However, the newly acquired knowledge on the physiological roles of the endocannabinoid system has significantly enhanced these prospects. At the June 27, 2004 workshop ‘‘Future Directions in Cannabinoid Therapeutics II: From the Bench to the Clinic’’, sponsored by the University of California Center for Medicinal Cannabis Research, we on the Scientific Planning Committee were asked to identify the areas of research with the most immediate promise for the development of novel therapeutic agents. The Committee identified four broad areas involving modulation of the endocannabinoid system as particularly promising in this regard: agonists for central CB1 cannabinoid receptors and peripheral CB2 receptors, antagonists of CB1 receptors, inhibitors of endocannabinoid deactivation, and endocannabinoid-like compounds that act through mechanisms distinct from CB1 and CB2 receptors activation. Below, we summarize the data presented at the Workshop and the consensus of its participants on the most exciting opportunities for drug discovery.Two endogenous agonists of cannabinoid receptors have been well characterized and are now widely used in research: anandamide , and 2-arachidonoylglycerol . Both molecules derive chemically from the polyunsaturated fatty acid, arachidonic acid, which is used in nature as the starting material for other important signaling compounds,cannabis growing system such as the eicosanoids. Additional endocannabinoid-related compounds present in the body include virodhamine, which may act as an endogenous antagonist of CB1 receptors, and arachidonoylserine, which may engage an as-yet-uncharacterized cannabinoid-like receptor expressed in the vasculature.

As is well-known, the Cannabis plant contains more than 60 cannabinoids, which include -D9 -tetrahydrocannabinol , cannabigerol, cannabidiol, cannabinol, cannabichromene and cannabicyclol. Attention has been mostly focused on D9 -THC, because of its multiple biological properties. Nevertheless, less studied compounds such as cannabidiol may also be important, although we do not yet know at which receptors they may act to achieve their effects. D9 -THC is the only natural cannabinoid presently used in the clinic. In addition to these plant-derived cannabinoids, an extensive set of synthetic cannabinergic agonists has been developed over the last 30 years. Products of these efforts include CP-55940 , created by opening one of the rings of the tricyclic D9 -THC structure and introducing other small changes in its structure; HU-210 , a very potent cannabinoid agonist resembling some D9 -THC metabolites; and WIN55212-2 , which belongs to an altogether different class of chemicals, the aminoalkylindoles. Additionally, the metabolically stable synthetic analog of anandamideR-methanandamide is routinely used as a pharmacological probe to circumvent the short half life of the natural substance. Two important new additions to this armamentarium under discussion at the workshop include a peripherally acting cannabinoid agonist in preclinical development by Novartis for the treatment of neuropathic and inflammatory pain , andBAY-387271 , a centrally acting cannabinoid agonist in Phase II clinical studies for the treatment of stroke. The interest of the pharmaceutical industry in the application of cannabinoid agonists to the treatment of pain conditions is not recent. Indeed, most of the compounds now in experimental use derive from such an interest. Historically however cannabinoid agonist development has not proved clinically fruitful, largely because of the profound psychotropic side effects of centrally active cannabinoid agonists, hence the attention given to peripherally acting cannabinoids, which exhibit significant analgesic efficacy and low central activity in animal models. Neuroprotection is a relatively new area for cannabinoid agonists, but one that appears to be already well advanced.

