Delta-9-tetrahydrocannabinol modulates pain sensitivity among persons receiving opioid agonist therapy for opioid use disorder: A within-subject, randomized, placebo-controlled laboratory study.

The opioid and cannabinoid receptor systems are inextricably linked-overlapping at the anatomical, functional and behavioural levels. Preclinical studies have reported that cannabinoid and opioid agonists produce synergistic antinociceptive effects. Still, there are no experimental data on the effects of cannabinoid agonists among humans who receive opioid agonist therapies for opioid use disorder (OUD). We conducted an experimental study to investigate the acute effects of the delta-9-tetrahydrocannabinol (THC) among persons receiving methadone therapy for OUD. Using a within-subject, crossover, human laboratory design, 25 persons on methadone therapy for OUD (24% women) were randomly assigned to receive single oral doses of THC (10 or 20 mg, administered as dronabinol) or placebo, during three separate 5-h test sessions. Measures of experimental and self-reported pain sensitivity, abuse potential, cognitive performance and physiological effects were collected. Mixed-effects models examined the main effects of THC dose and interactions between THC (10 and 20 mg) and methadone doses (low-dose methadone defined as <90 mg/day; high dose defined as >90 mg/day). Results demonstrated that, for self-reported rather than experimental pain sensitivity measures, 10 mg THC provided greater relief than 20 mg THC, with no substantial evidence of abuse potential, and inconsistent dose-dependent cognitive adverse effects. There was no indication of any interaction between THC and methadone doses. Collectively, these results provide valuable insights for future studies aiming to evaluate the risk-benefit profile of cannabinoids to relieve pain among individuals receiving opioid agonist therapy for OUD, a timely endeavour amidst the opioid crisis.

Feasibility and effects of galantamine on cognition in humans with cannabis use disorder.

BACKGROUND: As long-term use of medicinal and recreational cannabis becomes more common and concentrations of delta-9-tetrahydrocannabinol (THC) in cannabis increase, it is timely to identify strategies to counteract the cognitive effects of cannabinoids. OBJECTIVE: Galantamine is an acetylcholinesterase inhibitor approved for the treatment of Alzheimer's disease and other dementias. This study aimed to investigate the feasibility of galantamine administration to individuals with cannabis use disorder (CUD), and the effects of galantamine on cognition. We hypothesized galantamine would be well tolerated and would not have procognitive effects in the absence of acute cannabis intoxication. METHODS: Thirty individuals with CUD (73.5% male, 26.5% female) participated in a randomized, double-blind, parallel-group trial. Participants completed a baseline session followed by a 10-day outpatient treatment period, during which they received either 8 mg/day of galantamine orally or placebo. Cognitive assessments were conducted at three time points and self-reported measures that may impact cognitive performance (cannabis withdrawal, craving, and mood) were completed at six time points. RESULTS: There were no significant differences in demographic and baseline variables between groups (galantamine vs. placebo). There were no significant adverse effects from galantamine. Cannabis withdrawal and craving continuously decreased over the study. We saw evidence of a modest improvement in cognitive outcomes during the 10-day period, exemplified by a statistically significant increase in measures of response inhibition (increased median reaction time on the Stop Signal Task), and a trend for improvement in measures of attention (increased RVP A'), for both groups. Analyses did not show, however, a significant main effect for treatment or treatment-by-time interactions. CONCLUSIONS: The findings of this pilot study support the feasibility of the administration of galantamine for individuals with CUD. Adequately powered, randomized, placebo-controlled trials are required to investigate the potential of galantamine to improve cognitive deficits associated with CUD.

Effects of progesterone stimulated allopregnanolone on craving and stress response in cocaine dependent men and women.

