Ziva D. Cooper, Ph.D. - US grants

DESCRIPTION (provided by applicant): In this application for a KO1 Mentored Research Scientist Development Award, Dr. Ziva Cooper has proposed a comprehensive plan to integrate a training plan towards becoming an independent researcher in the field of human behavioral pharmacology with her interest in investigating human laboratory models of polysubstance abuse. Substances are rarely abused independently, thus, determining the physiological and behavioral effects, and the health risks associated with abused drugs administered independently and simultaneously under well-controlled conditions is an imperative preliminary step to advance the area of substance-abuse treatment. Abuse of marijuana among the cocaine-dependent population is widespread. Although there has been a great deal of research advancing the treatment of cocaine and marijuana dependence independently, there have been no studies investigating potential treatments for dependence on both substances. Understanding the precise nature of the interaction between marijuana and cocaine is an essential first step to developing pharmacotherapy strategies for their co-abuse. The research aims of the proposed studies are to first determine the behavioral and physiological effects of experimenter-administered marijuana in combination with smoked cocaine that contribute to the abuse liability and health risks associated with the drug combination. Next, the influence of marijuana on relapse to smoked cocaine self-administration will be determined using a human laboratory relapse model. The training goals for Dr. Cooper are to 1) acquire a more comprehensive knowledge of methodology, safety, and ethics of conducting research with psychoactive substances in the human laboratory; 2) gain expertise in methodology and data analysis for research on experimenter and self-administered marijuana and smoked cocaine in the human laboratory 3) research contemporary statistical approaches to human laboratory research 4) increase proficiency in manuscript and grant writing. Overall, this award will ensure Dr. Cooper's successful transition to an independent investigator in the field of human behavioral pharmacology of substance use disorders.

DESCRIPTION (provided by applicant): Abuse of synthetic cannabinoids ('Spice') as an alternative to cannabis is increasing rapidly. Despite their widespread use, the risks of these products are unknown. Based upon the pharmacology of the primary constituents of Spice, JWH-018 and JWH-073, the synthetic cannabinoids pose a greater risk for substance use disorder than cannabis. The proposed studies are critical in order to conduct subsequent human laboratory studies to address the physiological risks and behavioral effects of these widely-abused compounds by providing agents appropriate for research in humans. The proposed study will provide techniques, methods and models for future research with this class of compounds and can be extended to other chemical classes of cannabinoids that may emerge. Aim 1: JWH Synthesis: Although the JWH compounds are widely available on the illicit market, none are manufactured according to standards required for controlled human laboratory investigation. Therefore, we will synthesize JWH-018 and JWH-073 using cGMP for human pharmaceuticals. The purity and integrity of synthesized compounds will be verified by an independent FDA-registered laboratory. Aim 2: Cigarette Preparation: We will develop procedures for standardizing synthetic cannabinoid cigarette production. Cigarettes of various JWH-018 and JWH-073 concentrations will be prepared using NIDA placebo cannabis plant matter. To verify the effectiveness of the method in producing consistent, concentration-specific JWH-018 and JWH-073 cigarettes, cigarettes will be analyzed using high-performance liquid chromatography tandem mass spectrometry (HPLC/MS/MS) (Teske et al., 2012). Aim 3: Determine the optimal conditions required for reliable in vitro detection of JWH-018 and JWH-073 and respective metabolites in human plasma using HPLC/MS/MS. Human plasma will be spiked with increasing concentrations of the parent compounds and metabolites and stored at varying temperatures (-80, -20, or 4¿ C) and duration (24 hr. - 4 wks.). Stability of the compounds and metabolites will be assessed as a function of time and temperature. Impact. The proposed study will accomplish the first steps needed to address the immediate, significant public health concern of the rapid rise in synthetic cannabinoid abuse, and is possible because of our substantial expertise in synthesizing compounds of particular