Preclinical studies have made a convincing case for the efficacy of cannabinoid agents not only in experimental brain ischemia, but also in models of Parkinson’s disease and other forms of degenerative brain disorders. The results of a Phase II clinical trial with BAY-387271 are awaited with great excitement. Also highlighted during the conference were various derivatives of cannabidiol.Like D9 -THC, 7-OH-DMH-CBD is a potent inhibitor of electrically evoked contractions in the mouse vas deferens. However, 7-OH-DMH-CBD does not significantly bind to either CB1 or CB2 receptors and its inhibitory effects on muscle contractility are not blocked by CB1 or CB2 receptor antagonists, suggesting that the compound may target an as-yet-uncharacterized cannabinoid-like receptor. This hypothesis is reinforced by pharmacological experiments, which suggest that 7-OH-DMH-CBD displays anti-inflammatory and intestinal-relaxing properties, but does not exert overt psychoactive effects in mice. However, the nature of this hypothetical receptor and its relationship to other cannabinoid-like sites in the vasculature and in the brain hippocampus remains to be determined.Another way to reduce central side effects is to target peripheral CB2 receptors, which are expressed in the brain only during inflammatory states and even then are limited to microglia. Selective CB2 receptor agonists include the compounds AM1241 and HU-308 . Compounds of this type offer a great deal of promise in the treatment of pain and inflammation. Studies conducted on multiple animal models of pain have shown that the CB2-selective agonist AM1241 has robust analgesic effects and is very potent in neuropathic pain models. These effects are maintained in CB1-defificient, but not in CB2-defificient mice.CB1 cannabinoid receptors are present on the cell surface of neurons within the brain reward circuitry. Furthermore, endocannabinoids may be released from dopamine neurons in the ventral tegmental area , and from medium spiny neurons in the nucleus accumbens of the brain reward circuit. Additionally, endocannabinoids and D9 -THC activate CB1 receptors and by doing so regulate reward strength and drug craving. Though we do not know how this occurs, it is likely that these mechanisms extend to all drugs of abuse,hydroponic rack system because collectively these drugs show the propensity to increase VTA dopamine neuron activity, which might be coupled to augmented endocannabinoid production from the dopamine neurons themselves.

Finally, cannabinoid receptor antagonists block the effects of endocannabinoids in these reward circuits. Preclinical work shows that priming injections of cannabinoid agonists reinstate heroin-seeking behavior after a prolonged period of abstinence in rats trained to self-administer heroin. The cannabinoid antagonist rimonabant fully prevents heroin-induced reinstatement of heroin-seeking behavior. Additionally, rimonabant significantly attenuates cannabinoid-induced reinstatement of heroinseeking behavior. All these findings clearly support the hypothesis of a functional interaction between opioid and cannabinoid systems in the neurobiological mechanisms of relapse and might suggest a potential clinical use of cannabinoid antagonists for preventing relapse to heroin abuse. It has also been shown that cannabinoid antagonists can prevent drug reinstatement with cocaine, alcohol, and nicotine. Thus, it seems that the future of cannabinoid antagonists in substance abuse treatment is particularly promising, especially in the clinical setting, where poly drug abuse is exceedingly more common than isolated single-drug abuse.The available data suggest that CB1 antagonism produces relatively mild side effects in people. Yet several potential risks were discussed and three in particular received a great deal of attention. First, the possibility of neuropsychiatric sequelae, such as anhedonia and anxiety: preclinical studies have consistently shown such effects in animals, though they have not yet been observed in the clinic. Second, pain and hyperalgesia, because of the pervasive role played by the endocannabinoid system in the control of pain processing. Last, hypertension, as indicated by the contribution of the endocannabinoids to blood pressure regulation and the pressor effects of rimonabant in animal models of hypertension.The endocannabinoid signaling system differs from classical neurotransmitter systems, picking up where classical neurotransmitters leave off. That is, the activation of receptors initiates a series of chemical events that leads to the release of endocannabinoids from the postsynaptic spine e the final step of which is the enzymatic production and subsequent release of anandamide and/or 2-AG. Once released, the endocannabinoids are then directed to the presynaptic cell and the CB1 receptor responds by inhibiting further release of that cell’s neurotransmitters. The termination of this cascade is accomplished via a transporter that internalizes the endocannabinoids, after which intracellular enzymes such as fatty-acid amide hydrolase break them down. There is a general consensus that endocannabinoids are transported into cells via a facilitated diffusion mechanism. This process may differ both kinetically and pharmacologically from cell to cell. In brain neurons, endocannabinoid transport is blocked by certain agents, which include the compounds AM404, OMDM-8 and AM1172 . However, the pharmacological properties of these drugs in vivo are only partially understood.

