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Official websites use. Share sensitive information only on official, secure websites. The last decades have seen a major gain in understanding the action of cannabinoids and the endocannabinoid system in reward processing and the development of addictive behavior. Cannabinoids induce their reinforcing properties by an increase in tonic dopamine levels through a cannabinoid type 1 CB 1 receptor—dependent mechanism within the ventral tegmental area. Cues that are conditioned to cannabis smoking can induce drug-seeking responses ie, craving by eliciting phasic dopamine events. In conclusion, pharmacological blockade of endocannabinoid signaling should lead to a reduction in drug craving and subsequently should reduce relapse behavior in addicted individuals. Indeed, there is increasing preclinical evidence that targeting the endocannabinoid system reduces craving and relapse, and allosteric modulators at CB 1 receptors and fatty acid amide hydrolase inhibitors are in clinical development for cannabis use disorder. Cannabidiol, which mainly acts on CB 1 and CB 2 receptors, is currently being tested in patients with alcohol use disorder and opioid use disorder. The endocannabinoid system is comprised of cannabinoid CB 1 and CB 2 receptors and endogenous agonists of these receptors—so-called endocannabinoids—and the processes playing a role in biosynthesis, release, transport, and metabolism of these endogenous lipid-signaling molecules. Endocannabinoids such as anandamide and 2-arachidonylglycerol 2-AG are highly lipophilic compounds that are not stored in vesicles after production. After their release on demand from depolarized postsynaptic neurons, endocannabinoids act retrogradely, activating CB 1 receptors on presynaptic terminals, leading to either transient endocannabinoid-mediated short-term depression or long-term depression LTD of synaptic transmission. This powerful modulatory action on synaptic transmission of the main transmitter systems has significant functional implications on many physiological functions including reward processing. The last decades have seen a major gain in understanding the involvement of the endocannabinoid system in reward processing and development of addictive behavior. More than million people regularly consume cannabis products, and this nonmedical cannabis use is associated with a high health burden. Here, I will summarize our knowledge of the interaction of the endocannabinoid system with the reward system, then focus on the addictive properties of cannabis products and synthetic cannabinoids and the development of CUD, and finally discuss the potential use of cannabinoid drugs for the treatment of addictive behavior. The distribution of these receptors within the central nervous system and periphery correlates with its role in the control of motor function, cognition and memory, appetite, immune function, sleep, stress response, thermoregulation, analgesia, and reward processing. The CB 1 receptor, which is one of the most abundant G-protein-coupled receptors GPCRs in the brain, is highly expressed in the basal ganglia nuclei, hippocampus, cortex, and cerebellum. The CB 2 receptor is abundantly expressed in peripheral organs with immune function, including macrophages, spleen, tonsils, thymus, and leukocytes, as well as the lung and testes. The crystal structures of the cannabinoid receptors have recently been revealed, providing further insight into complex ligand-receptor interactions. The endocannabinoid system participates in natural and drug reward through interaction with the dopaminergic reward system. The reward pathway originates in the ventral tegmental area VTA and A10 dopamine neurons mainly project to the nucleus accumbens NAc where dopamine is released in response to rewards. Cannabinoids increase both tonic dopamine levels by an increase in the firing rate of dopamine A10 neurons 25 , 26 as well as phasic dopamine events through a CB 1 -receptor—dependent mechanism within the VTA. Peters et al 28 , 29 propose the following disinhibition mechanism: similar to a mechanism described for opioids, 30 cannabinoids act via GABAergic interneurons within the VTA to disinhibit dopamine neurons. Drug-conditioned cues, eg, cues that are conditioned to cannabis smoking, increase phasic dopamine events through a CB 1 -receptor—dependent mechanism within the VTA. This GABA suppression results in disinhibition of dopamine neurons, which further promotes their phasic firing activity Figure 1. Disrupting endocannabinoid signaling within the VTA thus reduces these cue-evoked phasic dopamine responses and therefore interrupts reward-seeking behavior. Endocannabinoids not only act on the level of dopamine cell bodies within the VTA to interfere with primary and secondary reinforcement processes, but also on projection sites within the NAc. This interaction involves medium spiny neurons MSNs and prefrontal glutamate afferents, especially glutamate release at the prelimbic cortex—NAc synapses. The disinhibition mechanism within the VTA and the endocannabinoid-based