? DESCRIPTION (provided by applicant): The use of synthetic cannabinoids (SC), commonly referred to as `Spice,' is increasing at an alarming rate. In spite of such widespread human use there have been no studies directly investigating the abuse liability of SCs in laboratory animals. We propose studies in male and female non-human primates (NHPs) to assess the behavioral and physiological risks of 3 SCs (JWH018, JWH-073, and HU-210) relative to delta9-tetrahydrocannabinol (THC). The clinical significance of our proposal is enhanced by our use of cannabinoid vapors in a self-administration paradigm; the administration route most relevant to human cannabinoid abuse. Aim 1a. Reinforcing Efficacy: Compare the reinforcing effects of THC and JWH-018 vapors using our established methods of vapor self-administration. Aim 1b. Drug Substitution. Determine if a history of THC self-administration affects SC self-administration by examining the ability of 3 SCs and THC to maintain self- administration in one group of monkeys trained to inhale THC and in another group of monkeys trained to inhale JWH-018. Aim 2. Medication Model: Establish a paradigm for probing pharmacotherapies for cannabinoid-use disorders (CUD) using our established vapor vs. non-drug choice procedures. The effects of 1) a compound that increases oxytocin release (SOC1), 2) a hypocretin antagonist (SB334867), and 3), as a positive control, the CB1 antagonist rimonabant will be compared in monkeys trained to self-administer THC and monkeys trained to self-administer JWH-018. Aim 3. Chronic Exposure: Establish the physiological and behavioral effects of chronic exposure to experimenter-delivered JWH-018, JWH-073, HU-210, and THC vapor. After determining dose-response functions for physiological, e.g., heart rate, and operant effects of the SCs and THC, we will expose animals to equipotent doses of the 4 drugs thrice a day for 4 weeks (1 drug/phase). We will measure the effects of rimonabant-precipitated withdrawal at the beginning and at the end of 4 weeks for each of the 4 drugs. Aim 4. Novel Compound Evaluation: Given the continuous development of new SCs, one group of monkeys will be trained to assess the reinforcing effects of up to 3 novel SCs that emerge over the first 2.5 years of this proposal, or we will test other compounds currently identified in Spice that appear with increased frequency. Impact: SC use is a public health concern with minimal preclinical data available. The proposed studies are designed to fill a critical gap in our knowledge regarding the risks of these drugs in a species (non-human primates) and route of administration (vapor inhalation) with direct clinical relevance. The findings will 1) inform and predict the risks associated with SCs as they emerge on the drug market, 2) establish a preclinical model for testing potential therapeutic approaches for CUD and SC disorders, and 3) provide methods for laboratory studies using the increasing popular route of vapor delivery, i.e., vaping.

Project Summary: An estimated 60% of medical cannabis patients report concomitant use of prescription opioids to alleviate pain, yet there is an enormous gap in our understanding of how the drug combination impacts opioid abuse liability and analgesic effectiveness. Studies in our laboratory have demonstrated that cannabis (1) produces dose-related increases in analgesia measured with the Cold Pressor Test (CPT), a reliable and validated pain induction technique that has predictive validity for analgesics that are used for chronic pain, and (2) enhances the analgesic effects of a sub-threshold analgesic dose of the popularly prescribed opioid, oxycodone (OXY; 2.5 mg) without increasing cannabis?s abuse liability. However, these studies did not directly assess the impact of the combination on oxycodone?s abuse liability, a critical public health concern given the rising rates of prescription opioid abuse. Furthermore, the cannabis used previously had negligible concentrations of cannabidiol (CBD), a non-intoxicating cannabinoid that is hypothesized to decrease the abuse liability of tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, and opioids. CBD is also hypothesized to alleviate chronic (neuropathic) pain. Despite the widespread medical use and availability of cannabis with varying THC:CBD ratios, no studies have assessed how cannabis with varying ratios of THC:CBD affects cannabis?s abuse liability or analgesia when administered alone, or opioid abuse liability and analgesia when given in combination. The proposed study would be the first examination of the abuse liability and analgesic effectiveness of vaporized cannabis with high (~30:1) equal (~1:1) and low (~1:30) THC:CBD ratios, a route of administration and THC:CBD ratios that are ecologically relevant. Healthy cannabis users (N=20, 10M, 10F) with limited opioid experience will complete 8 outpatient laboratory sessions, during which they will be administered a sub- threshold analgesic dose of OXY (2.5 mg) or placebo, followed by inhalations of 30:1, 1:1, 1:30 THC:CBD, or placebo cannabis vapor via Volcano® vaporizers. The 30:1 dose will match the 1:1 dose on total THC content, but contain < 1 mg of CBD; the 1:30 dose will match the 1:1 dose on total CBD content, but contain < 1 mg THC. This design allows us to examine the independent and combined effects of THC and CBD on measures of abuse liability (positive subjective effects, self-administration) and analgesia when administered alone and when combined with OXY. Reducing the therapeutic dose and abuse liability of RxOPs while effectively treating pain is a public health priority. Cannabinoids hold promise, but there is an alarming absence of scientific data to inform if they mitigate or enhance adverse effects. The proposed study would provide urgently needed data on the effects of THC and CBD on abuse liability, therapeutic utility of medical cannabis and cannabinoids for chronic pain, and their effects when combined with RxOPs.