Once inside cells, endocannabinoids are hydrolyzed by three principal enzyme systems.Potent and selective FAAH inhibitors have been developed and shown to exert profound antianxiety and antihypertensive effects in animals. The latter effects were discussed at length at the workshop, highlighting the important role of anandamide in two important examples of vascular allostasis e shock and hypertension. In addition to FAAH, another amide hydrolase has been recently characterized, which may participate in the degradation of anandamide and other fatty-acid ethanolamides such as oleoylethanolamine . This amidase prefers acid pH values and has a different tissue distribution than FAAH, being notably high in lung, spleen and inflammatory cells. Inhibitors of this enzyme are being developed. Finally, 2-AG is hydrolyzed by an enzymatic system separate from FAAH, which probably involvesa monoacylglycerol lipase recently cloned from the rat brain. Inhibitors of this enzyme are currently under development.College students often drink alcohol and use drugs simultaneously during parties and other social events . Dual marijuana and alcohol use is especially prevalent, with 47% of marijuana users reporting simultaneous use of alcohol . Furthermore, individuals who have a cannabis use disorder are at increased likelihood for the development of an alcohol use disorder , and rates of substance use disorders and treatment admissions are highest among individuals that use marijuana or alcohol compared to other substances . Approximately 68% of individuals with current CUD and over 86% of those with a history of CUD meet criteria for an AUD. Cannabis dependence doubles the risk for long-term persistent alcohol consequences and dual marijuana and alcohol users consume higher levels of alcohol and experience more alcohol-related consequences than only drinkers . Despite these additional risks, 60% of college students do not perceive regular marijuana use to be harmful .The combination of low perceived risk, policy changes surrounding marijuana legalization, and the rise in marijuana use over the past 10 years heightens the importance of effective interventions for alcohol and marijuana use. In the adult substance use treatment literature, it is relatively well-established that alcohol use negatively impacts treatment of other substances . In contrast, literature examining the impact of marijuana use on the treatment of other substances is mixed. With the exception of a few studies that do not show marijuana use to negatively influence alcohol or smoking cessation outcomes , many studies have demonstrated that using marijuana before or during alcohol treatment is associated with higher levels of drinking at follow-up . For example, among alcohol dependent individuals, those who used marijuana during alcohol treatment reported fewer days abstinent from alcohol one year following treatment than those who did not use marijuana . Thus, marijuana use seems to have a negative impact on alcohol treatment outcomes. A number of studies have also examined secondary changes in marijuana use following receipt of an alcohol-specific intervention. A recent integrative data analysis study indicated that alcohol BMIs may not facilitate changes in marijuana use among college students ; instead, regardless of treatment condition, college students who successfully reduced their drinking at short- and long-term follow-ups were more likely to be non-users of marijuana or reduce their marijuana use at follow-up. This complementary relationship between marijuana and alcohol use is also supported by research indicating that the risk factors for initiation and maintenance of problematic use are similar across substances . Together, these studies suggest that interventions for alcohol may lead to secondary changes in marijuana use. Consistent with this hypothesis, young adults who participated in an in-person BMIs for alcohol use in an emergency department setting reported greater decreases in marijuana use at the 6-month follow-up than those who received feedback only . Similarly, weekly marijuana users who were seeking treatment for cigarette smoking and completed a brief alcohol intervention within the context of the smoking cessation intervention, demonstrated reductions not only in heavy drinking and tobacco smoking but also in marijuana use . In the college setting, BMIs that target multiple substances have also been associated with reductions in poly-drug use . One explanation for the differential influence of alcohol interventions on marijuana use across these studies may be related to the populations examined. Thus far, alcohol interventions delivered to acute-risk populations have had an impact on marijuana use outcomes, while collectively, interventions delivered to ‘college students’ have not.