Combining noninvasive brain stimulation with behavioral pharmacology methods to study mechanisms of substance use disorder

Psychotropic drugs and transcranial magnetic stimulation (TMS) are effective for treating certain psychiatric conditions. Drugs and TMS have also been used as tools to explore the relationship between brain function and behavior in humans. Combining centrally acting drugs and TMS has proven useful for characterizing the neural basis of movement. This combined intervention approach also holds promise for improving our understanding of the mechanisms underlying disordered behavior associated with psychiatric conditions, including addiction, though challenges exist. For example, altered neocortical function has been implicated in substance use disorder, but the relationship between acute neuromodulation of neocortex with TMS and direct effects on addiction-related behaviors is not well established. We propose that the combination of human behavioral pharmacology methods with TMS can be leveraged to help establish these links. This perspective article describes an ongoing study that combines the administration of delta-9-tetrahydrocannabinol (THC), the main psychoactive compound in cannabis, with neuroimaging-guided TMS in individuals with problematic cannabis use. The study examines the impact of the left dorsolateral prefrontal cortex (DLPFC) stimulation on cognitive outcomes impacted by THC intoxication, including the subjective response to THC and the impairing effects of THC on behavioral performance. A framework for integrating TMS with human behavioral pharmacology methods, along with key details of the study design, are presented. We also discuss challenges, alternatives, and future directions

Unique Prediction of Cannabis Use Severity and Behaviors by Delay Discounting and Behavioral Economic Demand

Few studies have simultaneously evaluated delay discounting and behavioral economic demand to determine their unique contribution to drug use. A recent study in cannabis users found that monetary delay discounting uniquely predicted cannabis dependence symptoms, whereas cannabis demand uniquely predicted use frequency. This study sought to replicate and extend this research by evaluating delay discounting and behavioral economic demand measures for multiple commodities and including a use quantity measure. Amazon.com’s Mechanical Turk was used to sample individuals reporting recent cannabis use (n = 64) and controls (n = 72). Participants completed measures of monetary delay discounting as well as alcohol and cannabis delay discounting and demand. Cannabis users and controls did not differ on monetary delay discounting or alcohol delay discounting and demand. Among cannabis users, regression analyses indicated that cannabis delay discounting uniquely predicted use severity, whereas cannabis demand uniquely predicted use frequency and quantity. These effects remained significant after controlling for other delay discounting and demand measures. This research replicates previous outcomes relating delay discounting and demand with cannabis use and extends them by accounting for the contribution of multiple commodities. This research also demonstrates the ability of online crowdsourcing methods to complement traditional human laboratory techniques

Sex Differences in the Subjective Effects of Oral Δ\u3csup\u3e9\u3c/sup\u3e-THC in Cannabis Users

Previous studies suggest that there are sex differences in endocannabinoid function and the response to exogenous cannabinoids, though data from clinical studies comparing acute cannabinoid effects in men and women under controlled laboratory conditions are limited. To further explore these potential differences, data from 30 cannabis users (N=18 M, 12 F) who completed previous Δ9-tetrahydrocannabinol (Δ9-THC) discrimination studies were combined for this retrospective analysis. In each study, subjects learned to discriminate between oral Δ9-THC and placebo and then received a range of Δ9-THC doses (0, 5, 15 and a “high” dose of either 25 or 30 mg). Responses on a drug-discrimination task, subjective effects questionnaire, psychomotor performance tasks, and physiological measures were assessed. Δ9-THC dose-dependently increased drug-appropriate responding, ratings on “positive” visual analog scale (VAS) items (e.g., Good Effects, Like Drug, Take Again), and items related to intoxication (e.g., High, Stoned). Δ9-THC also dose-dependently impaired performance on psychomotor tasks and elevated heart rate. Sex differences on VAS items emerged as a function of dose. Women exhibited significantly greater subjective responses to oral drug administration than men at the 5 mg Δ9-THC dose, whereas men were more sensitive to the subjective effects of the 15 mg dose of Δ9-THC than women. These results demonstrate dose-dependent separation in the subjective response to oral Δ9-THC administration by sex, which might contribute to the differential development of problematic cannabis use

Neurophysiological Capacity in a Working Memory Task Differentiates Dependent from Nondependent Heavy Drinkers and Controls

