Unique treatment potential of cannabidiol for the prevention of relapse to drug use: preclinical proof of principle

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“Cannabidiol (CBD), the major non-psychoactive constituent of Cannabis sativa, has received attention for therapeutic potential in treating neurologic and psychiatric disorders.

Recently, CBD has also been explored for potential in treating drug addiction. Substance use disorders are chronically relapsing conditions and relapse risk persists for multiple reasons including craving induced by drug contexts, susceptibility to stress, elevated anxiety, and impaired impulse control. Here, we evaluated the “anti-relapse” potential of a transdermal CBD preparation in animal models of drug seeking, anxiety and impulsivity.

Rats with alcohol or cocaine self-administration histories received transdermal CBD at 24 h intervals for 7 days and were tested for context and stress-induced reinstatement, as well as experimental anxiety on the elevated plus maze. Effects on impulsive behavior were established using a delay-discounting task following recovery from a 7-day dependence-inducing alcohol intoxication regimen.

CBD attenuated context-induced and stress-induced drug seeking without tolerance, sedative effects, or interference with normal motivated behavior. Following treatment termination, reinstatement remained attenuated up to ≈5 months although plasma and brain CBD levels remained detectable only for 3 days. CBD also reduced experimental anxiety and prevented the development of high impulsivity in rats with an alcohol dependence history.

The results provide proof of principle supporting potential of CBD in relapse prevention along two dimensions CBD: beneficial actions across several vulnerability states, and long-lasting effects with only brief treatment. The findings also inform the ongoing medical marijuana debate concerning medical benefits of non-psychoactive cannabinoids and their promise for development and use as therapeutics.”

https://www.nature.com/articles/s41386-018-0050-8

“Non-psychoactive cannabis ingredient could help addicts stay clean. Preclinical study using rats shows that Cannabidiol can reduce the risk of relapse”  https://www.sciencedaily.com/releases/2018/03/180323104821.htm

“Non-psychoactive cannabis ingredient could reduce risk of relapse among recovering addicts. A preclinical study in rats has shown that there might be value in using a non-psychoactive and non-addictive ingredient of the Cannabis sativa plant to reduce the risk of relapse among recovering drug and alcohol addicts.”  https://www.news-medical.net/news/20180323/Non-psychoactive-cannabis-ingredient-could-reduce-risk-of-relapse-among-recovering-addicts.aspx

“Non-psychoactive cannabis ingredient could help addicts stay clean”  https://www.springer.com/gp/about-springer/media/research-news/all-english-research-news/non-psychoactive-cannabis-ingredient-could-help-addicts-stay-clean/15548156

“Non-psychoactive cannabinoid may enable drug addiction recovery”  https://www.drugabuse.gov/news-events/news-releases/2018/03/non-psychoactive-cannabinoid-may-enable-drug-addiction-recovery

Medical marijuana laws and adolescent marijuana use in the United States: A systematic review and meta‐analysis

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“Synthesis of the current evidence does not support the hypothesis that US medical marijuana laws (MMLs) until 2014 have led to increases in adolescent marijuana use prevalence. None of the 11 studies found significant estimates of pre–post MML changes compared with contemporaneous changes in non‐MML states for marijuana use prevalence among adolescents. In summary, current evidence does not support the hypothesis that MML passage is associated with increased marijuana use prevalence among adolescents in states that have passed such laws up until 2014.”  https://onlinelibrary.wiley.com/doi/full/10.1111/add.14136

“Medical Marijuana Hasn’t Affected Teen Pot Use: Meta-Analysis. Medical marijuana laws have had little impact on recreational pot use among U.S. teens, according to a meta-analysis of 11 studies dating back to 1991. The findings appear to debunk claims by opponents of medical marijuana that the laws have led to greater cannabis use among adolescents, wrote researcher Deborah Hasin, PhD, of Columbia University’s Mailman School of Public Health, New York City, and colleagues in the journal Addiction.”  https://www.medpagetoday.com/psychiatry/addictions/71342

Medical marijuana laws and adolescent marijuana use in the United States: A systematic review and meta-analysis.

