Cannabinoids as Potential Molecules for Addiction Disorders

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“Addictions are a group of chronic and recurrent diseases of the brain characterized by a pathological search for reward or relief through the use of a substance or other action. This situation implies an inability to control behavior, difficulty in permanent abstinence, a compelling desire to consume, decreased recognition of significant problems caused by behavior and interpersonal relationships, and a dysfunctional emotional response. The result is a decrease in the quality of life of the affected person, generating problems in their work, academic activities, social relationships, or family or partner relationships. Unfortunately, there are not enough pharmacotherapeutic solutions to treat addictions due to the complexity of their physiopathology and signaling pathways. Therefore, it is an imperative search for new pharmacological alternatives which may be used for this purpose.

This review summarizes the main recent findings of the potential therapeutic effects of different cannabinoids on treating several addictions, including alcohol, opioids, methamphetamine, cocaine, and nicotine use disorders.

Highlights Standpoints: It has been demonstrated that many phyto, synthetic, and endogenous cannabinoids may act as therapeutic molecules in this psychiatric pathology through their action on multiple cannabinoid receptors. To highlight, cannabinoid receptors, types 1 and 2 (CB1 and CB2) have a crucial role in modulating the anti-addictive properties of these compounds.”

Adherence, Safety, and Effectiveness of Medical Cannabis and Epidemiological Characteristics of the Patient Population: A Prospective Study

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“Background: Despite the absence of rigorous prospective studies, there has been an increase in the use of cannabis-based medicinal products. During the study period, the use of medical cannabis in Israel was tightly regulated by national policy. Through a prospective study of approximately 10,000 patients, we aimed to characterize the medical cannabis patient population as well as to identify treatment adherence, safety, and effectiveness.

Methods and findings: In this study of prescribed medical cannabis patients, adherence, safety, and effectiveness were assessed at 6 months. Treatment adherence was assessed by the proportion of patients purchasing the medication out of the total number of patients (excluding deceased cases and patients transferred to another cannabis clinic). Safety was assessed by the frequency of the side-effects, while effectiveness was defined as at least moderate improvement in the patient condition without treatment cessation or serious side-effects. The most frequent primary indications requiring therapy were cancer (49.1%), followed by non-specific pain (29.3%). The average age was 54.6 ± 20.9 years, 51.1% males; 30.2% of the patients reported prior experience with cannabis. During the study follow-up, 1,938 patients died (19.4%) and 1,735 stopped treatment (17.3%). Common side-effects, reported by 1,675 patients (34.2%), were: dizziness (8.2%), dry mouth (6.7%), increased appetite (4.7%), sleepiness (4.4%), and psychoactive effect (4.3%). Overall, 70.6% patients had treatment success at 6 months. Multivariable logistic regression analysis revealed that the following factors were associated with treatment success: cigarette smoking, prior experience with cannabis, active driving, working, and a young age. The main limitation of this study was the lack of data on safety and effectiveness of the treatment for patients who refused to undergo medical assessment even at baseline or died within the first 6 months.

Conclusions: We observed that supervised medical-cannabis treatment is associated with high adherence, improvement in quality of life, and a decrease in pain level with a low incidence of serious adverse events.”

“This is a large study describing certain characteristics of medical cannabis users in a tightly regulated environment. The treatment appears to be safe and efficacious.”

Opioid-sparing effect of cannabinoids for analgesia: an updated systematic review and meta-analysis of preclinical and clinical studies

