The association between cannabis use and depression: a systematic review and meta-analysis of longitudinal studies.

BACKGROUND: Longitudinal studies reporting the association between cannabis use and developing depression provide mixed results. The objective of this study was to establish the extent to which different patterns of use of cannabis are associated with the development of depression using meta-analysis of longitudinal studies. METHOD: Peer-reviewed publications reporting the risk of developing depression in cannabis users were located using searches of EMBASE, Medline, PsychINFO and ISI Web of Science. Only longitudinal studies that controlled for depression at baseline were included. Data on several study characteristics, including measures of cannabis use, measures of depression and control variables, were extracted. Odds ratios (ORs) were extracted by age and length of follow-up. RESULTS: After screening for 4764 articles, 57 articles were selected for full-text review, of which 14 were included in the quantitative analysis (total number of subjects = 76058). The OR for cannabis users developing depression compared with controls was 1.17 [95% confidence interval (CI) 1.05-1.30]. The OR for heavy cannabis users developing depression was 1.62 (95% CI 1.21-2.16), compared with non-users or light users. Meta-regression revealed no significant differences in effect based on age of subjects and marginal difference in effect based on length of follow-up in the individual studies. There was large heterogeneity in the number and type of control variables in the different studies. CONCLUSIONS: Cannabis use, and particularly heavy cannabis use, may be associated with an increased risk for developing depressive disorders. There is need for further longitudinal exploration of the association between cannabis use and developing depression, particularly taking into account cumulative exposure to cannabis and potentially significant confounding factors.

The effect of cannabis edibles on driving and blood THC.

BACKGROUND: Cannabis has been shown to impact driving due to changes produced by delta-9-tetrahydrocannabinol (THC), the psychoactive component of cannabis. Current legal thresholds for blood THC while driving are based predominantly on evidence utilizing smoked cannabis. It is known that levels of THC in blood are lower after eating cannabis as compared to smoking yet the impact of edibles on driving and associated blood THC has never been studied. METHODS: Participants drove a driving simulator before and after ingesting their preferred legally purchased cannabis edible. In a counterbalanced control session, participants did not consume any THC or cannabidiol (CBD). Blood was collected for measurement of THC and metabolites as well as CBD. Subjective experience was also assessed. RESULTS: Participants consumed edibles with, on average, 7.3 mg of THC, which is less than the maximum amount available in a single retail package in Ontario, providing an ecologically valid test of cannabis edibles. Compared to control, cannabis edibles produced a decrease in mean speed 2 h after consumption but not at 4 and 6 h. Under dual task conditions in which participants completed a secondary task while driving, changes in speed were not significant after the correction for multiple comparison. No changes in standard deviation of lateral position (SDLP; 'weaving'), maximum speed, standard deviation of speed or reaction time were found at any time point or under either standard or dual task conditions. Mean THC levels were significantly increased, relative to control, after consuming the edible but remained relatively low at approximately 2.8 ng/mL 2 h after consumption. Driving impairment was not correlated with blood THC. Subjective experience was altered for 7 h and participants were less willing/able to drive for up to 6 h, suggesting that the edible was intoxicating. INTERPRETATION: This is the first study of the impact of cannabis edibles on simulated driving. Edibles were intoxicating as revealed by the results of subjective assessments (VAS), and there was some impact on driving. Detection of driving impairment after the use of cannabis edibles may be difficult.

Screening Medications for the Treatment of Cannabis Use Disorder.

Cannabis use has been increasingly accepted legally and in public opinion. However, cannabis has the potential to produce adverse physical and mental health effects, and cannabis use disorder (CUD) occurs in a substantial percentage of both occasional and daily cannabis users. Many people have difficulty discontinuing use despite receiving treatment. Therefore, it would be beneficial to develop safe and effective medications for treating CUD. To achieve this, methods have been developed for screening and evaluating potential medications using animal models and controlled experimental protocols in human volunteers. In this chapter, we describe: (1) animal models available for assessing the effect of potential medications on specific aspects of CUD, (2) the main findings obtained so far with these animal models, (3) the approaches used to assess potential medications in humans in laboratory experiments and clinical trials, and (4) the effectiveness of several potential pharmacotherapies on particular aspects of CUD modeled in these human studies.