OBJECTIVES: Fluctuations in progesterone levels during the menstrual cycle have been shown to affect physiological and subjective effects of cocaine. Furthermore, our laboratory has demonstrated that following drug-cue exposure, cocaine dependent women with high levels of circulating progesterone display lower diastolic and systolic blood pressure responses and report lower levels of anxiety and drug craving compared to cocaine dependent women with low levels of progesterone. In the current study we examined the role of the progesterone derived neuroactive steroid allopregnanolone (ALLO) on stress arousal, inhibitory control and drug craving in cocaine dependent subjects. METHODS: Plasma levels of ALLO were measured using GC/MS in 46 treatment-seeking cocaine dependent men and women on day 5 of a 7-day treatment regimen of micronized progesterone (15M/8F) (400mg/day) or placebo (14M/9F) administered in a double blind, randomized manner. As a control, levels of the testosterone derived neurosteroid androstanediol (ADIOL) were also measured. All subjects participated in laboratory sessions on days 5-7 of progesterone/placebo administration in which they were exposed to a series of 5-min personalized guided imagery of either a stressful situation, cocaine use or of a neutral setting and dependent variables including subjective craving, mood, Stroop task as a measure of inhibitory control performance and plasma cortisol were assessed. Participants were grouped by high or low ALLO level and levels of dependent variables compared between ALLO groups. RESULTS: Progesterone relative to placebo significantly increased ALLO levels with no sex differences. There were no effects of micronized progesterone on the testosterone derived ADIOL. Individuals in the high versus the low ALLO group showed decreased levels of cortisol at baseline, and a higher cortisol response to stress; higher positive mood scores at baseline and improved Stroop performance in the drug-cue and stress conditions, and reduced cocaine craving across all imagery conditions. CONCLUSIONS: As expected, cocaine dependent individuals administered progesterone showed significantly higher ALLO plasma levels. High levels of ALLO appeared to normalize basal and stress response levels of cortisol, decrease cocaine craving and also contribute to improvements in positive emotion and Stroop performance in response to stress and drug-cue exposures. These findings suggest that the neuroactive steroid ALLO plays a significant role in mediating the positive effects of progesterone on stress arousal, cognitive performance and drug craving in cocaine dependence.

Concomitant cannabis abuse/dependence in patients treated with opioids for non-cancer pain.

BACKGROUND AND OBJECTIVES: Cannabis use is common among patients taking prescription opioids, although rates of concomitant cannabis use disorder (CUD) have been largely unexamined. CUD may increase safety risks in those taking opioid pain medications but it is unknown whether cannabis and opioids function as substitutes (cannabis use is associated with less prescription opioid use), or rather as complements (cannabis is associated with increased use of prescription opioids). METHODS: We examined rates of CUD in a national sample of Veterans Health Administration (VHA) patients (n = 1,316,464) with non-cancer pain diagnoses receiving opioid medications in fiscal year 2012. Using bivariate analysis to identify potentially confounding variables associated with CUD (e.g., psychotropic medication, other substance use disorders) in this population, we then utilized logistic regression to examine rates of cannabis use disorder among individuals receiving different numbers of opioid prescriptions (0, 1-2, 3-10, 11-19, 20+). RESULTS: Descriptive analysis, largely confirmed by logistic regression, demonstrated that greater numbers of prescription opioid fills were associated with greater likelihood of CUD. This relationship was reduced somewhat for those receiving the most opioid prescriptions (20+) in the logistic regression, which controlled for potentially confounding variables. DISCUSSION AND CONCLUSIONS: These results warrant increased attention to CUDs among patients receiving numerous opioid prescriptions. Increasing legalization of cannabis is likely to further increase use and abuse of cannabis in patients prescribed opioids. SCIENTIFIC SIGNIFICANCE: These findings suggest that clinicians should be alert to concomitant CUD and prescription opioid use, as these substances appear to complement each other.

The effects of exogenous progesterone on drug craving and stress arousal in cocaine dependence: impact of gender and cue type.

