Preclinical Assessment of the Abuse Potential of Purified Botanical Cannabidiol: Self-Administration, Drug Discrimination, and Physical Dependence.

Cannabidiol (CBD) is a constituent of the cannabis plant with a diverse array of pharmacological activities as well as potential therapeutic uses. An oral formulation of CBD (Epidiolex in the US; Epidyolex in Europe) is approved for treating seizures associated with rare and severe forms of epilepsy. These studies, which supported the approval of the medication, investigated abuse-related effects of CBD in rats and nonhuman primates (NHPs) using drug self-administration, drug discrimination, and physical dependence procedures and characterized its pharmacokinetics. In NHPs (n = 5) that self-administered midazolam (0.01 or 0.032 mg/kg/infusion), CBD (0.1-3.2 mg/kg/infusion) failed to maintain responding above vehicle levels. CBD maintained very modest levels of self-administration in rats (n = 7-8) that self-administered heroin (0.015 mg/kg/infusion) and did not increase drug-lever responding, up to a dose of 150 mg/kg (by mouth), in rats (n = 6) trained to discriminate 0.5 mg/kg (i.p.) midazolam. In juvenile (5-6 weeks old) and adult (10-11 weeks old) male and female rats, discontinuation of chronic treatment (twice daily for 20 days) with an oral formulation of CBD (20 or 100 mg/kg, by mouth) did not reliably produce signs of withdrawal. Pharmacokinetic studies confirmed that the dosing regimens used in these studies resulted in therapeutically relevant plasma levels. Taken together, the lack of reliable self-administration, the failure to increase drug-lever responding in rats trained to discriminate midazolam, and the absence of withdrawal signs upon discontinuation of chronic treatment indicate that CBD has very low abuse potential and is unlikely to produce physical dependence. SIGNIFICANCE STATEMENT: Legalization of cannabis across the United States and elsewhere has led to intense investigation into the safety and therapeutic potential of cannabis and its constituent materials, including cannabidiol (CBD). Results of these preclinical abuse potential studies on CBD indicate no rewarding properties, physical dependence potential, or similarity to a benzodiazepine. Together with data from in vitro pharmacology and human abuse potential studies, the abuse potential of Epidiolex in humans is likely to be negligible.

The Blood Donation Ambivalence Survey: measuring conflicting attitudes about giving blood.

OBJECTIVES: This study was designed to develop and conduct initial validation testing for a novel measure of ambivalence about donating blood. BACKGROUND: Previous studies of living organ, bone marrow and stem cell donors have identified donation-related ambivalence as a predictor of decisions about donation and post-donation outcomes. Ambivalence about blood donation has not received the same attention. METHODS: In Study 1, a sample of young adults (N = 396) were administered test items of ambivalence, and exploratory (EFA) and confirmatory factor analyses (CFA) were performed to identify the Blood Donation Ambivalence Survey. In Study 2, a separate sample of young adults (N = 241) completed the Blood Donation Ambivalence Survey in addition to questionnaires assessing known predictors of blood donation. RESULTS: Exploratory and confirmatory factor analyses indicated a two-factor structure reflecting commitment to donating blood and indecision about giving blood. The commitment subscale was positively related to known predictors of increased donation behaviour (e.g. donation intention, self-efficacy), whereas the indecision subscale was positively related to known predictors of decreased donation behaviour (e.g. donation anxiety, negative affect). Furthermore, a history of blood donation was associated with greater commitment and less indecision. CONCLUSIONS: The present findings provide strong initial support for the reliability and validity of a novel measure of blood donor ambivalence.

Initial validation of a virtual blood draw exposure paradigm for fear of blood and needles.

Fear of blood, injections, and needles commonly prevents or delays individuals' receipt of health care, such as vaccines or blood draws. Innovative methods are needed to overcome these fears and reduce anxiety related to activities of this nature. The present study describes initial testing of an arm illusion paradigm that may prove useful during early phases of graded exposure for people with blood and needle fear. Seventy-four undergraduate students aged 18-29 years were tested. In line with study aims, results indicated that the virtual blood draw paradigm promoted strong perceptions of arm ownership and elicited significant changes in physiological indices (blood pressure, heart rate, electrodermal activity, respiratory rate) in response to key procedure elements (e.g., needle insertion). Further, bivariate correlations indicated that individual differences in self-reported blood and needle fear collected prior to the illusion paradigm were significantly associated with presyncopal symptoms reported following the procedure. In regression analyses, self-reported measures of blood and needle fear explained unique variance in presyncopal symptoms even after controlling for general state anxiety. These findings provide initial support for the virtual blood draw paradigm as a promising tool to help provide graded exposure to medical procedures involving needles and blood draw.

Sequential Treatment of Comorbid Insomnia and Generalized Anxiety Disorder.

