Medical Cannabis Legalization and Opioid Prescriptions: Evidence on US Medicaid Enrollees during 1993-2014.

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“While the US has been experiencing an opioid epidemic, 29 states and Washington DC have legalized cannabis for medical use. This study examined whether statewide medical cannabis legalization was associated with reduction in opioids received by Medicaid enrollees.

FINDINGS:

For Schedule III opioid prescriptions, medical cannabis legalization was associated with a 29.6% (p=0.03) reduction in number of prescriptions, 29.9% (p=0.02) reduction in dosage, and 28.8% (p=0.04) reduction in related Medicaid spending. No evidence was found to support the associations between medical cannabis legalization and Schedule II opioid prescriptions. Permitting medical cannabis dispensaries was not associated with Schedule II or Schedule III opioid prescriptions after controlling for medical cannabis legalization. It was estimated that, if all the states had legalized medical cannabis by 2014, Medicaid annual spending on opioid prescriptions would be reduced by 17.8 million dollars.

CONCLUSION:

Statewide medical cannabis legalization appears to have been associated with reductions in both prescriptions and dosages of Schedule III (but not Schedule II) opioids received by Medicaid enrollees in the US.”

https://www.ncbi.nlm.nih.gov/pubmed/29989239

https://onlinelibrary.wiley.com/doi/abs/10.1111/add.14382

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Neural correlates of interactions between cannabidiol and Δ(9) -tetrahydrocannabinol in mice: implications for medical cannabis.

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“It has been proposed that medicinal strains of cannabis and therapeutic preparations would be safer with a more balanced concentration ratio of Δ(9) -tetrahydrocannabinol (THC) to cannabidiol (CBD), as CBD reduces the adverse psychotropic effects of THC.

The aim of this study was to investigate whether CBD modulated the functional effects and c-Fos expression induced by THC, using a 1:1 dose ratio that approximates therapeutic strains of cannabis and nabiximols.

These data confirm that CBD modulated the pharmacological actions of THC and provide new information regarding brain regions involved in the interaction between CBD and THC.”

https://www.ncbi.nlm.nih.gov/pubmed/26377899

“A number of studies now support the view that cannabidiol (CBD) may reduce the negative psychotropic effects of THC while enhancing its positive therapeutic actions. Our results are consistent with the notion that cannabis plant strains that contain THC and CBD at 1:1 ratios may be preferable to street cannabis for medicinal applications because they maximize therapeutic efficacy while minimizing the adverse effects of THC.”  https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.13333

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Reinforcing effects of opioid/cannabinoid mixtures in rhesus monkeys responding under a food/drug choice procedure.

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“Cannabinoid receptor agonists such as delta-9-tetrahydrocannabinol (Δ9-THC) enhance the antinociceptive potency of mu opioid receptor agonists such as morphine, indicating that opioid/cannabinoid mixtures might be effective for treating pain. However, such enhancement will be beneficial only if cannabinoids do not also enhance adverse effects of opioids, including those related to abuse.

In rhesus monkeys, cannabinoids fail to enhance and often decrease self-administration of the mu opioid receptor agonist heroin, suggesting that opioid/cannabinoid mixtures do not have greater reinforcing effects (abuse potential) compared with opioids alone. Previous studies on the self-administration of opioid/cannabinoid mixtures used single-response procedures, which do not easily differentiate changes in reinforcing effects from other effects (e.g., rate decreasing).

CONCLUSION:

Overall, these results extend previous studies to include choice behavior and show that cannabinoids do not substantially enhance the reinforcing effects of mu opioid receptor agonists.”

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Effects of cannabidiol plus naltrexone on motivation and ethanol consumption.

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“The aim of this study was to explore if the administration of naltrexone (NTX) together with cannabidiol (CBD) may improve the efficacy in reducing alcohol consumption and motivation rather than any of the drugs given separately.

The administration of CBD + NTX significantly reduced motivation and ethanol intake in the oral self-administration procedure in a greater proportion than the drugs given alone. Only the combination of both drugs significantly reduced Oprm1, TH and 5-HT1A gene expressions in the NAc, VTA and DR, respectively. Interestingly, the administration of WAY100635 significantly blocked the actions of CBD + NTX but had no effects by itself.