AIMS: Exogenous progesterone has been shown to attenuate the rewarding effects of cocaine. However, its effects on provoked drug craving, stress arousal and cognitive performance has not been systematically investigated in cocaine dependent men and women. Thus, we conducted a double-blind placebo-controlled study assessing the efficacy of progesterone in reducing provoked drug craving, stress system arousal and improving cognitive performance in cocaine dependent men and women. METHODS: Forty-two early abstinent treatment-seeking cocaine dependent individuals were randomly assigned to either daily doses of placebo (12M/9F) or micronized progesterone (12M/9F) (400 mg/day), for 7 days. Under experimental conditions, all subjects were exposed to three 5-min personalized guided imagery conditions (stress, cocaine cue, relaxing), one per day, consecutively in a random, counterbalanced order. Subjective craving, mood, hypothalamic-pituitary-adrenal (HPA) and cardiovascular output, and a cognitive measure of inhibitory control (Stroop Color Word Task) were assessed pre- and post imagery. RESULTS: Progesterone relative to placebo significantly decreased cue-induced craving and cortisol responses and increased cue-induced ACTH. In addition, women but not men receiving progesterone reported lower ratings of negative emotion and higher ratings of relaxed mood following stress exposure. Improved Stroop performance was observed in all participants receiving progesterone, across all conditions. CONCLUSIONS: Progesterone was selectively effective in reducing cocaine cue-induced but not stress-related cocaine craving as well as specific measures of the provoked arousal state. Findings suggest that progesterone's effects on drug craving and arousal are moderated by both the type of environmental cue exposure and gender.

Cognitive enhancement as a treatment for drug addictions.

Drug addiction continues to be an important public health problem, with an estimated 22.6 million current illicit drug users in the United States alone. For many addictions, including cocaine, methamphetamine, and marijuana addiction, there are no approved pharmacological treatments. Behavioral treatments are effective but effects vary widely across individuals. Treatments that are effective across multiple addictions are greatly needed, and accumulating evidence suggests that one such approach may be pharmacological or behavioral interventions that enhance executive inhibitory control in addicts. Current evidence indicates that most forms of chronic drug use may be associated with significant cognitive impairments, especially in attention, working memory, and response inhibition functions. In some studies, these impairments predict poor treatment retention and outcome. A number of cognitive enhancing agents, including galantamine, modafinil, atomoxetine, methylphenidate, and guanfacine, have shown promising findings in human studies. Specific behavioral interventions, including cognitive remediation, also show promise. However, whether improvement of selective cognitive functions reduces drug use behavior remains to be determined. Cognitive enhancement to improve treatment outcomes is a novel strategy worthy of future research, as are related questions such as whether these approaches may be broadly beneficial to most addicts or best reserved for substance users with specific demonstrated cognitive impairments. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Stress decreases the ability to resist smoking and potentiates smoking intensity and reward.

We have developed a novel human laboratory model to examine two primary aspects of stress-precipitated tobacco relapse: (1) Does stress reduce the ability to resist the first cigarette? (2) Once the first cigarette is initiated, does stress facilitate subsequent smoking? Using a within-subject design, daily smokers (n = 37) who were nicotine deprived overnight received a personalized imagery induction (stress or neutral) on two separate days, and then had the option of initiating a tobacco self-administration session or delaying initiation for up to 50 min in exchange for three levels of monetary reinforcement. Subsequently, the tobacco self-administration session entailed a 1-hour period in which subjects could choose to smoke using a smoking topography system. Following the stress induction, subjects were less able to resist smoking, smoked more intensely (increased puffs, shorter inter-puff interval, and greater peak puff velocity), and perceived greater satisfaction and reward from smoking. Stress significantly increased hypothalamus-pituitary-adrenal (HPA) axis reactivity, tobacco craving, negative emotion, and physiologic reactivity relative to the neutral condition. In addition, increased cortisol, ACTH, and tobacco craving were associated with reduced ability to resist smoking following stress. These findings have implications for understanding the impact of stress on smoking relapse and model development to assess smoking lapse behavior.

Cognitive function as an emerging treatment target for marijuana addiction.

