[DRAFT] The Endocannabinoid System – Ch 1: Substance Use Disorder & The ECS

Introduction

SUD (Substance Use Disorder) is the repeated use of a drug that leads to clinically significant distress, making it a serious public health concern affecting over 30 million victims globally. Prolongated SUD may result in permanent neurological modifications including neuroplastic changes in the brain reward, stress, and executive function systems. Currently, there is no established pharmacotherapy for SUDs and current pharmacotherapies (e.g., opiate substitution with methadone; naltrexone for alcohol use disorder; nicotine replacement) have limited efficacy in relapse prevention. Fortunately, the endocannabinoid system has become a target of interest to treat SUD given its role in common neurobiological processes such as the modulation of the rewarding and motivational effects of substances and substance-related cues. Animal and human studies suggest that cannabis-based medicines (e.g., rimonabant, nabiximols) reduce craving and relapse in abstinent substance users, by impairing reconsolidation of drug-reward memory, the salience of drug cues, and inhibiting the reward-facilitating effect of drugs.

Literature

In a review by the Pharmacy el Toro in Spain, researchers studied the cerebellar morphological changes in cannabis effects both in experimental animals and human subjects and the possible relevance of these changes for addiction. Interestingly, the cerebellum seems to be involved in the effects of addictive drugs and addiction-related processes and also presents a high density of cannabinoid receptors. This cerebellar involvement in addiction-related processes may be partially explained by the connections this area has with other parts of the brain considered as part of the addiction circuitry. This is the case for the ventral tegmental area, striatal zones, prefrontal cortices, amygdala, and hippocampus. It is also noteworthy that the cerebellum presents a high density of cannabinoid receptors, the proteins through which cannabinoids like Δ9-Tetrahydrocannabinol (THC) exert their effects on neural function. A number of investigations have reported cerebellar alterations following repeated cannabis or THC exposure. These changes were found even when marijuana exposure took place at prenatal stages. Withdrawal symptoms caused by THC have also been associated with cerebellar changes, especially in preclinical studies. Importantly, these studies include a demonstration of a reduction of THC withdrawal caused by preventing the activation of signaling pathways within the cerebellum, thereby providing direct evidence for the cerebellar role in THC withdrawal. In addition, neuroimaging studies on cannabis-dependent subjects have demonstrated that the presentation of cannabis-associated cues reliably activates the cerebellum of these subjects.

A review published by the National Institutes of Health in the US explores the nature of cannabis addiction by evaluating the acute changes in DA circuitry associated with cannabis intake in preclinical and clinical studies that provide the basis for the reinforcing effects of cannabis. Pre-clinical and clinical findings reveal that THC administration has reinforcing properties that alter salience processing via increased dopaminergic signaling like other drugs of abuse. In cannabis users, withdrawal symptoms have also been associated with reductions in CB1R availability. Current, treatments for CUD seem to target aspects of binge intoxication, withdrawal-negative effect, and preoccupation-anticipation. Pharmacological treatments for the binge-intoxication stage of cannabis addiction have focused on cannabinoid receptors. One mechanism of action involves the direct antagonism of CB1Rs. CB1R selective antagonists such as rimonabant have been shown to block the subjective intoxicating and tachycardic effects of smoked cannabis. Despite the potential acute benefits, direct antagonism with rimonabant is associated with anxiety and depression. Up to 10% of patients experienced anxiety and depression following the use of rimonabant. On the other hand, therapies targeting specific symptoms of withdrawal (such as anxiety, irritability, sleep disturbances, and decreased appetite) should be administered in conjunction with treatments that target reduction in cannabis use and prevention of relapse. Promising candidates for the treatment of CUD that prevent relapse include naltrexone, gabapentin, and N-acetylcysteine (NAC). The greatest reduction in multiple withdrawal symptoms has been shown with treatment using CB1R agonists such as dronabinol (oral THC), nabixmols (a combination of THC and CBD), and nabilone.

Finally, a review made by the Monash University, the University of Wollongong, and The Australian Centre for Cannabinoid Clinical and Research Excellence in Australia, explore the role of the endocannabinoid system in substance use disorder and the proposed pharmacological action supporting cannabinoid drugs’ therapeutic potential in addictions, with a focus on CBD. Agonist substitution with CB1R agonists may have the potential for the treatment of cannabis use disorder by reducing withdrawal symptoms and the reinforcing effect of cannabis. Dronabinol—a stereoisomer of THC, and Nabilone—a synthetic analog of THC, originally intended for nausea and weight loss, have both been shown to have efficacy for cannabis withdrawal. However, Dronabinol and Nabilone may not prevent cannabis use or relapse. It is likely that while these substances are efficacious in attenuating withdrawal symptoms by acting as a “proxy substance,” they do not directly normalize substance use-related circuits and behavior. Likewise, a number of human case studies suggest nabiximols to be efficacious, in combination with behavioral therapy, in reducing cannabis use and withdrawal symptoms. However, case study evidence should be taken cautiously. Further case-control studies indicate nabiximols to be effective in reducing withdrawal, but not cannabis use. Nor did it improve the abstinence rate. It was noted that while therapeutics may assist in short-term withdrawal, it is unlikely that ongoing abstinence can be achieved without psychosocial or clinical support. Additionally, the THC component of nabiximols causes the drug to have abuse potential and should not be used lightly. Human studies have also been conducted investigating the efficacy of rimonabant in cannabis, nicotine, and alcohol use. Cannabis and nicotine use have both shown sensitivity to rimonabant antagonism. Rimonabant attenuated the acute physiological effects of cannabis including the subjective level of intoxication, and clinical trials demonstrate rimonabant to be effective in increasing smoking cessation. However, the efficacy of rimonabant for alcohol cessation has been less promising. Despite promising findings of rimonabant against substance use and relapse, it has been found to produce significant negative psychiatric effects including depression, anxiety, and an elevated suicide rate, preventing it from being a viable treatment option.

