Cannabidiol in Medical Marijuana: Research Vistas and Potential Opportunities.

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“The high and increasing prevalence of medical marijuana consumption in the general population invites the need for quality evidence regarding its safety and efficacy. Herein, we synthesize extant literature pertaining to the phytocannabinoid cannabidiol (CBD) and its brain effects.

The principle phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) and CBD are the major pharmacologically active cannabinoids. The effect of CBD on brain systems as well as on phenomenological measures (e.g. cognitive function) are distinct and in many cases opposite to that of Δ9-THC.

Cannabidiol is without euphoriant properties, and exerts antipsychotic, anxiolytic, anti-seizure, as well as anti-inflammatory properties.

It is essential to parcellate phytocannabinoids into their constituent moieties as the most abundant cannabinoid have differential effects on physiologic systems in psychopathology measures. Disparate findings and reports related to effects of cannabis consumption reflect differential relative concentration of Δ9-THC and CBD.

Existing literature, notwithstanding its deficiencies, provides empirical support for the hypothesis that CBD may exert beneficial effects on brain effector systems/substrates subserving domain-based phenomenology. Interventional studies with purified CBD are warranted with a call to target-engagement proof-of-principle studies using the research domain criteria (RDoC) framework.” https://www.ncbi.nlm.nih.gov/pubmed/28501518

http://www.sciencedirect.com/science/article/pii/S1043661817303559

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Cannabis as a substitute for prescription drugs – a cross-sectional study

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“The use of medical cannabis is increasing, most commonly for pain, anxiety and depression. Emerging data suggest that use and abuse of prescription drugs may be decreasing in states where medical cannabis is legal. The aim of this study was to survey cannabis users to determine whether they had intentionally substituted cannabis for prescription drugs.

A total of 1,248 (46%) respondents reported using cannabis as a substitute for prescription drugs. The most common classes of drugs substituted were narcotics/opioids (35.8%), anxiolytics/benzodiazepines (13.6%) and antidepressants (12.7%). A total of 2,473 substitutions were reported or approximately two drug substitutions per affirmative respondent.

These patient-reported outcomes support prior research that individuals are using cannabis as a substitute for prescription drugs, particularly, narcotics/opioids, and independent of whether they identify themselves as medical or non-medical users. This is especially true if they suffer from pain, anxiety and depression. Additionally, this study suggests that state laws allowing access to, and use of, medical cannabis may not be influencing individual decision-making in this area.”

https://www.dovepress.com/cannabis-as-a-substitute-for-prescription-drugs-ndash-a-cross-sectiona-peer-reviewed-article-JPR

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The endocannabinoid system as a target for novel anxiolytic drugs.

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“The endocannabinoid (eCB) system has attracted attention for its role in various behavioral and brain functions, and as a therapeutic target in neuropsychiatric disease states, including anxiety disorders and other conditions resulting from dysfunctional responses to stress. In this mini-review, we highlight components of the eCB system that offer potential ‘druggable’ targets for new anxiolytic medications, emphasizing some of the less well-discussed options. We discuss how selectively amplifying eCBs recruitment by interfering with eCB-degradation, via fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), has been linked to reductions in anxiety-like behaviors in rodents and variation in human anxiety symptoms. We also discuss a non-canonical route to regulate eCB degradation that involves interfering with cyclooxygenase-2 (COX-2). Next, we discuss approaches to targeting eCB receptor-signaling in ways that do not involve the cannabinoid receptor subtype 1 (CB1R); by targeting the CB2R subtype and the transient receptor potential vanilloid type 1 (TRPV1). Finally, we review evidence that cannabidiol (CBD), while representing a less specific pharmacological approach, may be another way to modulate eCBs and interacting neurotransmitter systems to alleviate anxiety. Taken together, these various approaches provide a range of plausible paths to developing novel compounds that could prove useful for treating trauma-related and anxiety disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/28434588

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Substitution of medical cannabis for pharmaceutical agents for pain, anxiety, and sleep.

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“A prior epidemiological study identified a reduction in opioid overdose deaths in US states that legalized medical cannabis (MC). One theory to explain this phenomenon is a potential substitution effect of MC for opioids. This study evaluated whether this substitution effect of MC for opioids also applies to other psychoactive medications.

New England dispensary members ( n = 1,513) completed an online survey about their medical history and MC experiences. Among respondents that regularly used opioids, over three-quarters (76.7%) indicated that they reduced their use since they started MC. This was significantly ( p < 0.0001) greater than the patients that reduced their use of antidepressants (37.6%) or alcohol (42.0%). Approximately two-thirds of patients decreased their use of anti-anxiety (71.8%), migraine (66.7%), and sleep (65.2%) medications following MC which significantly ( p < 0.0001) exceeded the reduction in antidepressants or alcohol use. The patient’s spouse, family, and other friends were more likely to know about their MC use than was their primary care provider.

In conclusion, a majority of patients reported using less opioids as well as fewer medications to treat anxiety, migraines, and sleep after initiating MC. A smaller portion used less antidepressants or alcohol. Additional research is needed to corroborate these self-reported, retrospective, cross-sectional findings using other data sources.”

https://www.ncbi.nlm.nih.gov/pubmed/28372506

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Endocannabinoid signalling modulates susceptibility to traumatic stress exposure.