Background—Determining the brain-behavior profiles that differentiate heavy drinkers who are and are not alcohol dependent will inform treatment efforts. Working memory is linked to substance use disorders and can serve as a representation of the demand placed on the neurophysiology associated with cognitive control. Methods—Behavior and brain activity (via fMRI) were recorded during an N-Back working memory task in controls (CTRL), nondependent heavy drinkers (A-ND) and dependent heavy drinkers (A-D). Typical and novel step-wise analyses examined profiles of working memory load and increasing task demand, respectively. Results—Performance was significantly decreased in A-D during high working memory load (2-Back), compared to CTRL and A-ND. Analysis of brain activity during high load (0-Back vs. 2-Back) showed greater responses in the dorsal lateral and medial prefrontal cortices of A-D than CTRL, suggesting increased but failed compensation. The step-wise analysis revealed that the transition to Low Demand (0-Back to 1-Back) was associated with robust increases and decreases in cognitive control and default-mode brain regions, respectively, in A-D and A-ND but not CTRL. The transition to High Demand (1-Back to 2-Back) resulted in additional engagement of these networks in A-ND and CTRL, but not A-D. Conclusion—Heavy drinkers engaged working memory neural networks at lower demand than controls. As demand increased, nondependent heavy drinkers maintained control performance but relied on additional neurophysiological resources, and dependent heavy drinkers did not display further resource engagement and had poorer performance. These results support targeting these brain areas for treatment interventions

A Pilot Investigation of Acute Inhibitory Control Training in Cocaine Users

Background—Disrupted response inhibition and presence of drug-cue attentional bias in cocaine-using individuals have predicted poor treatment outcomes. Inhibitory control training could help improve treatment outcomes by strengthening cognitive control. This pilot study assessed the effects of acute inhibitory control training to drug- and non-drug-related cues on response inhibition performance and cocaine-cue attentional bias in cocaine-using individuals. Methods—Participants who met criteria for a cocaine-use disorder underwent five sessions of inhibitory control training to either non-drug-related cues (i.e., rectangles) or cocaine cues (n=10/condition) in a single day. Response inhibition and attentional bias were assessed prior to and following training using the stop-signal task and visual-probe task with eye tracking, respectively. Results—Training condition groups did not differ on demographics, inhibitory control training performance, response inhibition, or cocaine-cue attentional bias. Response inhibition performance improved as a function of inhibitory control training in both conditions. Cocaine-cue attentional bias was observed, but did not change as a function of inhibitory control training in either condition. Conclusions—Response inhibition in cocaine-using individuals was augmented by acute inhibitory control training, which may improve treatment outcomes through better behavioral inhibition. Future studies should investigate longer-term implementation of inhibitory control training, as well as combining inhibitory control training with other treatment modalities

Buspirone Maintenance Does Not Alter the Reinforcing, Subjective, and Cardiovascular Effects of Intranasal Methamphetamine

Background—Medications development efforts for methamphetamine-use disorder have targeted central monoamines because these systems are directly involved in the effects of methamphetamine. Buspirone is a dopamine autoreceptor and D3 receptor antagonist and partial agonist at serotonin 1A receptors, making it a logical candidate medication for methamphetamine-use disorder. Buspirone effects on abuse-related behaviors of methamphetamine have been mixed in clinical and preclinical studies. Experimental research using maintenance dosing, which models therapeutic use, is limited. This study evaluated the influence of buspirone maintenance on the reinforcing effects of methamphetamine using a self-administration procedure, which has predictive validity for clinical efficacy. The impact of buspirone maintenance on the subjective and cardiovascular response to methamphetamine was also determined. Methods—Eight research participants (1 female) reporting recent illicit stimulant use completed a placebo-controlled, crossover, double-blind protocol in which the pharmacodynamic effects of intranasal methamphetamine (0, 15, and 30 mg) were assessed after at least 6 days of buspirone (0 and 45 mg/day) maintenance. Results—Intranasal methamphetamine functioned as a reinforcer and produced prototypical stimulant-like subjective (e.g., increased ratings of Good Effects and Like Drug) and cardiovascular (e.g., elevated blood pressure) effects. These effects of methamphetamine were similar under buspirone and placebo maintenance conditions. Maintenance on buspirone was well tolerated and devoid of effects when administered alone. Conclusions—These data suggest that buspirone is unlikely to be an effective pharmacotherapy for methamphetamine-use disorder. Given the central role of monoamines in methamphetamine-use disorder, it is reasonable for future studies to continue to target these systems

Associations of First Trimester Co-Use of Tobacco and Cannabis with Prenatal Immune Response and Psychosocial Well-Being

PURPOSE: This study aims to describe the association of first trimester co-use of tobacco and cannabis with maternal immune response and psychosocial well-being, relative to tobacco use only. METHODS: A preliminary midpoint analysis included 138 pregnant women with biologically verified tobacco use, 38 of whom (28%) also tested positive for recent cannabis use. Maternal perceived stress (Perceived Stress Scale), depressive symptoms (Edinburgh Postnatal Depression Scale), and serum immune markers (IL-1β, IL-2, IL-6, IL-8, IL-10, TNFα, CRP, MMP8), were collected, although cytokine data were only available for 122 women. RESULTS: Participant average age was 29.1 years, approximately half had a high school education or less, and half were unemployed. Compared to tobacco only users, co-users were more likely to be non-White, younger and more economically disadvantaged. In the adjusted linear regression models, TNF-α levels were significantly lower among co-users relative to tobacco only users, after adjusting for age, race/ethnicity, body mass index and tobacco use group (tobacco cigarettes, electronic nicotine delivery devices [ENDS] or both). TNF-α was the only immune marker found to be significant in this analysis. Measured stress levels (M = 5.9, SD = 3.3; potential range 0-16) and depression scores (M = 7.8, SD = 5.8; potential range 0-30) were low across all participants and did not differ as a function of co-use. CONCLUSION: Preliminary results suggest women co-using during the first trimester exhibit decreased pro-inflammatory immune responsivity on one out of eight markers. Further research is needed to determine the impact of this immune modulation on fetal health outcomes and the unique contribution of cannabis