Project Summary: Rates of Cannabis Use Disorder (CUD) have doubled over the last ten years in the US. Although increasing, overall rates of cannabis use and CUD are still lower among women relative to men. However, epidemiological reports document a telescoping effect; women transition from first use to CUD at a faster rate than men. Preclinical studies with laboratory animals demonstrate that relative to males, females are more sensitive to the reinforcing effects of cannabinoids, perhaps explaining the accelerated progression to CUD observed in the epidemiological reports. To date, no studies have prospectively probed cannabis?s sex- dependent differences in abuse-liability in humans. To understand cannabis?s acute effects that underlie the accelerated trajectory to CUD observed in women, the proposed study will compare the dose-dependent effects of smoked cannabis on endpoints directly associated with abuse-liability between light- and heavy- cannabis using men and women, including positive subjective effects and cannabis self-administration. In addition to abuse-related endpoints, understanding sex differences in the analgesic responses to smoked cannabis have significant public health implications. Nearly 50% of medical cannabis users are women, with pain cited as the primary indication for which treatment is sought. Thus, assessing both the abuse liability and analgesic efficacy of cannabis as a function of sex is of critical importance. Preclinical studies point to three factors that contribute to sex-dependent responses to ?-9- tetrahydrocannabinol (THC) and other cannabinoid 1 receptor (CBR1) agonists; 1) estradiol increases the sensitivity to CBR1 agonist abuse-related effects, 2) pharmacokinetics (pK) of THC differ, with females exhibiting faster conversion from THC to its primary psychoactive metabolite than males and 3) enhanced development of tolerance to the antinociceptive effects (but not other endpoints) in females after chronic administration. The proposed prospective clinical study will directly address sex-dependent differences in cannabis?s effects as a function of these factors. We will 1) compare the abuse-related and analgesic effects of smoked cannabis between men to women while controlling for menstrual cycle effects, 2) evaluate differences in the pK of THC and respective metabolites between men and women, and 3) investigate cannabis?s sex-dependent effects as a function of frequency of cannabis use (light versus heavy cannabis users). Specifically, healthy light (N=60, 30M, 30F) and heavy (N=60, 30M, 30F) cannabis users will be recruited for this 3-session, double-blind, placebo-controlled, laboratory study. All participants will be administered placebo (0% THC), lower (3% THC), and higher (10% THC) strengths of cannabis in counter- balanced order. Cannabis?s abuse-related effects, analgesia, and pharmacokinetics will be assessed as a function of sex and frequency of cannabis use. Findings from this study will fill a critical gap in our knowledge and be integral in understanding sex as a biological variable in predicting, preventing, and treating CUD.

Project Summary: Chronic pain is a significant public health burden for which there are few effective treatments; individuals with chronic pain are a central component to the current opioid epidemic. Delta-9- tetrahydrocannabinol (THC), the primary psychoactive chemical of cannabis, holds promise as a therapeutic candidate to treat chronic pain. However, analgesia is accompanied by intoxication and abuse liability, thus limiting its clinical utility. Terpenes are organic compounds that contribute to the aromatic nature and flavor of cannabis; it has been hypothesized that these compounds may interact synergistically with THC to enhance its therapeutic effects with reduced adverse consequences. As such, terpenes may increase the analgesic effects of low, minimally intoxicating, doses of THC, and/or reduce adverse consequences of higher THC doses. Preclinical research demonstrates that the terpenes myrcene and ß-caryophyllene (BCP) elicit antinociceptive effects and have opioid-sparing properties. These effects are, in part, mediated by the mu-opioid receptor. It is unknown if these findings translate to humans. Understanding if these terpenes have analgesic properties alone, or in combination with THC, is fundamental to developing novel cannabinoid-based therapeutics to treat pain. In addition, investigating adverse effects of these terpenes (abuse liability, intoxication) will clarify their clinical potential. At a time when pharmacotherapeutic strategies to decrease reliance on opioids for pain relief are desperately needed, probing the 1) analgesic effects, 2) potential THC- and opioid-sparing properties, and 3) mechanism of these terpenes is of significant interest. The proposed double-blind, placebo-controlled studies will be the first to rigorously assess the dose-dependent analgesic effects of ecologically-relevant doses of myrcene and BCP and determine their THC- and opioid-sparing effects. Study findings will be essential in understanding the clinical potential of terpenes alone and in conjunction with THC for pain management. The proposed double-blind, placebo-controlled, within-subject studies in recreational cannabis smokers (N=30, 15M, 15F in each study) will first ascertain the dose-dependent analgesic potential of vaporized myrcene and BCP alone and in combination with sub-analgesic (5 mg) and analgesic (15 mg) doses of THC (Specific Aim 1). The myrcene/THC and BCP/THC dose combinations that produce the greatest analgesia and minimal intoxication and abuse liability will then be tested for their opioid sparing effects (Specific Aim 2). Opioid modulation of combined terpene/THC analgesia will be assessed with co-administration of naltrexone, an opioid antagonist (Specific Aim 2). Findings from these studies address a significant public health priority by investigating terpenes as a safe, well tolerated novel pharmacotherapeutic strategy to manage pain. This is an urgent area of research as alternatives to opioids and strategies to decrease use of high opioid doses are desperately needed.