CONCLUSION AND IMPLICATIONS:

The combination of low doses of CBD plus NTX resulted more effective to reduce ethanol consumption and motivation to drink. These effects, appears to be mediated, at least in part, by 5-HT1A receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/29859012

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14380

Naltrexone belongs to a class of drugs known as opiate antagonists. It works in the brain to prevent opiate effects (e.g., feelings of well-being, pain relief). It also decreases the desire to take opiates. This medication is also used to treat alcohol abuse. It can help people drink less alcohol or stop drinking altogether. It also decreases the desire to drink alcohol when used with a treatment program that includes counseling, support, and lifestyle changes.” https://www.webmd.com/drugs/2/drug-7399/naltrexone-oral/details

“Cannabidiol reduces ethanol consumption, motivation and relapse in mice. Taken together, these results reveal that the administration of CBD reduced the reinforcing properties, motivation and relapse for ethanol. These findings strongly suggest that CBD may result useful for the treatment of alcohol use disorders.”   https://www.ncbi.nlm.nih.gov/pubmed/28194850

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Ventilatory-depressant effects of opioids alone and in combination with cannabinoids in rhesus monkeys.

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“Pain is a serious health problem that is commonly treated with opioids, although the doses of opioids needed to treat pain are often similar to those that decrease respiration. Combining opioids with drugs that relieve pain through non-opioid mechanisms can decrease the doses of opioids needed for analgesia, resulting in an improved therapeutic window, but only if the doses of opioids that decrease respiration are not similarly decreased. Using small doses of opioids to treat pain has the potential to reduce the number of overdoses and deaths.

This study investigated whether the cannabinoid receptor agonists Δ9-tetrahydrocannabinol (Δ9-THC) and CP 55,940 modify the ventilatory-depressant effects of morphine and fentanyl in three monkeys.

In summary, cannabinoid receptor agonists, which increase the potency of opioids to produce antinociception, did not increase their potency to depress ventilation. Thus, the therapeutic window is greater for opioids when they are combined with cannabinoid receptor agonists, indicating a possible advantage for these drug mixtures in treating pain.”

https://www.ncbi.nlm.nih.gov/pubmed/29807027

https://www.sciencedirect.com/science/article/pii/S0014299918303108

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Computational investigation on the binding modes of Rimonabant analogues with CB1 and CB2.

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“The human cannabinoid G protein coupled receptor 1 (CB1) is highly expressed in central nervous system. CB1-selective antagonists show therapeutic promise in a wide range of disorders, such as obesity-related metabolic disorders, dyslipidemia, drug abuse and type 2 diabetes.

Rimonabant (SR141716A), MJ08 and MJ15 are selective CB1 antagonists with selectivity >1000 folds over CB2 despite of 42% sequence identity between CB1 and CB2. The integration of homology modeling, automated molecular docking and molecular dynamics simulation were used to investigate the binding modes of these selective inverse agonists/antagonists with CB1 and CB2 and their selectivity.

Our analyses showed that the hydrophobic interactions between ligands and hydrophobic pockets of CB1 account for the main binding affinity. In addition, instead of interacting with ligands directly as previously reported, the Lys1923.28in CB1 was engaged in indirect interactions with ligands to keep inactive-state CB1 stable by forming the salt bridge with Asp1762.63 . Lastly, our analyses indicated that the selectivity of these antagonists came from the difference in geometry shapes of binding pockets of CB1 and CB2.

The present study could guide future experimental works on these receptors and has the guiding significance for the design of functionally selective drugs targeting CB1 or CB2 receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/29797785

https://onlinelibrary.wiley.com/doi/abs/10.1111/cbdd.13337

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Randomised Controlled Trial (RCT) of cannabinoid replacement therapy (Nabiximols) for the management of treatment-resistant cannabis dependent patients: a study protocol.

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“The cannabis extract nabiximols (Sativex®) effectively supresses withdrawal symptoms and cravings in treatment resistant cannabis dependent individuals, who have high relapse rates following conventional withdrawal treatments.

This study examines the efficacy, safety and cost-effectiveness of longer-term nabiximols treatment for outpatient cannabis dependent patients who have not responded to previous conventional treatment approaches.