A Prototypical First-Generation Electronic Cigarette Does Not Reduce Reports of Tobacco Urges or Withdrawal Symptoms Among Cigarette Smokers

It is unknown whether first-generation electronic cigarettes reduce smoking urges and withdrawal symptoms following a 24 h deprivation period. This study tested whether a first-generation electronic cigarette reduces smoking urges and withdrawal symptoms in cigarette smokers. Following 24 h of tobacco deprivation, using a within-subjects design, eight nontreatment seeking tobacco cigarette smokers (3 females) administered 10 puffs from a conventional cigarette or a first-generation electronic cigarette containing liquid with 0, 8 or 16 mg/ml nicotine. Conventional cigarettes ameliorated smoking urges and electronic cigarettes did not, regardless of nicotine concentration. First-generation electronic cigarettes may not effectively substitute for conventional cigarettes in reducing smoking urges, regardless of nicotine concentration

Influence of Pregabalin Maintenance on Cannabis Effects and Related Behaviors in Daily Cannabis Users

No medications are approved for cannabis use disorder (CUD), though a small clinical trial demonstrated that the voltage-dependent calcium channel (VDCC) ligand gabapentin reduced cannabis use in treatment seekers. VDCCs are modulated by cannabinoid (CB) ligands, and there are shared effects between CB agonists and VDCC ligands. This overlapping neuropharmacology and the initial clinical results supported the evaluation of pregabalin, a next-generation VDCC ligand, as a CUD medication. Two separate placebo-controlled, double-blind, counterbalanced, within-subjects human laboratory studies tested placebo and 300 (N = 2 females, 11 males; Experiment [EXP] 1) or 450 (N = 3 females, 11 males; EXP 2) mg/day pregabalin in cannabis users who were not seeking treatment or trying to reduce/quit their cannabis use. The protocol consisted of two outpatient maintenance phases (11 days in EXP 1 and 15 days in EXP 2) that concluded with four experimental sessions within each phase. During experimental sessions, maintenance continued, and participants completed two 2-day blocks of sampling and self-administration sessions to determine the reinforcing effects of smoked cannabis (0% and 5.9% delta⁹-tetrahydrocannabinol [THC]), as well as subjective, attentional bias, performance, and physiological responses. In addition, naturalistic cannabis use, side effects, sleep quality, craving, and other self-reported substance use were measured during pregabalin maintenance. Cannabis was self-administered and produced prototypical effects, but pregabalin generally did not impact the effects of cannabis or alter naturalistic use. These human laboratory results in cannabis users not trying to reduce/quit their use do not support the efficacy of pregabalin as a stand-alone pharmacotherapy for CUD

N-Acetylcysteine Reduces Cocaine-Cue Attentional Bias and Differentially Alters Cocaine Self-Administration Based on Dosing Order

Background—Disrupted glutamate homeostasis is thought to contribute to cocaine-use disorder, in particular, by enhancing the incentive salience of cocaine stimuli. n-Acetylcysteine might be useful in cocaine-use disorder by normalizing glutamate function. In prior studies, n-acetylcysteine blocked the reinstatement of cocaine seeking in laboratory animals and reduced the salience of cocaine stimuli and delayed relapse in humans. Methods—The present study determined the ability of maintenance on n-acetylcysteine (0 or 2400 mg/day, counterbalanced) to reduce the incentive salience of cocaine stimuli, as measured by an attentional bias task, and attenuate intranasal cocaine self-administration (0, 30, and 60 mg). Fourteen individuals (N = 14) who met criteria for cocaine abuse or dependence completed this within-subjects, double-blind, crossover-design study. Results—Cocaine-cue attentional bias was greatest following administration of 0 mg cocaine during placebo maintenance, and was attenuated by n-acetylcysteine. Cocaine maintained responding during placebo and n-acetylcysteine maintenance, but the reinforcing effects of cocaine were significantly attenuated across both maintenance conditions in participants maintained on n-acetylcysteine first compared to participants maintained on placebo first. Conclusions—These results collectively suggest that a reduction in the incentive salience of cocaine-related stimuli during n-acetylcysteine maintenance may be accompanied by reductions in cocaine self-administration. These results are in agreement with, and link, prior preclinical and clinical trial results suggesting that n-acetylcysteine might be useful for preventing cocaine relapse by attenuating the incentive salience of cocaine cues