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“To conduct a systematic review and meta-analysis of studies in order to estimate the effect of US medical marijuana laws (MMLs) on past-month marijuana use prevalence among adolescents.

METHODS:

A total of 2999 papers from 17 literature sources were screened systematically. Eleven studies, developed from four ongoing large national surveys, were meta-analyzed. Estimates of MML effects on any past-month marijuana use prevalence from included studies were obtained from comparisons of pre-post MML changes in MML states to changes in non-MML states over comparable time-periods. These estimates were standardized and entered into a meta-analysis model with fixed-effects for each study. Heterogeneity among the study estimates by national data survey was tested with an omnibus F-test. Estimates of effects on additional marijuana outcomes, of MML provisions (e.g. dispensaries) and among demographic subgroups were abstracted and summarized. Key methodological and modeling characteristics were also described. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed.

RESULTS:

None of the 11 studies found significant estimates of pre-post MML changes compared with contemporaneous changes in non-MML states for marijuana use prevalence among adolescents. The meta-analysis yielded a non-significant pooled estimate (standardized mean difference) of -0.003 (95% confidence interval = -0.012, +0.007). Four studies compared MML with non-MML states on pre-MML differences and all found higher rates of past-month marijuana use in MML states pre-MML passage. Additional tests of specific MML provisions, of MML effects on additional marijuana outcomes and among subgroups generally yielded non-significant results, although limited heterogeneity may warrant further study.

CONCLUSIONS:

Synthesis of the current evidence does not support the hypothesis that US medical marijuana laws (MMLs) until 2014 have led to increases in adolescent marijuana use prevalence. Limited heterogeneity exists among estimates of effects of MMLs on other patterns of marijuana use, of effects within particular population subgroups and of effects of specific MML provisions.”

https://www.ncbi.nlm.nih.gov/pubmed/29468763

Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability.

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“Cannabinoids combined with opioids produce synergistic antinociceptive effects, decreasing the lowest effective antinociceptive opioid dose (i.e., opioid-sparing effects) in laboratory animals.

Although pain patients report greater analgesia when cannabis is used with opioids, no placebo-controlled studies have assessed the direct effects of opioids combined with cannabis in humans or the impact of the combination on abuse liability.

This double-blind, placebo-controlled, within-subject study determined if cannabis enhances the analgesic effects of low dose oxycodone using a validated experimental model of pain and its effects on abuse liability.

Cannabis enhances the analgesic effects of sub-threshold oxycodone, suggesting synergy, without increases in cannabis’s abuse liability. These findings support future research into the therapeutic use of opioid-cannabinoid combinations for pain.”

Role of the Endocannabinoid System in the Neurobiology of Suicide

Cover of The Neurobiological Basis of Suicide

“In the past decade, remarkable advances have been made in cannabinoid (CB) research. The brain endocannabinoid (eCB) system modulates several neurobiological processes and its dysfunction is suggested to be involved in the pathophysiology of mood and drug use disorders.

The CB1 receptor–mediated signaling, in particular, has been shown to play a critical role in the neural circuitry that mediates mood, motivation, and emotional behaviors. This chapter presents the data pertaining to the involvement of the eCB system in depression, suicide, and alcohol addiction.

It appears that the eCB system might have a critical role in the regulation of mood and emotional responses that are impaired in patients with depression and suicidal behavior.

The data provided in this chapter support the notion that the eCB system might be an additional target for the development of a drug against alcohol use, depression, and suicidal behavior.

Among therapeutic agents, antidepressants are the most widely used drugs for the treatment of depression-related disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/23035286

https://www.ncbi.nlm.nih.gov/books/NBK107200/

“Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from cannabis sativa L. The antidepressant action of cannabis as well as the interaction between antidepressants and the endocannabinoid system has been reported. Results of this study show that Δ9-THC and other cannabinoids exert anti-depressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866040/

Acute ethanol inhibition of adult hippocampal neurogenesis involves CB1 cannabinoid receptor signaling.

