine corrected cannabinoid levels were numerically lower in the varenicline group and higher in the placebo group compared to baseline [Change from baseline: Varenicline -1.7 ng/mg (95% CI: -4.1,0.8) vs. Placebo: 1.9 ng/mg (95% CI: -0.4,4.3); Δ = 3.5 (95% CI: 0.1,6.9)]. Adverse events related to study treatment did not reveal new safety signals. CONCLUSIONS: Findings support the feasibility of conducting clinical trials of varenicline as a candidate pharmacotherapy for CUD, and indicate that a full-scale efficacy trial, powered based on effect sizes and variability yielded in this study, is warranted.

Latency to cannabis dependence mediates the relationship between age at cannabis use initiation and cannabis use outcomes during treatment in men but not women.

BACKGROUND: Time from first cannabis use to cannabis dependence (latency) may be an important prognostic indicator of cannabis-related problems and treatment outcomes. Gender differences in latency have been found; however, research in this general area is limited. As cannabis use increases and perceived risk declines, a better understanding of how these factors interact in predicting treatment outcomes is critical. METHODS: A secondary data analysis of a randomized, double-blind, placebo-controlled pharmacotherapy trial for cannabis dependence (N = 302) examined the associations between age of cannabis use onset, time to cannabis dependence (latency), and gender on cannabis use during the trial. Mediation analysis tested whether the association between age of onset and cannabis use during the trial was mediated by latency to cannabis dependence differentially for men and women. RESULTS: Age of use initiation was inversely correlated with latency to dependence prior to treatment [HR(95% CI) = 1.18 (1.06, 1.30); p = .002] and cannabis use during treatment (ß=-1.27; SE = 0.37; p < .001). There was a significant mediation effect between age of onset, latency, and cannabis use that varied by gender. Earlier age of onset predicted longer latency, and subsequently, greater cannabis use during the trial in men (21.4% mediated; p < .05), but not women. Other substance use, race, and past psychiatric diagnosis did not predict latency either independently or in interaction models. CONCLUSION: Findings support existing evidence that early cannabis use onset is associated with worse outcomes and add new knowledge on the differential associations between age of onset, latency to cannabis dependence, and treatment outcomes for men and women.

Psychopathology and disability in children with unexplained chest pain presenting to the pediatric emergency department.

OBJECTIVE: Chest pain is a common presentation in the pediatric emergency department (PED). In the majority of cases, no clear medical cause is found. Among adults with noncardiac chest pain, psychopathology including panic disorder is common. We assessed the likelihood and type of psychopathology as well as the health status of children and adolescents with unexplained chest pain who presented to the PED. METHODS: We performed a semistructured diagnostic interview of children 8 to 17 years old who presented to an urban, tertiary-care PED with a primary complaint of chest pain for which no medical cause was found. We used Diagnostic Statistical Manual of Mental Disorders, Fourth Edition criteria to diagnose psychopathology. We also assessed pain severity, extent of other somatic complaints, quality of life, and functional disability using standard, validated instruments. RESULTS: We enrolled 32 children with a mean age of 12.8 (SD, 2.9) years (range, 8-17 years); 47% were female. Twenty-six (81%) were diagnosed with a Diagnostic Statistical Manual of Mental Disorders, Fourth Edition anxiety disorder; 9 (28%) had full-criteria panic disorder. Quality of life was compromised in multiple domains, and children reported a range of functional disabilities due to chest pain. Other somatic symptoms, including other pain complaints, were commonly reported in this sample. CONCLUSION: Unexplained chest pain in the PED is frequently associated with potentially treatable anxiety disorders. Emergency physicians should consider the possibility of anxiety disorders in patients with medically unexplained chest pain.

Self-reported cognition and marijuana use in older adults: Results from the national epidemiologic survey on alcohol and related conditions-III.