The agranular and granular insula differentially contribute to gambling-like behavior on a rat slot machine task: effects of inactivation and local infusion of a dopamine D4 agonist on reward expectancy.

RATIONALE: Rats, like humans, are susceptible to the reinforcing effects of reward-related stimuli presented within a compound stimulus array, putatively analogous to the so-called near-miss effect. We have previously demonstrated using a rodent slot machine task (rSMT) that the reward expectancy these stimuli elicit is critically mediated by the dopamine D4 receptor. D4 receptors are principally located in prefrontal regions activated during slot machine play in humans, such as the insular cortex. The insula has recently attracted considerable interest as it appears to play a crucial role in substance and behavioral addictions. However, the insula is a heterogeneous area, and the relative contributions of subregions to addictive behaviors are unclear. METHODS: Male Long Evans rats were trained to perform the rSMT, and then bilateral cannula targeting either the granular or agranular insula were implanted. The effects of inactivation and local administration of a D4 agonist were investigated. RESULTS: Temporary inactivation of the agranular, but not the granular insula impaired performance on the rSMT. In contrast, local infusion of the D4 agonist PD168077 into the agranular insula had no effect on task performance, but when administered into the granular insula, it improved animals' ability to differentiate winning from non-winning trials. The agranular insula may therefore modulate decision making when conflicting stimuli are present, potentially due to its role in generating a cohesive emotional percept based on both externally and internally generated signals, whereas the granular insular is not critical for this process. Nevertheless, D4 receptors within the granular insula may amplify the incentive salience of aversive environmental stimuli. DISCUSSION: These data provide insight into the neurobiological mechanism underpinning maladaptive reward expectancy during gambling and provide further evidence that D4 receptors represent a potential target for developing pharmacotherapies for problem gambling.

Dopamine D3 receptors expressed by all mesencephalic dopamine neurons.

A polyclonal antibody was generated using synthetic peptides designed in a specific sequence of the rat D(3) receptor (D(3)R). Using transfected cells expressing recombinant D(3)R, but not D(2) receptor, this antibody labeled 45-80 kDa species in Western blot analysis, immunoprecipitated a soluble fraction of [(125)I]iodosulpride binding, and generated immunofluorescence, mainly in the cytoplasmic perinuclear region of the cells. In rat brain, the distribution of immunoreactivity matched that of D(3)R binding, revealed using [(125)I]R(+)trans-7-hydroxy-2-[N-propyl-N-(3'-iodo-2'-propenyl)amino] tetralin ([(125)I]7-trans-OH-PIPAT), with dense signals in the islands of Calleja and mammillary bodies, and moderate to low signals in the shell of nucleus accumbens (AccSh), frontoparietal cortex, substantia nigra (SN), ventral tegmental area (VTA) and lobules 9 and 10 of the cerebellum. Very low or no signals could be detected in other rat brain regions, including dorsal striatum, or in D(3)R-deficient mouse brain. Labeling of perikarya of AccSh and SN/VTA appeared with a characteristic punctuate distribution, mostly at the plasma membrane where it was not associated with synaptic boutons, as revealed by synaptophysin immunoreactivity. In SN/VTA, D(3)R immunoreactivity was found on afferent terminals, arising from AccSh, in which destruction of intrinsic neurons by kainate infusions produced a loss of D(3)R binding in both AccSh and SN/VTA. D(3)R-immunoreactivity was also found in all tyrosine hydroxylase (TH)-positive neurons observed in SN, VTA and A8 retrorubral fields, where it could represent D(3) autoreceptors controlling dopamine neuron activities, in agreement with the elevated dopamine extracellular levels in projection areas of these neurons found in D(3)R-deficient mice.

Smoking cessation guidelines: evidence-based recommendations of the French Health Products Safety Agency.