Nevertheless, the evidence indicates CB1R antagonism to have robust effects on some SUDs, highlighting a potential target for SUD treatment. One such candidate drug that antagonizes CB1R, and is increasingly being investigated as a therapeutic option for SUD, is cannabidiol (CBD). CBD is non-rewarding and acts on a number of receptor systems including the opioid, serotonergic, and cannabinoid systems. Indeed, CBD has a good safety profile, with generally mild side effects in animal preclinical studies or human studies. This, coupled with the limited abuse liability of CBD, makes it a good therapeutic candidate. Systemically administered CBD has also been demonstrated to regulate mesolimbic DA activity, and potentially attenuate substance-induced dysregulation of the mesolimbic circuitry, suggesting its utility against SUDs. Though its efficacy may be dependent on a range of factors including the sequence of administration (i.e., whether CBD is administered in conjunction with, prior to, or post-substance-use), and dose ratio.

Limitations

Limitations within the articles include some methodological factors that may have had an influence on the discussed results. In neuroimaging studies, variables such as the number of subjects, their age, IQ scores, socioeconomic status, gender, amount of drug used, total time using the drug, age at which the drug was used for the first time, and duration of abstinence are not comparable in some studies. And the use in some cases pre-clinical studies to further a proof a yet not elucidated mechanism within the endocannabinoid system. 

Conclusions

When discussing the effects of addiction on the Endocannabinoid System there are several factors to take into account. The ECS regulates several processes of addiction making it a prospective candidate for addictive-related symptoms treatments. While early research supports CBD’s promise, further investigation and validation of CBD’s efficacy, across preclinical and clinical trials will be necessary. Indeed, CBD has been found to have therapeutic potential in alleviating affective and cognitive processing disturbances that may be induced by chronic substance (e.g., cannabis) use, proving potential utility in moderating the deleterious course of impairment, particularly in adolescent initiates of substance use. Nonetheless, CBD alone may not be sufficiently effective in maintaining long-term abstinence without ongoing support and behavioral therapy, as evidenced by its lack of efficacy over treatments, such as cognitive-behavioral therapy and motivational enhancement therapy. A combination of pharmacotherapy and behavioral therapy may increase treatment potency and adherence, and CBD may be better suited as an adjunct treatment to primary behavioral or psychosocial therapy. Additionally, other receptor and enzyme functions targeted by CBD, such as cannabinoid CB2Rs, non-cannabinoid transient receptor potential vanilloid type-1 (TRPV1) and type2 (TRPV2) receptors, and ECS’ catabolic enzymes FAAH and MAGL, should also be investigated for their role in the ECS and SUD. Moreover, with CB1R agonists as potential treatments, it is necessary to consider the abuse potential of these drugs. Dronabinol, nabilone, and nabixmols seem to have a lower abuse potential than smoked cannabis.

On the other hand, with a recent increase in the rates of cannabis use disorder (CUD) and a decrease in the perceived risk of cannabis use, it is imperative to assess the addictive potential of cannabis. THC causes tolerance through repeated activation of CB1 receptors. Repeated activation of CB1 receptors initiates events inside the brain cell that at first lead to desensitization, which is the weakening of the response to THC, followed by internalization, which is the removal of CB1 receptors from the cell’s surface. This is the reason why chronic users require more quantities of THC to generate the same level of THC-accompanied effects commonly desired by recreational users. CB1 receptors are like a baseball pitcher who throws a lot of pitches. Eventually, the pitcher’s muscles can’t carry out the task of throwing the ball as hard as it once could. This weakening strength is observed by the coach who then pulls the pitcher out of the game. Similarly, there are proteins in the cell that act like the coach to detect weak receptors and pull them from the game. Interestingly, chronic cannabis use is associated with a downregulation of CB1R – THC’s target receptor – that is restored after 4 weeks of abstinence in humans. Today, many different pharmacological treatments have been investigated for the reduction of cannabis withdrawal symptoms, primarily through modulation of cannabinoid receptors but also through other neurotransmitter systems including glutamate, dopamine, norepinephrine, serotonin, and GABA.

However, with increases in cannabis use and decreases in perceived risk, it is crucial to reconsider the addictive potential of cannabis. Chronic cannabis use is associated with an increased risk of developing SUD; about 9% of those who use cannabis present with characteristic symptoms of dependence according to DSM-IV criteria. Despite cannabis does not present a very pronounced physical withdrawal syndrome, typically, symptoms of cannabis withdrawal occur 1 to 2 days after cessation of heavy use and can last between 7 and 14 days. The most common symptoms observed during cannabis withdrawal include irritability, anxiety, decreased appetite, restlessness, and sleep disturbances.

Chye Y, Christensen E, Solowij N and Yücel M (2019) The Endocannabinoid System and Cannabidiol’s Promise for the Treatment of Substance Use Disorder. Front. Psychiatry 10:63. doi: 10.3389/fpsyt.2019.00063

Moreno-Rius, J. Cerebellum (2019) 18: 593. https://doi.org/10.1007/s12311-018-0993-7

Zehra A, Burns J, Liu CK, et al. Cannabis Addiction and the Brain: a Review. J Neuroimmune Pharmacol. 2018;13(4):438–452. doi:10.1007/s11481-018-9782-9