Novel Pharmacologic Approaches to Treating Cannabis Use Disorder.

With large and increasing numbers of people using cannabis, the development of cannabis use disorder (CUD) is a growing public health concern. Despite the success of evidence-based psychosocial therapies, low rates of initial abstinence and high rates of relapse during and following treatment for CUD suggest a need for adjunct pharmacotherapies. Here we review the literature on medication development for the treatment of CUD, with a particular focus on studies published within the last three years (2010-2013). Studies in both the human laboratory and in the clinic have tested medications with a wide variety of mechanisms. In the laboratory, the following medication strategies have been shown to decrease cannabis withdrawal and self-administration following a period of abstinence (a model of relapse): the cannabinoid receptor agonist, nabilone, and the adrenergic agonist, lofexidine, alone and in combination with dronabinol (synthetic THC), supporting clinical testing of these medication strategies. Antidepressant, anxiolytic and antipsychotic drugs targeting monoamines (norepinephrine, dopamine, and serotonin) have generally failed to decrease withdrawal symptoms or laboratory measures of relapse. In terms of clinical trials, dronabinol and multiple antidepressants (fluoxetine, venlafaxine and buspirone) have failed to decrease cannabis use. Preliminary results from controlled clinical trials with gabapentin and N-acetylcysteine (NAC) support further research on these medication strategies. Data from open label and laboratory studies suggest lithium and oxytocin also warrant further testing. Overall, it is likely that different medications will be needed to target distinct aspects of problematic cannabis use: craving, ongoing use, withdrawal and relapse. Continued research is needed in preclinical, laboratory and clinical settings.

Thermal sensitivity as a measure of spontaneous morphine withdrawal in mice.

INTRODUCTION: Opioid withdrawal syndrome is a critical component of opioid abuse and consists of a wide array of symptoms including increases in pain sensitivity (hyperalgesia). A reliable preclinical model of hyperalgesia during opioid withdrawal is needed to evaluate possible interventions to alleviate withdrawal. The following study describes a method for assessing increases in thermal sensitivity on the hotplate in a mouse model of spontaneous morphine withdrawal. METHODS: C57BL/6J mice received 5.5days of 30, 56, or 100mg/kg morphine or saline (s.c., twice daily). In Experiment I, thermal sensitivity data were collected at baseline and at 8, 24, 32, 48h and 1week following the final injection. Thermal sensitivity was assessed by examining latency to respond on a hotplate across a range of temperatures (50, 52, 54, and 56°C). In Experiment II, 0.01mg/kg buprenorphine was administered 30min prior to each testing session during the withdrawal period. In Experiment III, jumping during a 30min period was assessed at baseline and at 0, 8, 24, 32, and 48h following the final morphine injection. RESULTS: During the withdrawal period, thermal sensitivity increased significantly in all morphine-treated mice as compared to saline-treated mice. Thermal sensitivity was greater in mice treated with 56mg/kg morphine compared to 30mg/kg and peaked earlier than in mice treated with 100mg/kg (32h v 1wk). The increase in thermal sensitivity following 56mg/kg morphine was attenuated by a dose of buprenorphine that did not produce antinociception alone (i.e., 0.01mg/kg). In general, the results of the jumping experiment paralleled those obtained in Experiment I. DISCUSSION: Response latency on the hotplate is a reliable and sensitive measure of spontaneous morphine withdrawal in mice, making it an ideal behavior for assessing the potential of medications and environmental interventions to alleviate opioid withdrawal.

The effect of environmental factors on morphine withdrawal in C57BL/6J mice: running wheel access and group housing.

RATIONALE: There is evidence to suggest that the rewarding effects of drugs of abuse can be altered by environmental manipulations such as housing conditions and access to running wheels. There is less information about how these environmental manipulations alter withdrawal behaviors following the termination of chronic drug administration. OBJECTIVES: The objective of this study is to examine the effects of access to running wheels and group housing on spontaneous morphine withdrawal. METHODS: C57BL/6J mice were assigned to one of the three housing conditions: wheel access (singly housed), no wheels (singly housed), or group-housed (no wheels). Mice received 30 or 56 mg/kg morphine or saline (s.c.) twice daily for 5.5 days. At baseline and at 8, 24, 32, and 48 h following the final injection, latency to respond on a hot plate was determined across a range of temperatures (50, 52, 54, and 56 °C). RESULTS: Latency to respond decreased as a function of temperature. Response latencies during the withdrawal period were decreased in mice without wheel access treated with both 30 and 56 mg/kg of morphine. This increase in thermal sensitivity was significantly attenuated in singly housed mice with wheel access and in group-housed mice; however, the effects were less pronounced in the group-housed mice and depended upon the time during withdrawal. CONCLUSIONS: Both wheel access and group housing attenuate the increase in thermal sensitivity seen in morphine-treated mice during morphine withdrawal.

Opioid antinociception, tolerance and dependence: interactions with the N-methyl-D-aspartate system in mice.

This study explored the involvement of N-methyl-D-aspartate (NMDA) in the effects of µ-opioid agonists. A hot-plate procedure was used to assess antinociception and tolerance in mice in which the NR1 subunit of the NMDA receptor was reduced [knockdown (KD)] to approximately 10%, and in mice treated with the NMDA antagonist, (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959). The µ opioid agonists, morphine, l-methadone and fentanyl, were approximately three-fold less potent in the NR1 KD mice than in wild-type (WT) controls; however, the development of morphine tolerance and dependence did not differ markedly in the NR1 KD and the WT mice. Acute administration of the NMDA antagonist, LY235959, produced dose-dependent, leftward shifts in the morphine dose-effect curve in the WT mice, but not in the NR1 KD mice. Chronic administration of LY235959 during the morphine tolerance regimen did not attenuate the development of tolerance in the NR1 KD or the WT mice. These results indicate that the NR1 subunit of the NMDA receptor does not play a prominent role in µ opioid tolerance.