Tobacco use is the leading preventable cause of death in developed countries. Millions of smokers are willing to stop, but few of them are able to do so. Clinicians should only use approaches that have demonstrated their efficacy in helping patients to stop smoking. This article summarizes the evidence-based major findings and clinical recommendations for the treatment of tobacco dependence of the French Health Products Safety Agency (AFSSAPS). Clinicians should enquire about the smoking status of each patient and provide information about health consequence of smoking and effective treatments available. These treatments include counseling (mainly individual or social support and behavioral and cognitive therapy) and pharmacological treatment with either nicotine replacement therapy (NRT) or bupropion LP. Pharmacological treatments should be used only for proven nicotine dependence, as assessed by the Fagerstrom test for Nicotine Dependence. The choice of pharmacologic treatment depends of the patient's preference and history and of the presence of contra-indications. The clinician should start with a single agent, but these treatments may be used in combination. Smoking behavior is a chronic problem that requires long-term management and follow-up. Access to intensive treatment combining pharmacological treatment and extensive behavioral and cognitive therapy should be available for highly dependent patients.

Cannabinoids: Friend or foe?

This issue of Clinical Pharmacology & Therapeutics focuses on cannabinoids. Our understanding of these interesting endogenous and synthetic compounds, and their role in the cannabinoid system, has evolved dramatically, in part because of the acquisition of new research tools. Cannabis has been used for centuries by humans for recreational and medicinal purposes, however, there is substantial evidence that cannabis use can expose people to varying complications (e.g., risk of addiction, cognitive impairment), thus, it is important to determine the benefit/risk of cannabis with precision and to implement policy measures based on evidence to maximize the benefits and minimize the harm. Novel cannabinoid drugs are emerging for medicinal use (e.g., dronabinol, nabiximols) and as illicit drugs (e.g., Spice, K2) perpetuating the perception that cannabinoid drugs can be a friend or foe. This special issue will cover these various aspects of cannabinoid pharmacology and therapeutics ranging from basic chemistry, pharmacokinetics, pharmacodynamics, and clinical trial results, to policy and education efforts in this area.

The dopamine D3 receptor and drug addiction.

Hedonic and reinforcing properties of drugs of abuse are closely related to brain dopamine neuron activity. All these drugs increase dopamine release in the shell of the nucleus accumbens, a brain region in which neurons co-express the D1 (D1R) and D3 (D3R) dopamine receptor subtypes, that converging pharmacological, human post-mortem and genetic studies suggest to be implicated in drug addiction. The D3R through a cross-talk with the D1R, is involved in induction and expression of behavioral sensitization to levodopa in rats bearing unilateral lesions of dopamine neurons. Behavioral sensitization, a cardinal feature of addiction arises from repeated administration of drugs of abuse thought to play a role in intensification of reinforcing efficacy of these drugs observed under certain conditions. Stimulation of the D3R also appears to enhance the reinforcing effect of cocaine in rats. By interacting with these processes, D3R agents have potential therapeutic applications for treating drug addiction. BP 897 (N-[4-(4-(2-methoxyphenyl)piperazin-1-yl) butyl] naphtalen 2-carboxamide dichlorhydrate), a partial and highly selective D3R agonist in vitro, behaves as an agonist or an antagonist in vivo depending on the response considered. BP 897 has the unprecedented property to reduce cocaine-seeking behavior induced by presentation of a cocaine-associated cue, without having any intrinsic reinforcing effect. As drug-associated cues maintain drug-seeking in animals and elicit craving and relapse in humans, D3R agents like BP 897 may represent new medications for drug addiction, with minimal liability to maintaining dependence.

Dopamine D3 receptor agents as potential new medications for drug addiction.

All drugs abused by humans increase dopamine in the shell of nucleus accumbens, which implicate the neurons of this structure in their hedonic and reinforcing properties. Among the various dopamine receptor subtypes, the D(1) (D(1)R) and D(3) (D(3)R) receptors co-localise in accumbal shell neurons. Synergistic D(1)R/D(3)R interactions at this level were found on gene expression and during induction and expression of behavioral sensitisation to levodopa in rats bearing unilateral lesions of dopamine neurons. Behavioral sensitisation to abused drugs is a component of their long-term effects. Converging pharmacologic, human postmortem and genetic studies suggest the involvement of the D(3)R in reinforcing effects of drugs; D(3)R agonists reduced cocaine self-administration in rats, without disrupting the maintenance of self-administration. These data suggest the use of D(3)R agonists as partial substitutes to treat cocaine dependence, by affecting its reward component. However, substitution therapies maintain dependence and may be inefficient on drug craving and relapse, which are the unsolved and critical problems in the treatment of drug addiction. Recently, a highly selective and partial D(3)R agonist was shown to reduce cocaine-associated cue-controlled behaviour in rats, without having any primary intrinsic effects. As drug-associated cues maintain drug-seeking in animals and elicit craving and relapse in humans, such D(3)R agents have potential therapeutic applications.