“Cannabinoid co-administration may enable reduced opioid doses for analgesia. This updated systematic review on the opioid-sparing effects of cannabinoids considered preclinical and clinical studies where the outcome was analgesia or opioid dose requirements. We searched Scopus, Cochrane Central Registry of Controlled Trials, Medline, and Embase (2016 onwards). Ninety-two studies met the search criteria including 15 ongoing trials. Meta-analysis of seven preclinical studies found the median effective dose (ED50) of morphine administered with delta-9-tetrahydrocannabinol was 3.5 times lower (95% CI 2.04, 6.03) than the ED50 of morphine alone. Six preclinical studies found no evidence of increased opioid abuse liability with cannabinoid administration. Of five healthy-volunteer experimental pain studies, two found increased pain, two found decreased pain and one found reduced pain bothersomeness with cannabinoid administration; three demonstrated that cannabinoid co-administration may increase opioid abuse liability. Three randomized controlled trials (RCTs) found no evidence of opioid-sparing effects of cannabinoids in acute pain. Meta-analysis of four RCTs in patients with cancer pain found no effect of cannabinoid administration on opioid dose (mean difference -3.8 mg, 95% CI -10.97, 3.37) or percentage change in pain scores (mean difference 1.84, 95% CI -2.05, 5.72); five studies found more adverse events with cannabinoids compared with placebo (risk ratio 1.13, 95% CI 1.03, 1.24). Of five controlled chronic non-cancer pain trials; one low-quality study with no control arm, and one single-dose study reported reduced pain scores with cannabinoids. Three RCTs found no treatment effect of dronabinol. Meta-analyses of observational studies found 39% reported opioid cessation (95% CI 0.15, 0.64, I2 95.5%, eight studies), and 85% reported reduction (95% CI 0.64, 0.99, I2 92.8%, seven studies). In summary, preclinical and observational studies demonstrate the potential opioid-sparing effects of cannabinoids in the context of analgesia, in contrast to higher-quality RCTs that did not provide evidence of opioid-sparing effects.”

Recreational cannabis legalizations associated with reductions in prescription drug utilization among Medicaid enrollees

“The potential substitution of cannabis for prescription medication has attracted a substantial amount of attention within the context of medical cannabis laws (MCLs). However, much less is known about the association between recreational cannabis laws (RCLs) and prescription drug use. With recent evidence supporting substitution of cannabis for prescription drugs following MCLs, it is reasonable to ask what effect RCLs may have on those outcomes. We use quarterly data for all Medicaid prescriptions from 2011 to 2019 to investigate the effect of state-level RCLs on prescription drug utilization. We estimate this effect with a series of two-way fixed effects event study models. We find significant reductions in the volume of prescriptions within the drug classes that align with the medical indications for pain, depression, anxiety, sleep, psychosis, and seizures. Our results suggest substitution away from prescription drugs and potential cost savings for state Medicaid programs.”

[Cannabinoids reduce opioid use in older patients with pain : Retrospective three-year analysis of data from a general practice]

“Background: Relevant data for the prescription and therapeutic effects of medical cannabinoids (CAM) are still missing in everyday medicine especially for elderly and geriatric patients.

Aim of the study: Documentation of prescription (duration, age) of CAM (dronabinol, nabiximols, cannabinoid extracts) and co-medicated opioids in a doctor’s office specializing in pain.

Methods: Analysis of the consumption of opioids (morphine equivalent) and CAM (THC equivalent) for age and gender.

Results: In all, 178 patients with chronic pain were treated for a period of 366 days (median; range 31-2590 days). Median age was 72 years (26-96 years); 115 were women (64.8%). Of these, 34 were younger than 65 years, 42 were 65-80 years and 40 were more than 80 years old. Of the 63 men, 29 were younger than 65 years, 24 were 65-80 years and 10 were older than 80 years. Indications for CAM were chronic pain and the limitations for opioids because of side effects and worsening of quality of life. To total of 1001 CAM were prescribed, 557 (55.6%) dronabinol as liquid, 328 (32.7%) as full spectrum extracts and 66 (6.6%) as oro-mucosal nabiximols spray. 50 prescriptions (5%) contained more than one CAM simultaneously. The daily consumption of dronabinol liquor and extracts were 9.6 mg/day (median), and of spray 13.6 mg. The dosage over time did not change in patients older than 64; in younger patients, there was a non-significant increasing trend. Women requested lower THC dosages compared to men (8.1 mg vs. 14.8 mg). Furthermore, 10 patients (5.6%) stopped CAM because of failing effectivity, 7 (3.9%) because of failing cost coverage and only 5 because of adverse side effects. 115 patients (65%) with CAM also received opioids a median 65 mg/day morphine equivalents. This opioid dosage was significantly reduced in course of time by 24 mg/day morphine equivalents or 50%. This reduction was independent on CAM dosage, age and gender.