Marijuana use among older adults is on an unprecedented rise, yet little is known about its effects on cognition in this population where, due to advanced age, risk for cognitive decline is high. Thus, we investigated whether marijuana use and use characteristics were associated with self-reported cognition among older adults ages ≥ 50 years using the National Epidemiologic Survey on Alcohol and Related Conditions-III. Respondents either had never used marijuana ("never": n = 10,976), used but not in the past 12 months ("former": n = 2990), or used in the past 12 months ("current": n = 712). Self-reported cognition was measured using the Executive Function Index. Marijuana and substance use characteristics were obtained using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-5. Covariates included demographics, mental health and disability, and comorbid mental and substance use disorder. Using general linear models of cross-sectional data, we found that current users, particularly those with cannabis use disorder, reported worse cognition than never or former users, but these effects were small in magnitude. Among both former and current users, greater duration of past use was associated with worse cognition. Frequent use within the past 12 months was associated with worse cognition among current users, but daily users reported better cognition compared to monthly or weekly users. Thus, marijuana use may impact self-reported cognition in older adulthood, although these effects may be subtle, specific to particular use characteristics, and possibly affected by self-awareness of deficits. Future work using objective measures such as neuropsychological testing or neuroimaging may better elucidate these effects.

The effect of oxytocin, gender, and ovarian hormones on stress reactivity in individuals with cocaine use disorder.

RATIONALE: Cocaine use disorder (CUD) is associated with dysregulation of the hypothalamic-pituitary-adrenal axis, which plays a critical role in the human stress response. Men and women with CUD differ in reactivity to social stressors. The hypothalamic neuropeptide oxytocin is involved in anxiolytic and natural reward processes, and has shown therapeutic potential for addictive disorders and stress reduction. OBJECTIVES: To examine the impact of oxytocin (oxytocin (OXY) vs. placebo (PBO)) and gender (female (F) vs. male (M)) on response to a social stress task in individuals with CUD. To explore whether ovarian hormones moderate this stress response. METHODS: One hundred twelve adults with CUD were randomized to receive 40 IU intranasal oxytocin (n = 56) or matching placebo (n = 56). Forty minutes after drug administration, participants were exposed to a social stressor. Generalized linear mixed models were used to examine neuroendocrine (cortisol) and subjective (craving, stress) response at pre-stressor, stressor + 0, + 10, + 30, + 60 min. RESULTS: Gender moderated the effect of oxytocin on neuroendocrine response (p = 0.048); women receiving oxytocin (F + OXY) showed blunted cortisol response compared to the other three groups (F + PBO; M + OXY; M + PBO). There was a main effect of gender on subjective stress response; women reported greater stress following the stressor compared to men (p = 0.016). Oxytocin had no significant effect on craving or stress, and gender did not moderate the effect of oxytocin on either measure. Higher endogenous progesterone was associated with lower craving response in women (p = 0.033). CONCLUSIONS: Oxytocin may have differential effects in men and women with CUD. Women may be at greater risk for relapse in response to social stressors, but ovarian hormones may attenuate this effect.

Cortisol reactivity and situational drug use in cocaine-dependent females.

In this double-blind study, cocaine-dependent women were administered a pharmacological stressor or placebo prior to two cue-reactivity procedures. The Inventory of Drug Taking Situations is a self-report questionnaire measuring antecedents to relapse and is comprised of three subscales: negative, positive, and temptation situational drug use. It was hypothesized that women with higher IDTS scores would have a greater cortisol response to the cue-reactivity task while receiving yohimbine versus placebo. All three subscales showed significance during the same times after yohimbine administration and immediately post-cue exposure. Our results may suggest an association between situational and physiological risk factors in this population.

Exogenous progesterone for cannabis withdrawal in women: Feasibility trial of a novel multimodal methodology.