Alcoholism: Clinical and Experimental Research

“Chronic ethanol exposure has been found to inhibit adult hippocampal neurogenesis in multiple models of alcohol addiction. Together, these findings suggest that acute CB1R cannabinoid receptor activation and binge ethanol treatment reduce neurogenesis through mechanisms involving CB1R. ”   https://www.ncbi.nlm.nih.gov/pubmed/29417597  http://onlinelibrary.wiley.com/doi/10.1111/acer.13608/abstract

“Alcohol-induced neurodegeneration” http://www.diva-portal.org/smash/record.jsf?pid=diva2%3A666727&dswid=174

“Defective Adult Neurogenesis in CB1 Cannabinoid Receptor Knockout Mice.  Pharmacological studies suggest a role for CB1 cannabinoid receptors (CB1R) in regulating neurogenesis in the adult brain.”  http://molpharm.aspetjournals.org/content/66/2/204.full

“Activation of Type 1 Cannabinoid Receptor (CB1R) Promotes Neurogenesis in Murine Subventricular Zone Cell Cultures”   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660454/

“Several studies and patents suggest that the endocannabinoid system has neuro-protective properties and might be a target in neurodegenerative diseases”  https://www.ncbi.nlm.nih.gov/pubmed/27364363

“The endocannabinoid system and neurogenesis in health and disease.”   https://www.ncbi.nlm.nih.gov/pubmed/17404371

“The role of cannabinoids in adult neurogenesis. Pharmacological targeting of the cannabinoid system as a regulator of neurogenesis may prove a fruitful strategy in the prevention or treatment of mood or memory disorders.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543605/

“Regulation of Adult Neurogenesis by Cannabinoids”  https://www.researchgate.net/publication/264424221_Regulation_of_Adult_Neurogenesis_by_Cannabinoids

“Delta-9-Tetrahydrocannabinol (∆9-THC) Induce Neurogenesis and Improve Cognitive Performances of Male Sprague Dawley Rats. Administration of ∆9-THC was observed to enhance the neurogenesis in the brain, especially in hippocampus thus improved the cognitive function of rats.”  https://www.ncbi.nlm.nih.gov/pubmed/28933048

“Cannabidiol Reduces Aβ-Induced Neuroinflammation and Promotes Hippocampal Neurogenesis through PPARγ Involvement. CBD was observed to stimulate hippocampal neurogenesis.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230631/

“Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. Chronic administration of the major drugs of abuse including opiates, alcohol, nicotine, and cocaine has been reported to suppress hippocampal neurogenesis in adult rats. Plant-derived, or synthetic cannabinoids may promote hippocampal neurogenesis. Cannabinoids appear to be the only illicit drug whose capacity to produce increased hippocampal newborn neurons is positively correlated with its anxiolytic- and antidepressant-like effects. In summary, since adult hippocampal neurogenesis is suppressed following chronic administration of opiates, alcohol, nicotine, and cocaine, the present study suggests that cannabinoids are the only illicit drug that can promote adult hippocampal neurogenesis following chronic administration.”  https://www.jci.org/articles/view/25509

 

Epidemiological characteristics, safety and efficacy of medical cannabis in the elderly.

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“There is a substantial growth in the use of medical cannabis in recent years and with the aging of the population, medical cannabis is increasingly used by the elderly.

We aimed to assess the characteristics of elderly people using medical cannabis and to evaluate the safety and efficacy of the treatment.

Our study finds that the therapeutic use of cannabis is safe and efficacious in the elderly population. Cannabis use may decrease the use of other prescription medicines, including opioids.”

https://www.ncbi.nlm.nih.gov/pubmed/29398248

“Medical cannabis significantly safer for elderly with chronic pain than opioids: study” https://medicalxpress.com/news/2018-02-medical-cannabis-significantly-safer-elderly.html
“Medical cannabis significantly safer for elderly with chronic pain than opioids” https://www.eurekalert.org/pub_releases/2018-02/aabu-mcs021318.php

Cannabis Use is Associated with Lower Odds of Prescription Opioid Analgesic Use Among HIV-Infected Individuals with Chronic Pain.

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“Chronic pain is common in the United States and prescribed opioid analgesics use for noncancer pain has increased dramatically in the past two decades, possibly accounting for the current opioid addiction epidemic. Co-morbid drug use in those prescribed opioid analgesics is common, but there are few data on polysubstance use patterns.