Cannabis is the most widely used illicit substance in the world, and demand for effective treatment is increasing. However, abstinence rates following behavioral therapies have been modest, and there are no effective pharmacotherapies for the treatment of cannabis addiction. We propose a novel research agenda and a potential treatment strategy, based on observations that both acute and chronic exposure to cannabis are associated with dose-related cognitive impairments, most consistently in attention, working memory, verbal learning, and memory functions. These impairments are not completely reversible upon cessation of marijuana use, and moreover may interfere with the treatment of marijuana addiction. Therefore, targeting cognitive impairment associated with chronic marijuana use may be a promising novel strategy for the treatment of marijuana addiction. Preclinical studies suggest that medications enhancing the cholinergic transmission may attenuate cannabis-induced cognitive impairments, but these cognitive enhancing medications have not been examined in controlled human studies. Preliminary evidence from individuals addicted to other drugs suggests that computerized cognitive rehabilitation may also have utility to improve cognitive function in marijuana users. Future clinical studies optimally designed to measure cognitive function as well as drug use behavior would be needed to test the efficacy of these treatments for marijuana addiction.

Sex steroid hormones, stress response, and drug craving in cocaine-dependent women: implications for relapse susceptibility.

Cocaine dependence is associated with an enhanced sensitivity to stress and drug craving. Increases in stress-induced craving and hypothalamic-pituitary-adrenal reactivity are also predictive of cocaine relapse outcomes. More important, sex differences in these responses have also been reported. To further understand the basis of the sex differences, the authors examined the influence of sex steroid hormones on subjective and physiological stress responses and drug craving in cocaine-dependent women. Women who had low progesterone levels (n=5) were compared with those with high progesterone levels (n=5) and with those with moderate levels of estradiol and progesterone (n=9) in their responses during exposure to stress, cocaine cues, and neutral imagery conditions. The high progesterone group showed significantly lower stress-induced and drug cue-induced cocaine craving ( p<.05) and reduced drug cue-induced anxiety levels ( p<.08) and lower drug cue-induced systolic and diastolic blood pressure levels compared with the low progesterone group. These data suggest that there are significant effects of sex steroid hormones on stress and drug cue-induced cocaine craving, anxiety, and cardiovascular responses. In particular, high progesterone during the midluteal phase of the cycle was associated with decreased stress-induced and drug cue-induced craving and decreased cue-induced anxiety and blood pressure responses. These findings are consistent with previous preclinical and clinical studies of progesterone's effects on the behavioral responses to cocaine and warrant further research to examine the effects of progesterone on stress-induced cocaine craving, stress arousal, and cocaine relapse susceptibility in women.

Biological treatments for amfetamine dependence : recent progress.

Amfetamine abuse has grown into a worldwide epidemic. Methamfetamine, a derivative of amfetamine made from readily accessible chemicals, has plagued the US since the 1960s, with an alarming recent surge in the numbers of those meeting the criteria for amfetamine abuse and dependence. We review this problem using a computerised literature search (PubMed 1964-2007) to summarise knowledge from animal and human studies about treatments for amfetamine dependence, while exploring the potential of pharmacogenetics to help uncover new treatment targets. Several promising therapeutic targets have come from animal models of reward, drug-taking behaviour and withdrawal. Although preclinical and selected clinical results have been promising, clinical studies have yielded inconsistent results. To improve these outcomes, pharmacogenetic studies may be used to identify candidate alleles that predict therapeutic response. Exciting preclinical findings and a steady progression of clinical results offer hope for the development of a treatment for amfetamine dependence.

Emerging pharmacological strategies in the fight against cocaine addiction.

Cocaine addiction continues to be an important public health problem worldwide. At present, there are no proven pharmacotherapies for cocaine addiction. The studies reviewed here revealed a number of emerging targets for cocaine pharmacotherapy. First, disulfiram, a medication with dopaminergic effects, reduced cocaine use in a number of clinical trials. Second, GABA medications, tiagabine and topiramate, were found promising in clinical trials. Third, a beta-adrenergic blocker, propranolol, may be effective especially among cocaine-addicted individuals with high withdrawal severity. Fourth, treatment with a stimulant medication, modafinil, has reduced cocaine use. Last, a cocaine vaccine that slows entry of cocaine into the brain holds promise. These promising findings need to be further tested in controlled clinical trials.