This is the first outpatient community-based randomised controlled study of nabiximols as an agonist replacement medication for treating cannabis dependence, targeting individuals who have not previously responded to conventional treatment approaches. The study and treatment design is modelled upon an earlier study with this population and more generally on other agonist replacement treatments (e.g. nicotine, opioids).”

https://www.ncbi.nlm.nih.gov/pubmed/29776349

“There is a need for more effective treatment approaches for cannabis dependent patients who are unable to discontinue their illicit use through psychosocial interventions alone. Longer-term agonist replacement treatment approaches rather than acute withdrawal management are likely to be more effective, with the combination of THC:CBD nabiximols preparation being potentially advantageous over synthetic THC analogues. This is the first large-scale outpatient RCT of nabiximols for this population, and has required the development of clinical and research methods specific to agonist treatment with a plant-derived cannabinoid formulation, building upon clinical research models previously used in opioid agonist treatment approaches.”

https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-018-1682-2

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Effects of exercise on experimentally manipulated craving for cannabis: A preliminary study.

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“Cannabis is the most commonly used illicit drug in the United States, and craving for cannabis is related to cannabis use.

Exercise has been demonstrated to reduce craving for substances.

The findings suggest that moderate exercise may be useful for reducing craving, particularly among those who use larger quantities of cannabis.”

 https://www.ncbi.nlm.nih.gov/pubmed/29792472

“Exercise activates the endocannabinoid system.”  https://www.ncbi.nlm.nih.gov/pubmed/14625449

“Aerobic exercise training reduces cannabis craving and use in non-treatment seeking cannabis-dependent adults.”  https://www.ncbi.nlm.nih.gov/pubmed/21408154

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The endocannabinoid-alcohol crosstalk: recent advances on a bi-faceted target.

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“Increasing evidence focuses on the endocannabinoid system as a relevant player in the induction of aberrant synaptic plasticity and related addictive phenotype following chronic excessive alcohol drinking.

Besides, the endocannabinoid system is implicated in the pathogenesis of alcoholic liver disease.

Interestingly, whereas the involvement of CB1 cannabinoid receptors in alcohol rewarding properties is established, the central and peripheral action of CB2 cannabinoid signalling is still to be elucidated.

This review aims at giving the input to deepen knowledge on the role of the endocannabinoid system, highlighting the advancing evidence that suggests that CB1 and CB2 receptors may play opposite roles in the regulation of both the reinforcing properties of alcohol in the brain and the mechanisms responsible for cell injury and inflammation in the hepatic tissue.

The manipulation of the endocannabinoid system could represent a bi-faceted strategy to counteract alcohol-related dysfunction in central transmission and liver structural and functional disarrangement.”

https://www.ncbi.nlm.nih.gov/pubmed/29770478

https://onlinelibrary.wiley.com/doi/abs/10.1111/1440-1681.12967

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Review of the neurological benefits of phytocannabinoids.

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“Numerous physical, psychological, and emotional benefits have been attributed to marijuana since its first reported use in 2,600 BC in a Chinese pharmacopoeia. The phytocannabinoids, cannabidiol (CBD), and delta-9-tetrahydrocannabinol (Δ9-THC) are the most studied extracts from cannabis sativa subspecies hemp and marijuana. CBD and Δ9-THC interact uniquely with the endocannabinoid system (ECS). Through direct and indirect actions, intrinsic endocannabinoids and plant-based phytocannabinoids modulate and influence a variety of physiological systems influenced by the ECS.

METHODS:

In 1980, Cunha et al. reported anticonvulsant benefits in 7/8 subjects with medically uncontrolled epilepsy using marijuana extracts in a phase I clinical trial. Since then neurological applications have been the major focus of renewed research using medical marijuana and phytocannabinoid extracts.

RESULTS:

Recent neurological uses include adjunctive treatment for malignant brain tumors, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, neuropathic pain, and the childhood seizure disorders Lennox-Gastaut and Dravet syndromes. In addition, psychiatric and mood disorders, such as schizophrenia, anxiety, depression, addiction, postconcussion syndrome, and posttraumatic stress disorders are being studied using phytocannabinoids.

CONCLUSIONS:

In this review we will provide animal and human research data on the current clinical neurological uses for CBD individually and in combination with Δ9-THC. We will emphasize the neuroprotective, antiinflammatory, and immunomodulatory benefits of phytocannabinoids and their applications in various clinical syndromes.”

https://www.ncbi.nlm.nih.gov/pubmed/29770251

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938896/

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