mechanism within D1-MSNs provide the rationale that blockade of CB 1 receptors should lead to a reduction in drug-induced increases in tonic dopamine levels, drug-cue—associated phasic firing, and of 2-AG—dependent LTD within the NAc ie, mechanism-based intervention. As a consequence of these neurochemical and physiological events, drug-seeking behavior craving , drug memories, and subsequent relapse should be reduced. In the next paragraphs, interventions based on the disruption of endocannabinoid signaling and the consequences on addictive behavior are described. Cannabis is the most commonly used illegal drug in Europe. New forms of highly potent cannabis have been developed in recent years due to advances in cultivation, extraction, and production techniques. Hybrid multistem plants that provide high-potency cannabis have started to replace established forms of the plant in both Europe and Morocco, where much of the cannabis resin used in Europe comes from. Similar trends in cannabis potency have been observed in the United States over the last two decades. Most worry is due to the increased abuse of synthetic cannabinoids. In Europe, about 15 years ago, this problem mainly started with the use of spice products. However, withdrawal phenomena such as inner unrest, profuse sweating, and tremor, and a dependence syndrome after the consumption of spice products were soon described, 47 and when the admixture of the synthetic cannabinoid substances JWH and CP were found, it became clear that spice can be a dangerous product. They can lead to severe intoxication and death, disrupt neurodevelopmental processes, induce psychotic behavior, and lead to a rapid onset of CUD. As outlined in the previous chapter, we have a good understanding of the molecular interactions of cannabinoids with the reward system and can therefore provide mechanism-based interventions for CUD. Panlilio and Justinova 54 have recently provided an excellent summary of preclinical studies for pharmacological treatment development for CUD, and Sloan et al 55 have summarized the experimental clinical studies and randomized clinical trials RCTs for CUD. I will reflect on these two reviews and discuss the most recent RCTs and developments in terms of behavioral and neuromodulatory interventions. One approach is substitution therapy with dronabinol, which is an approved drug for other indications AIDS-induced anorexia, chemotherapy-induced nausea and vomiting. Although substitution therapy is a great success for opioid-use disorder, dronabinol substitution has not yielded promising results. CUD patients usually have no immediate or dramatic socioeconomic or psychosocial problems, which are often seen with cocaine, heroin, or alcohol dependence. Consequences of use are often long term and more subtle. Clearly, low motivation to quit in CUD patients applies to any other intervention and is thus an inherent problem for treatment. An alternative approach to substitution therapy is the blockade of the CB 1 receptor by antagonists, inverse agonists, or allosteric modulators. The application of rimonabant is the classic approach for a CB 1 -receptor blockade. Despite having an atomistic framework of CB 1 -receptor—ligand interactions, 14 - 17 the molecular mode of action of rimonabant is still not fully understood—at high micromolar concentrations, rimonabant behaves as an inverse agonist at CB 1 receptors. This inverse agonistic effect probably results from an off-target effect, namely by a direct inhibition of G-protein signaling. One promising approach goes along with the recent discovery in preclinical studies that the hormone pregnenolone acts as an allosteric CB 1 -receptor inhibitor and in doing so markedly reduces the effects of cannabis-like drugs. Importantly, the allosteric modulator AEF produces none of the problems associated with rimonabant, ie, precipitated withdrawal and mood-related side effects. A case report shows that CBD reduced self-reported cannabis use; however, in a human laboratory study, oral CBD did not reduce the reinforcing or positive subjective effects of smoked cannabis. Another possible pharmacological intervention is the use of fatty acid amide hydrolase FAAH inhibitors. FAAH is the principal catabolic enzyme of endogenous cannabinoids. In a recently published RCT, treatment with the novel FAAH inhibitor PF reduced symptoms of cannabis withdrawal and also reduced self-reported cannabis use at 4 weeks of treatment with no serious adverse events. This is notable, as the safety of FAAH inhibitors was questioned after the observation of very severe neurological deficits after trial treatment with BIA , an orally administered reversible FAAH inhibitor given to healthy volunteers in a phase 1 study designed to assess safety. Indeed, the promising finding with PF is currently being followed up by a well-powered multsite RCT, and results are expected by end of ClinicalTrials. Other approaches refer to behavioral therapies and neuromodulatory intervention strategies. It is recognized that biases in cognitive processing of drug-related stimuli are