We explored patterns of use of cigarette, alcohol, and illicit drugs in HIV-infected people with chronic pain who were prescribed opioid analgesics.

Almost half of the sample of people with HIV and chronic pain reported current prescribed opioid analgesic use (N = 372, 47.1%). Illicit drug use was common (N = 505, 63.9%), and cannabis was the most commonly used illicit substance (N = 311, 39.4%).

In multivariate analyses, only cannabis use was significantly associated with lower odds of prescribed opioid analgesic use (adjusted odds ratio = 0.57; 95% confidence interval: 0.38-0.87).

Conclusions/Importance: Our data suggest that new medical cannabis legislation might reduce the need for opioid analgesics for pain management, which could help to address adverse events associated with opioid analgesic use.”

https://www.ncbi.nlm.nih.gov/pubmed/29338578

http://www.tandfonline.com/doi/abs/10.1080/10826084.2017.1416408?journalCode=isum20

Cannabis use is associated with reduced prevalence of progressive stages of alcoholic liver disease.

Liver International

 

“Abusive alcohol use has well-established health risks including causing liver disease (ALD) characterized by alcoholic steatosis (AS), steatohepatitis (AH), fibrosis, cirrhosis (AC) and hepatocellular carcinoma (HCC). Strikingly, a significant number of individuals who abuse alcohol also use Cannabis, which has seen increased legalization globally. While cannabis has demonstrated anti-inflammatory properties, its combined use with alcohol and the development of liver disease remains unclear.

To determine the effects of cannabis use on the incidence of liver disease in individuals who abuse alcohol.

We analyzed the 2014 Healthcare Cost and Utilization Project – Nationwide Inpatient Sample (NIS) discharge records of patients 18years and older, who had a past or current history of abusive alcohol use(n=319,514). Using the International Classification of Disease, Ninth Edition codes, we studied the four distinct phases of progressive ALD with respect to three cannabisexposure groups: non-cannabis-users (90.39%), non-dependent-cannabis-users (8.26%) and dependent cannabis users (1.36%). We accounted for the complex survey sampling methodology and estimated the adjusted odds ratio (AOR) for developing AS, AH, AC and HCC with respect to cannabis use (SAS 9.4).

 

Our study revealed that among alcohol users, individuals who additionally use cannabis (dependent and non-dependent cannabis use) showed significantly lower odds of developing AS, AH, AC and HCC (AOR: 0.55[0.48-0.64], 0.57[0.53-0.61], 0.45[0.43-0.48] & 0.62[0.51-0.76]). Further, dependent users had significantly lower odds than non-dependent users for developing liver disease.

CONCLUSIONS:

Our findings suggest that cannabis use is associated with reduced incidence of liver disease in alcoholics.”

https://www.ncbi.nlm.nih.gov/pubmed/29341392

http://onlinelibrary.wiley.com/doi/10.1111/liv.13696/abstract

Investigating the relationships between alcohol consumption, cannabis use and circulating cytokines: a preliminary analysis.

Alcoholism: Clinical and Experimental Research

“In recent years, human and animal studies have converged to support altered inflammatory signaling as one molecular mechanism underlying the pathophysiology of alcohol use disorders (AUDs). Alcohol binds to receptors on immune cells, triggering signaling pathways that produce pro-inflammatory cytokines. Chronic inflammation is associated with tissue damage, which may contribute to negative effects of AUD.

Conversely, cannabis is associated with decreased inflammatory signaling, and animal studies suggest that cannabinoids may impact alcohol-induced inflammation.

We explored the relationship between self-reported alcohol and cannabis use and circulating levels of the pro-inflammatory cytokines IL-6, IL-8 and IL-1β in the blood.

A positive association between alcohol and IL-6 emerged. We also observed a negative association between cannabis and IL-1β.

These preliminary findings suggest that cannabinoid compounds may serve to mitigate inflammation associated with alcohol use.”

https://www.ncbi.nlm.nih.gov/pubmed/29286537

http://onlinelibrary.wiley.com/doi/10.1111/acer.13592/abstract;jsessionid=CE6DC7E1CC2712861F31EF048D2F7118.f02t04