Replicated association of the NR4A3 gene with smoking behaviour in schizophrenia and in bipolar disorder.

Schizophrenia and bipolar disorder are associated with dopamine neurotransmission and show high comorbidity with tobacco dependence. Recent evidence indicates that the family of the NR4A orphan nuclear receptors, which are expressed in dopamine neurons and in dopaminoceptive brain areas, may play a role in dopamine-mediated effects. We have, therefore, analysed the association of six single nucleotide polymorphisms (SNPs) within the three genes belonging to the NR4A orphan nuclear receptor family, NR4A1 (rs2603751, rs2701124), NR4A2 (rs12803, rs834835) and NR4A3 (rs1131339, rs1405209), with the degree of smoking in a sample of 204 unrelated schizophrenia patients, which included 126 smokers and 78 non-smokers. SNPs within the NR4A3 gene (rs1131339 and rs1405209) were significantly associated with heavy smoking in this cohort, using a stepwise analysis of the escalated number of cigarettes smoked per day (P = 0.008 and 0.006, respectively; satisfying the Nyholt significance threshold of 0.009, an adjustment for multiple testing). We then repeated the association analysis of the NR4A3 markers (rs1131339 and rs1405209) in a larger cohort of 319 patients with bipolar disorder, which included 167 smokers and 152 non-smokers. We have replicated the positive association with smoking of the NR4A3 SNP rs1131339 in this group (P = 0.04), providing an important confirmation of the involvement of the NR4A3 gene in nicotine addiction in patients with mental health disease, a population significantly at risk for nicotine addiction.

The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders.

The role of the D(3) receptor has remained largely elusive before the development of selective research tools, such as selective radioligands, antibodies, various highly specific pharmacological agents and knock-out mice. The data collected so far with these tools have removed some of the uncertainties regarding the functions mediated by the D(3) receptor. The D(3) receptor is an autoreceptor that controls the phasic, but not tonic activity of dopamine neurons. The D(3) receptor, via regulation of its expression by the brain-derived neurotrophic factor (BDNF), mediates sensitization to dopamine indirect agonists. This process seems responsible for side-effects of levodopa (dyskinesia) in the treatment of Parkinson's disease (PD), as well as for some aspects of conditioning to drugs of abuse. The D(3) receptor mediates behavioral abnormalities elicited by glutamate/NMDA receptor blockade, which suggests D(3) receptor-selective antagonists as novel antipsychotic drugs. These data allow us to propose novel treatment options in PD, schizophrenia and drug addiction, which are awaiting evaluation in clinical trials.

Disruption of nicotine conditioning by dopamine D(3) receptor ligands.

Tobacco smoking is the first cause of preventable death in modern countries. Nicotine replacement therapy or sustained release bupropion helps smoking cessation, but relapse rates are still very high. Nicotine, like other drugs of abuse, activates the dopamine mesolimbic system, which originates in the ventral tegmental area and projects notably to the nucleus accumbens. Situations or environmental stimuli previously associated with cigarette smoking, for example, smell of cigarette smoke, can elicit craving in abstinent smokers and promote relapse. Reducing the effects of nicotine-associated cues might therefore have potential therapeutic utility for smoking cessation. Such an approach has been validated for cocaine in animals, by using the dopamine D(3) receptor-selective partial agonist BP 897, which inhibits cocaine cue-induced drug-seeking behavior. Here we show that rats repeatedly injected with nicotine in a particular environment develop nicotine-conditioned locomotor responses, accompanied by an increase in D(3) receptor expression in the nucleus accumbens. This conditioned behavior was inhibited by BP 897 or a selective D(3) receptor antagonist, suggesting that antagonizing dopamine selectively at the D(3) receptor disrupts nicotine-conditioned effects and might represent a novel therapeutic approach for smoking cessation.