central to the development and maintenance of addiction. In a recent proof-of-principle laboratory experiment, a four-session computerized approach-bias-modification training protocol led to blunted cannabis-cue—induced craving at the end of training, as well as to reduced cannabis use. Neuromodulation via neurofeedback approaches 68 — currently discussed as a useful add-on tool in the management of AUD to enhance the cognitive abilities required to maintain abstinence—or repetitive transcranial magnetic stimulation rTMS may further offer a treatment alternative. A preliminary study in a few CUD patients showed that 20 sessions of rTMS targeting the left dorsolateral prefrontal cortex reduced craving and cannabis use in a 4-week follow-up period. In summary, several promising treatment approaches targeting the endocannabinoid system—especially allosteric modulators at CB 1 receptors and FAAH inhibitors—are in clinical development for CUD. In combination with behavioral and neuromodulatory approaches and psychosocial support, these pharmacological interventions might provide useful therapies in the near future. As already described, disrupting endocannabinoid signaling reduces cue-evoked phasic dopamine responses within the reward pathway and thereby blocks drug memories and reward-seeking behavior ie, craving. As a result, relapse behavior should be reduced as well. Rimonabant was a very promising candidate as a smoking cessation therapy. Convincing preclinical evidence was obtained that rimonabant can reduce conditioned place preference, nicotine self-administration, and cue-induced reinstatement behavior. Nevertheless, rimonabant provides the clinical proof of principle that pharmacological interventions, being it by neutral antagonists or by allosteric modulators at the CB 1 receptor are a promising target for the treatment of nicotine-dependent patients, especially in patients for whom smoking-cessation—induced weight gain is a deterrent to quit smoking and enter a treatment program. Rimonabant did not produce a significant reduction in relapse rate in an RCT of alcohol-dependent patients, 71 and approved pharmacological treatments for AUD are limited in their effectiveness. New drugs that can easily be introduced into the clinic are needed. Thus, a recent systematic review of preclinical studies shows that CBD attenuates cue-elicited and stress-elicited alcohol seeking, alcohol self-administration, withdrawal-induced convulsions, and impulsive discounting of delayed rewards in rodents. Chye et al 73 recently summarized all preclinical evidence on CBD in withdrawal, reward facilitation, self-administration, and reinstatement paradigms and provided a quite convincing profile of CBD for further clinical development for nicotine and opioid use disorders; however, the very few studies conducted so far in humans generated mixed results. Acute CBD administration, in contrast to placebo, significantly reduced cue-induced craving, and long-lasting beneficial effects on craving were also reported. Finally, recent findings revealing a role of CB 2 receptors in mediating the addictive properties of several drug classes have also opened up a promising new avenue for the clinical development of novel therapeutic approaches, including CB 2 -receptor allosteric modulators. The last decades have seen a major gain in understanding of the action of cannabinoids and the endocannabinoid system in reward processing and the development of addictive behavior. Unfortunately, the interest of major pharmaceutical industries for clinical development of new compounds targeting the endocannabinoid system has been severely dampened by the worldwide withdrawal of the already approved antiobesity medication rimonabant Acomplia due to serious psychiatric side effects. Therefore, only small biotechnology companies and academic-driven clinical developments will further drive medication development. In contrast to these slowly ongoing future medication developments, massive investments are being made in medical cannabis products including CBD. However, whether substitution therapy with medical cannabis—as proposed for CUD—is a promising approach is questionable. The same is true of CBD; it has a good safety profile, but preclinical and clinical evidence is mixed, and only large RCTs, especially in alcohol and opioid addiction, will give us conclusive insights into its effectiveness. A caveat for all these drug development efforts is that the endocannabinoid system does not only mediate primary and secondary reinforcing properties for drugs of abuse but is itself involved in reward processing. Therefore, any interference with this system may not only block craving and relapse for a given drug but may also interfere with any natural reward, such as eating, libido, social rewards, and many other rewards that drive our daily activities. As a library, NLM provides access to scientific literature. Dialogues Clin Neurosci. Show available content in en es fr. Find articles by Rainer Spanagel. Issue date Sep. All rights reserved. Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.