OBJECTIVE: To explore the efficacy of cognitive-behavior therapy (CBT) for patients with comorbid generalized anxiety disorder (GAD) and insomnia using 2 sequential treatments. METHOD: Using a single-case methodology, 10 women (mean age = 45) with chronic insomnia and GAD were randomly assigned to CBT for GAD followed by CBT for insomnia, or to CBT for insomnia followed by CBT for GAD. Sleep and anxiety were measured via diagnostic interviews, daily diaries, and self-report questionnaires. RESULTS: Time series analyses, group effect sizes, and indications of clinically significant change revealed improvements on anxiety, worry, and sleep after CBT for GAD. Following CBT for insomnia, positive changes were observed on sleep and, to a lesser extent, anxiety and worry. CONCLUSIONS: In the presence of comorbid GAD and insomnia, initiating treatment for GAD first produced superior clinical benefits in anxiety and sleep. The addition of insomnia-specific treatment led to additional improvements in worry and sleep quality.

Combined Treatment with Morphine and Δ9-Tetrahydrocannabinol in Rhesus Monkeys: Antinociceptive Tolerance and Withdrawal.

Opioid receptor agonists are effective for treating pain; however, tolerance and dependence can develop with repeated use. Combining opioids with cannabinoids can enhance their analgesic potency, although it is less clear whether combined treatment alters opioid tolerance and dependence. In this study, four monkeys received 3.2 mg/kg morphine alone or in combination with 1 mg/kg Δ(9)-tetrahydrocannabinol (THC) twice daily; the antinociceptive effects (warm water tail withdrawal) of morphine, the cannabinoid receptor agonists WIN 55,212 [(R)-(1)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate] and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol), and the κ opioid receptor agonist U-50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzenacetamide methanesulfonate) were examined before, during, and after treatment. To determine whether concurrent THC treatment altered morphine dependence, behavioral signs indicative of withdrawal were monitored when treatment was discontinued. Before treatment, each drug increased tail withdrawal latency to 20 seconds (maximum possible effect). During treatment, latencies did not reach 20 seconds for morphine or the cannabinoids up to doses 3- to 10-fold larger than those that were fully effective before treatment. Rightward and downward shifts in antinociceptive dose-effect curves were greater for monkeys receiving the morphine/THC combination than monkeys receiving morphine alone. When treatment was discontinued, heart rate and directly observable withdrawal signs increased, although they were generally similar in monkeys that received morphine alone or with THC. These results demonstrated that antinociceptive tolerance was greater during treatment with the combination, and although treatment conditions were sufficient to result in the development of dependence on morphine, withdrawal was not markedly altered by concurrent treatment with THC. Thus, THC can enhance some (antinociception, tolerance) but not all (dependence) effects of morphine.

Daily morphine administration increases impulsivity in rats responding under a 5-choice serial reaction time task.

BACKGROUND AND PURPOSE: Repeated administration of a µ opioid receptor agonist can enhance some forms of impulsivity, such as delay discounting. However, it is unclear whether repeated administration alters motor impulsivity. EXPERIMENTAL APPROACH: We examined the effects of acute administration of morphine and amphetamine prior to and during daily morphine administration in rats responding under a five-choice serial reaction time task. Rats (n = 5) were trained to detect a brief flash of light presented randomly in one of five response holes; responding in the target hole delivered food, whereas responding in the wrong hole or responding prior to illumination of the target stimulus (premature response) initiated a timeout. Premature responding served as an index of motor impulsivity. KEY RESULTS: Administered acutely, morphine (0.1-10 mg·kg(-1) , i.p.) increased omissions and modestly, although not significantly, premature responding without affecting response accuracy; amphetamine (0.1-1.78 mg·kg(-1) , i.p.) increased premature responding without changing omissions or response accuracy. After 3 weeks of 10 mg·kg(-1) ·day(-1) morphine, tolerance developed to its effects on omissions whereas premature responding increased approximately fourfold, compared with baseline. Effects of amphetamine were not significantly affected by daily morphine administration. CONCLUSIONS AND IMPLICATIONS: These data suggest that repeated administration of morphine increased effects of morphine on motor impulsivity, although tolerance developed to other effects, such as omissions. To the extent that impulsivity is a risk factor for drug abuse, repeated administration of µ opioid receptor agonists, for recreational or therapeutic purposes, might increase impulsivity and thus the risk for drug abuse.

Influence of effluent organic matter on copper speciation and bioavailability in rivers under strong urban pressure.

This study focuses on spatiotemporal variations in the type of dissolved organic matter (DOM) and copper binding ability both upstream and downstream of Paris. It also compares the relative influence of both natural DOM upstream of Paris and effluent dissolved organic matter (EfDOM) output from a wastewater treatment plant (WWTP) on trace metal speciation and bioavailability in aquatic systems. In addition to the typical high- and low-affinity binding sites, a third family of very high-affinity binding sites has been highlighted for EfDOM. In receiving waters downstream of Paris during low-flow periods, the percentage of high- and very high-affinity sites originating from EfDOM reaches nearly 60 %. According to the speciation computation, the free copper concentration upstream of Paris exceeds the downstream Paris concentration by a factor of 2 to 4. As regards copper bioavailability, the highest EC50tot values were observed for EfDOM and downstream DOM, with a very low aromaticity and low UV absorbance. This finding suggests that specific ultraviolet absorbance (SUVA) is unlikely to be useful in assessing metal speciation and toxicity in aquatic systems subject to strong urban pressures. These results also highlight that the copper speciation computation for surface water exposed to considerable human pressures should include not only the humic and/or fulvic part of dissolved organic carbon but more hydrophilic fractions as well, originating for example from EfDOM.