BACKGROUND: Sex differences in cannabis use disorder (CUD) and its treatment have been identified. Women report more severe withdrawal and have shown worse treatment outcomes. Ovarian hormones are implicated in these differences and research suggests that exogenous progesterone may be an effective pharmacotherapy. METHODS: The current randomized, placebo-controlled, feasibility trial tested a novel multimodal methodology for administering exogenous progesterone during acute cannabis withdrawal. Eight heavy cannabis using women received micronized progesterone (200 mg bid) (n = 3) or matching placebo (n = 5) during the early follicular phase of their menstrual cycle over a 5-day study period while abstaining from cannabis. Laboratory visits (days 1 and 5) included biological and self-report assessments, while home-based procedures (days 2-4) included ambulatory assessments, video data capture and tele-drug testing, and biological assessments. Primary outcomes were medication adherence and salivary hormone levels, and the exploratory outcome was cannabis withdrawal severity. RESULTS: Medication adherence rates were high as assessed via self-report (100.0%) and video data capture (98.0%). Salivary progesterone levels differed between groups over time (p < 0.027) and the progesterone group achieved levels within the normal range during the luteal phase in healthy adults. All tele-drug tests were negative confirming cannabis abstinence and there was an indication (p = 0.07) of reduced cannabis craving among participants receiving progesterone. CONCLUSION: More effective and sex-based treatments for cannabis use disorder are needed. The current study provides a novel multimodal methodology with low participant burden for investigating new medications for cannabis withdrawal. Clinical trials of progesterone for cannabis withdrawal may be warranted.

Neural correlates of oxytocin and cue reactivity in cocaine-dependent men and women with and without childhood trauma.

RATIONALE: Women with cocaine use disorder have worse treatment outcomes compared with men. Sex differences in cocaine addiction may be driven by differences in neurobiology or stress reactivity. Oxytocin is a potential therapeutic for stress reduction in substance use disorders, but no studies have examined the effect of oxytocin on neural response to drug cues in individuals with cocaine use disorders or potential sex differences in this response. OBJECTIVES: The goal of this study was to examine the effect of intranasal oxytocin on cocaine cue reactivity in cocaine dependence, modulated by gender and history of childhood trauma. METHODS: Cocaine-dependent men with (n = 24) or without (n = 19) a history of childhood trauma and cocaine-dependent women with (n = 16) or without (n = 8) a history of childhood trauma completed an fMRI cocaine cue reactivity task under intranasal placebo or oxytocin (40 IU) on two different days. fMRI response was measured in the right amygdala and dorsomedial prefrontal cortex (DMPFC). RESULTS: In the DMPFC, oxytocin reduced fMRI response to cocaine cues across all subject groups. However, in the amygdala, only men with a history of childhood trauma showed a significantly reduced fMRI response to cocaine cues on oxytocin versus placebo, while women with a history of childhood trauma showed an enhanced amygdala response to cocaine cues following oxytocin administration. Cocaine-dependent subjects with no history of childhood trauma showed no effect of oxytocin on amygdala response. CONCLUSIONS: Oxytocin can reduce cue reactivity in cocaine dependence, but its effect is modified by sex and childhood trauma history. Whereas men with cocaine dependence may benefit from oxytocin administration, additional studies are needed to determine whether oxytocin can be an effective therapeutic for cocaine-dependent women.

Oxytocin-Induced Changes in Intrinsic Network Connectivity in Cocaine Use Disorder: Modulation by Gender, Childhood Trauma, and Years of Use.

Cocaine use disorder (CUD) is a major public health concern with devastating social, economic, and mental health implications. A better understanding of the underlying neurobiology and phenotypic variations in individuals with CUD is necessary for the development of effective and targeted treatments. In this study, 39 women and 54 men with CUD completed a 6-min resting-state functional magnetic resonance imaging scan after intranasal oxytocin (OXY) or placebo administration. Graph-theory network analysis was used to quantify functional connectivity changes caused by OXY in striatum, anterior cingulate cortex (ACC), insula, and amygdala nodes of interest. OXY increased connectivity in the right ACC and left amygdala in males, whereas OXY increased connectivity in the right ACC and right accumbens in females. Machine learning was then used to associate treatment response (placebo minus OXY) in nodes of interest with years of cocaine use and severity of childhood trauma separately for males and females. Childhood trauma and years of cocaine use were associated with OXY-induced changes in ACC connectivity for both men and women, but connectivity changes in the amygdala were associated with years of cocaine use in men and connectivity changes in the right insula were associated with years of cocaine use in women. These findings suggest that salience network nodes (ACC and insula) are potential OXY treatment targets in CUD, with the amygdala as a treatment target for men and the accumbens as a treatment target for women.