Discussion: Patients with chronic pain profit from long-term CAM which safely and significantly lower the consumption of comedicated opioids, even at low dosages (< 7.5 mg/day). For women, low-dose THC may be sufficient. Older patients benefit from CAM, and adverse effects do not limit the (chronic) use and prescription of CAM in the elderly.”

Hepatic Cannabinoid Signaling in the Regulation of Alcohol-Associated Liver Disease

Logo of arcr“Purpose: The endocannabinoid system has emerged as a key regulatory signaling pathway in the pathophysiology of alcohol-associated liver disease (ALD). More than 30 years of research have established different roles of endocannabinoids and their receptors in various aspects of liver diseases, such as steatosis, inflammation, and fibrosis. However, pharmacological applications of the endocannabinoid system for the treatment of ALD have not been successful because of psychoactive side effects, despite some beneficial effects. Thus, a more delicate and detailed elucidation of the mechanism linking the endocannabinoid system and ALD may be of paramount significance in efforts to apply the system to the treatment of ALD.

Search results: According to the inclusion and exclusion criteria, the authors selected 47 eligible full-text articles out of 2,691 searched initially. Studies in the past 3 decades revealed the opposite effects of cannabinoid receptors CB1R and CB2R on steatosis, inflammation, and fibrosis in ALD.

Discussion and conclusions: This review summarizes the endocannabinoid signaling in the general physiology of the liver, the pathogenesis of ALD, and some of the potential therapeutic implications of cannabinoid-based treatments for ALD.”

“Over the past 30 years, it has been found that the endocannabinoid system is involved in a variety of pathways associated with the onset, or the progression, of several diseases, including ALD. The endocannabinoid system has been observed in both the hepatocytes and various nonparenchymal cells in the liver, in which the endocannabinoid production and its receptor activation may contribute to the development of a spectrum of ALD, ranging from simple alcoholic steatosis to more severe forms such as steatohepatitis and fibrosis. Therefore, understanding the precise physiology of the endocannabinoid system in the liver and unveiling the mechanism underlying the association between ALD progression and hepatic endocannabinoid signaling seem to bear a paramount significance for the advancement of ALD treatment, as well as for the treatment of other chronic liver diseases (e.g., NAFLD, viral hepatitis). Moreover, developing efficacious and highly selective cannabinoid receptor–modulating drugs could be a major breakthrough in the treatment of ALD.”

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Green Hope: Perspectives on Cannabis from People who Use Opioids

Sociological Inquiry“While states are implementing policies to legalize cannabis for medical or recreational purposes, it remains a Schedule 1 controlled substance with no medical uses according to US federal law. The perception of cannabis depends on social and cultural norms that impact political institutions involved in implementing policy. Because of negative social constructions, such as the “gateway hypothesis,” legalization of cannabis has been slow and contentious.

Recent studies suggest that cannabis can help combat the opioid epidemic.

This paper fills a gap in our understanding of how cannabis is viewed by people who are actively misusing opioids and not in treatment. Using ethnographic methods to recruit participants living in a state that legalized cannabis and a state where cannabis was illegal, survey and interview data were analyzed informed by a social constructionist lens.

Findings from their “insider perspective” suggest that for some people struggling with problematic opioid use, cannabis can be beneficial.”

The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases

ijms-logo“The Endocannabinoid System (ECS) is primarily responsible for maintaining homeostasis, a balance in internal environment (temperature, mood, and immune system) and energy input and output in living, biological systems.

In addition to regulating physiological processes, the ECS directly influences anxiety, feeding behaviour/appetite, emotional behaviour, depression, nervous functions, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre-and post-natal development.

The ECS is also involved in several pathophysiological diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases. In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development.