Cross-tolerance to cannabinoids in morphine-tolerant rhesus monkeys.

RATIONALE: Opioids remain the drugs of choice for treating moderate to severe pain, although adverse effects limit their use. Therapeutic utility might be improved by combining opioids with other drugs to enhance analgesic effects, but only if adverse effects are not similarly changed. OBJECTIVE: Cannabinoids have been shown to enhance the antinociceptive potency of opioids without increasing other effects; this study examined whether the effectiveness of cannabinoids is altered in morphine-dependent monkeys. METHODS: Four monkeys received up to 10 mg/kg morphine twice daily. Changes in the antinociceptive effects of opioid receptor agonists (morphine, U50,488) and cannabinoid receptor agonists (WIN 55,212, CP 55,940, and Δ(9)-tetrahydrocannabinol [THC]) were determined by measuring the latency for monkeys to remove their tails from 40, 50, 54, and 58 °C water. RESULTS: Before treatment, all drugs increased tail withdrawal latency from warm (54 °C) water. Chronic morphine treatment decreased the potency of each drug; the magnitude of rightward shift in dose-effect curves was greatest for morphine, WIN 55,212 and CP 55,940 with at least sixfold shifts for each drug during treatment. Discontinuation of morphine treatment resulted in signs that are indicative of withdrawal, including increased heart rate, decreased daytime activity, and tongue movement. CONCLUSION: Tolerance developed to the antinociceptive effects of morphine and cross-tolerance developed to cannabinoids under conditions that produced modest physical dependence. Compared with the doses examined in this study, much smaller doses of opioids have antinociceptive effects when given with cannabinoids; it is possible that tolerance will not develop to chronic treatment with opioid/cannabinoid mixtures.

Trophic behaviour of juvenile reef fishes inhabiting interlinked mangrove-seagrass habitats in offshore mangrove islets.

Stable isotope (δ(13)C and δ(15)N) and gut content analyses were used to investigate size-related feeding habits of four reef fishes (the beaugregory Stegastes leucostictus, the french grunt Haemulon flavolineatum, the schoolmaster snapper Lutjanus apodus and the yellowtail snapper Ocyurus chrysurus) inhabiting an offshore (non-estuarine) mangrove islet off Belize, Central America. Comparisons of isotopic niche space and Schoener diet similarity index suggested a low to moderate degree of niche overlap between fish size groups. The δ(13)C gradient between mangrove and seagrass prey as well as results of Bayesian mixing models revealed that sampled fishes relied mostly on seagrass prey items. Only small and large juveniles of the carnivorous species L. apodus derived a part of their diet from mangroves by targeting mangrove-associated Grapsidae crabs and fish prey, respectively. Isotopic niche shifts were particularly obvious for carnivorous fishes that ingested larger prey items (Xanthidae crabs and fishes) during their ontogeny. The utilization of mangrove food resources is less than expected and depends on the ecology and life history of the fish species considered. This research highlights that mangrove-derived carbon contributed relatively little to the diets of four fish taxa from an offshore mangrove islet.

The effects of leg crossing and applied tension on blood donor return.

BACKGROUND AND OBJECTIVES: Repeated isometric muscle tension (applied tension) during blood donation reduces vasovagal symptoms in many donors. Experiencing vasovagal symptoms has been found to reduce blood donor return. However, does practicing applied tension improve blood donor return? Follow-up results from a randomized controlled trial are presented. METHODS: Data were collected in mobile clinics held in several colleges and universities. During the baseline donation, participants either (1) practiced 'standard' applied tension consisting of repeated 5 s cycles of whole-body isometric muscle tension in the donation chair (N = 133), (2) practiced tension with legs crossed (N = 131), or (3) gave blood as usual (N = 140). Subsequent blood donations in the following 2 years were determined. RESULTS: Applied tension had no effect on immediate (at the end of the baseline blood donation) rating of intention to give blood or the dichotomous measure of whether or not the participant gave blood again in the following 2 years. However, men asked to practice applied tension with legs crossed gave approximately one unit more during the follow-up period compared with men in the control group (F1,106  = 5·32, P = 0·023). This was associated significantly with adherence - men assigned to the applied tension with legs crossed condition who did not practice as instructed were no more likely to return than controls. CONCLUSION: The results provide modest support for the idea that applied tension may increase subsequent blood donation though the results were limited to men who practiced the technique as instructed.