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He explained that there are several factors that affect the acquisition, sale and distribution of drugs that occurs in Mexico and that should be taken into account. On the other hand Health Commission President Miguel Angel Navarro has said that the Senate will have the legal framework for the recreational use of marijuana ready by Oct. Marijuana in America In Latin America at least seven countries have approved marijuana for medicinal purposes, and only one, Uruguay, legalized its use for recreational purposes, making it the first country in the world to do so. On Sept. In Puerto Rico, medical marijuana is also authorized. In Mexico, the recreational use of marijuana continues to be illegal despite the fact that in the Supreme Court of Justice of the Nation authorized the use and cultivation of marijuana for self-consumption and recreational purposes to four people who requested it. In Brazil, the Drug Law punishes the possession and consumption of drugs. Since , the Supreme Court of Brazil has been discussing the decriminalization of the carrying and personal consumption of illicit substances, but so far it has not reached a conclusion. That is to say, the substances of the plant are authorized, but not the plant itself. In Costa Rica cannabis is a substance prohibited by law, and although it penalizes its production, distribution and sale, it does not consider its use as a crime, but as a public health problem, as a disease that needs treatment and rehabilitation, according to the National Survey of Drug Consumption of the Institute of Drugs and Drug Dependence of Costa Rica, published in Other countries After Uruguay, Canada was the second country in the world, and the first country of the G7, to legalize marijuana for recreational purposes. With this legislation, adults will be able to carry and share up to 30 grams of legal marijuana in public. They will also be able to grow up to four plants in their homes and prepare products such as those that can be eaten for personal use. Consumers buy marijuana from retailers regulated by provinces, territories or, when none of these options is available, federally licensed producers. Marijuana also will not be sold in the same place as alcohol or tobacco. Meanwhile, eleven states in the United States and the District of Columbia now allow recreational use of marijuana. Medical marijuana is legal in some form in 30 states, according to the National Conference of State Legislatures. Anyone over the age of 21 can buy medical marijuana in Colorado, Washington, Oregon and Alaska. The revenues from those sales are equivalent to the entire candy industry. Portugal pioneered drug reform laws, decriminalizing possession of all drugs, not just cannabis, for personal use in As a result, the country has the most evidence about the impact and change it can have on drug policy in the country. Ireland, Australia, Jamaica and Germany approved measures in for medical use, while Australia also granted companies permission to apply for licenses to manufacture or grow marijuana products for medical purposes and to conduct related research. High courts in South Africa and Georgia also overturned bans on cannabis, legalizing the plant for individual use, a nd on medicinal cannabis, Sri Lanka, Thailand and the United Kingdom approved the use of the plant in In late November, Luxembourg, the small European nation, announced that marijuana would soon be legalized for recreational use by adults. The Yucatan Times Newsroom. This website uses cookies to improve your experience. We'll assume you're ok with this, but you can opt-out if you wish. Lorem ipsum dolor sit amet, consect etur adipiscing elit. Ut elit tellus, luctus nec ullamcorper mattis. News Yucatan Merida Campeche Q. Tuesday, September 24, Merida to host record numbers of meetings, conventions, and exhibitions in Artisans and merchants in Chichen Itza complain about the lack of Gertz Manero will continue to be the head of the FGR, After two years of absence, a new case of leprosy is Helene expected to rapidly intensify and make landfall in Florida as Home Feature Legal marijuana: the countries in the Americas that have legalized cannabis and those that have not. Feature Headlines National News. Photo: Okdiario. Share 0 Facebook Twitter Pinterest Email. Yucatan Times. AMLO states that in Yucatan the police forces are not dominated by crime. You may also like. Merida to host record numbers of meetings, conventions, and exhibitions in September 24, Artisans and merchants in Chichen Itza complain about the lack of sales this year September 24, After two years of absence, a new case of leprosy is detected Yucatan September 24, Our Company. About Links. Useful Links. Laest News. After two years of absence, a new case of leprosy is detected Yucatan. Facebook Twitter Instagram Youtube Tiktok.

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