The distribution of the components of the ECS system throughout the body, and the physiological/pathophysiological role of the ECS-signalling pathways in many diseases, all offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based therapeutic drugs that genetically or pharmacologically modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS that may be beneficial in the treatment of a number of diseases.

This manuscript in-depth review will investigate the potential of the ECS in the treatment of various diseases, and to put forth the suggestion that many of these secondary metabolites of Cannabis sativa L. (hereafter referred to as “C. sativa L.” or “medical cannabis”), may also have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases.”

Association Between Smoking Cannabis and Quitting Cigarettes in a Large American Cancer Society Cohort

Cancer Epidemiology, Biomarkers & Prevention“Background: Cannabis use is increasing, including among smokers, an at-risk population for cancer. Research is equivocal on whether using cannabis inhibits quitting cigarettes. The current longitudinal study investigated associations between smoking cannabis and subsequently quitting cigarettes.

Results: Adjusted cigarette quitting rates at follow-up did not differ significantly by baseline cannabis smoking status [never 36.2%, 95% confidence interval (CI), 34.5%-37.8%; former 34.1%, CI, 31.4%-37.0%; recent 33.6%, CI, 30.1%-37.3%], nor by frequency of cannabis smoking (low 31.4%, CI, 25.6%-37.3%; moderate 36.7%, CI, 30.7%-42.3%; high 34.4%, CI, 28.3%-40.2%) among recent baseline cannabis smokers. In cross-sectional analyses conducted at follow-up the proportion of cigarette smokers intending to quit smoking cigarettes in the next 30 days did not differ by cannabis smoking status (p=0.83).

Conclusions: Results do not support the hypothesis that cannabis smoking inhibits quitting cigarette smoking among adults.”

“Results do not support the hypothesis that cannabis smoking inhibits quitting cigarette smoking among adults.”

A Survey on the Effect That Medical Cannabis Has on Prescription Opioid Medication Usage for the Treatment of Chronic Pain at Three Medical Cannabis Practice Sites

Cureus | LinkedIn“Objective: The opioid epidemic continues to claim thousands of lives every year without an effective strategy useful in mitigating mortality. The use of medical cannabis has been proposed as a potential strategy to decrease opioid usage. The objective of this study was to determine how the use of medical cannabis affects prescribed opioid usage in chronic pain patients.

Methods: We conducted an online convenience sample survey of patients from three medical cannabis practice sites who had reported using opioids. A total of 1181 patients responded, 656 were excluded for not using medical cannabis in combination with opioid use or not meeting the definition of chronic pain, leaving 525 patients who had used prescription opioid medications continuously for at least three months to treat chronic pain and were using medical cannabis in combination with their prescribed opioid use.

Results: Overall, 40.4% (n=204) reported that they stopped all opioids, 45.2% (n=228) reported some decrease in their opioid usage, 13.3% (n=67) reported no change in opioid usage, and 1.1% (n=6) reported an increase in opioid usage. The majority (65.3%, n=299) reported that they sustained the opioid change for over a year. Almost half (48.2%, n=241) reported a 40-100% decrease in pain while 8.6% (n=43) had no change in pain and 2.6% (n=13) had worsening pain. The majority reported improved ability to function (80.0%, n=420) and improved quality of life (87.0%, n=457) with medical cannabis. The majority (62.8%, n=323) did not want to take opioids in the future. While the change in pain level was not affected by age and gender, the younger age group had improved ability to function compared with the middle and older age groups.

Conclusions: Patients in this study reported that cannabis was a useful adjunct and substitute for prescription opioids in treating their chronic pain and had the added benefit of improving the ability to function and quality of life.”

“Our results show a remarkable percentage of patients both reporting complete cessation of opioids and decreasing opioid usage by the addition of medical cannabis, with results lasting for over a year for the majority. Additional benefits of medical cannabis included improved ability to function and improved quality of life, especially for the younger age group. We believe our results lend further support that medical cannabis provided in a standardized protocol can lead to decreased pain and opioid usage, improved function, and quality of life measures, and even complete cessation of opioids in patients with chronic pain treated by opioids.”