Lithium carbonate in the management of cannabis withdrawal: a randomized placebo-controlled trial in an inpatient setting.

RATIONALE: Preclinical studies suggest that lithium carbonate (lithium) can reduce precipitated cannabinoid withdrawal in rats by stimulating release of the neuropeptide oxytocin, while two open-label studies indicate lithium may ameliorate cannabis withdrawal symptoms in humans. OBJECTIVES: This study was conducted to examine the efficacy and safety of lithium in the inpatient management of cannabis withdrawal and to determine whether lithium affects plasma oxytocin and the rate of elimination of plasma cannabinoids during abstinence. METHODS: Treatment-seeking cannabis-dependent adults (n = 38) were admitted for 8 days to an inpatient withdrawal unit and randomized to either oral lithium (500 mg) or placebo given twice a day under double-blind randomized controlled trial (RCT) conditions. Primary outcomes included withdrawal severity [cannabis withdrawal scale (CWS)], rates of detoxification completion, and adverse events. Plasma cannabinoids, plasma oxytocin and serum lithium levels were measured repeatedly over admission. Follow-up research interviews were conducted at 14, 30, and 90 days postdischarge. RESULTS: Lithium did not significantly affect total CWS scores relative to placebo, although it significantly reduced individual symptoms of "loss of appetite," "stomach aches," and "nightmares/strange dreams." No significant group differences were found in treatment retention or adverse events. Lithium did not increase plasma oxytocin levels nor influence the rate of elimination of cannabinoids. Both placebo- and lithium-treated participants showed reduced levels of cannabis use (verified by urinalysis) and improved health and psychosocial outcomes at 30- and 90-day follow-up relative to pretreatment baselines. CONCLUSIONS: Despite the strong rationale for the present study, the efficacy of lithium over placebo in the management of cannabis withdrawal was not demonstrated.

Systemically administered oxytocin decreases methamphetamine activation of the subthalamic nucleus and accumbens core and stimulates oxytocinergic neurons in the hypothalamus.

Recent preclinical evidence indicates that the neuropeptide oxytocin may have potential in the treatment of drug dependence and drug withdrawal. Oxytocin reduces methamphetamine self-administration, conditioned place preference and hyperactivity in rodents. However, it is unclear how oxytocin acts in the brain to produce such effects. The present study examined how patterns of neural activation produced by methamphetamine were modified by co-administered oxytocin. Male Sprague-Dawley rats were pretreated with either 2 mg/kg oxytocin (IP) or saline and then injected with either 2 mg/kg methamphetamine (IP) or saline. After injection, locomotor activity was measured for 80 minutes prior to perfusion. As in previous studies, co-administered oxytocin significantly reduced methamphetamine-induced behaviors. Strikingly, oxytocin significantly reduced methamphetamine-induced Fos expression in two regions of the basal ganglia: the subthalamic nucleus and the nucleus accumbens core. The subthalamic nucleus is of particular interest given emerging evidence for this structure in compulsive, addiction-relevant behaviors. When administered alone, oxytocin increased Fos expression in several regions, most notably in the oxytocin-synthesizing neurons of the supraoptic nucleus and paraventricular nucleus of the hypothalamus. This provides new evidence for central actions of peripheral oxytocin and suggests a self-stimulation effect of exogenous oxytocin on its own hypothalamic circuitry. Overall, these results give further insight into the way in which oxytocin might moderate compulsive behaviors and demonstrate the capacity of peripherally administered oxytocin to induce widespread central effects.