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“Stress is a ubiquitous risk factor for the exacerbation and development of affective disorders including major depression and posttraumatic stress disorder. Understanding the neurobiological mechanisms conferring resilience to the adverse consequences of stress could have broad implications for the treatment and prevention of mood and anxiety disorders. We utilize laboratory mice and their innate inter-individual differences in stress-susceptibility to demonstrate a critical role for the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) in stress-resilience. Specifically, systemic 2-AG augmentation is associated with a stress-resilient phenotype and enhances resilience in previously susceptible mice, while systemic 2-AG depletion or CB1 receptor blockade increases susceptibility in previously resilient mice. Moreover, stress-resilience is associated with increased phasic 2-AG-mediated synaptic suppression at ventral hippocampal-amygdala glutamatergic synapses and amygdala-specific 2-AG depletion impairs successful adaptation to repeated stress. These data indicate amygdala 2-AG signalling mechanisms promote resilience to adverse effects of acute traumatic stress and facilitate adaptation to repeated stress exposure.” https://www.ncbi.nlm.nih.gov/pubmed/28348378

“Natural cannabinoid found to play key role in anxiety. Stress-related mood and anxiety disorders affect millions of people in the United States. A new study examines the neurobiology behind these illnesses and finds that controlling a molecule that activates cannabinoid receptors can reduce the symptoms of anxiety.” http://www.medicalnewstoday.com/articles/316682.php

“Natural chemical helps brain adapt to stress”  https://www.sciencedaily.com/releases/2017/03/170329140945.htm

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Cannabidiol Affects MK-801-Induced Changes in the PPI Learned Response of Capuchin Monkeys (Sapajus spp.).

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“There are several lines of evidence indicating a possible therapeutic action of cannabidiol (CBD) in schizophrenia treatment.

Studies with rodents have demonstrated that CBD reverses MK-801 effects in prepulse inhibition (PPI) disruption, which may indicate that CBD acts by improving sensorimotor gating deficits.

In the present study, we investigated the effects of CBD on a PPI learned response of capuchin monkeys (Sapajus spp.).

A total of seven monkeys were employed in this study. In Experiment 1, we evaluated the CBD (doses of 15, 30, 60 mg/kg, i.p.) effects on PPI. In Experiment 2, the effects of sub-chronic MK-801 (0.02 mg/kg, i.m.) on PPI were challenged by a CBD pre-treatment.

No changes in PPI response were observed after CBD-alone administration. However, MK-801 increased the PPI response of our animals.

CBD pre-treatment blocked the PPI increase induced by MK-801.

Our findings suggest that CBD’s reversal of the MK-801 effects on PPI is unlikely to stem from a direct involvement on sensorimotor mechanisms, but may possibly reflect its anxiolytic properties.”

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Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorders.

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“Learning to associate cues or contexts with potential threats or rewards is adaptive and enhances survival. Both aversive and appetitive memories are therefore powerful drivers of behaviour but the inappropriate expression of conditioned responding to fear- and drug-related stimuli can develop into anxiety-related and substance abuse disorders, respectively. These disorders are associated with abnormally persistent emotional memories and inadequate treatment, often leading to symptom relapse.

Studies show that cannabidiol, the main non-psychotomimetic phytocannabinoid found in Cannabis sativa, reduces anxiety via serotonin1A and (indirect) cannabinoid receptor activation in paradigms assessing innate responses to threat.

Accumulating evidence from animal studies investigating the effects of cannabidiol on fear memory processing also indicates that it reduces learned fear in paradigms that are translationally relevant to phobias and post-traumatic stress disorder.

Cannabidiol does so by reducing fear expression acutely, and by disrupting fear memory reconsolidation and enhancing fear extinction, both of which can result in the lasting reduction of learned fear.

Recent studies have also begun to determine the effects of cannabidiol on drug memory expression using paradigms with translational relevance to addiction. Emerging evidence suggests that cannabidiol reduces the expression of drug memories acutely and by disrupting their reconsolidation.

Here we review the literature demonstrating the anxiolytic effects of cannabidiol before focusing on studies investigating its effects on various fear and drug memory processes. Understanding how cannabidiol regulates emotion and emotional memory processing may eventually lead to its use in treating anxiety-related and substance abuse disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/28268256

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Co-localization of the cannabinoid type 1 receptor with corticotropin-releasing factor-containing afferents in the noradrenergic nucleus locus coeruleus: implications for the cognitive limb of the stress response.

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“The noradrenergic system has been shown to play a key role in the regulation of stress responses, arousal, mood, and emotional states. Corticotropin-releasing factor (CRF) is a primary mediator of stress-induced activation of noradrenergic neurons in the nucleus locus coeruleus (LC).

The endocannabinoid (eCB) system also plays a key role in modulating stress responses, acting as an “anti-stress” neuro-mediator.

In the present study, we investigated the cellular sites for interactions between the cannabinoid receptor type 1 (CB1r) and CRF in the LC.

Taken together, these results indicate that the eCB system is poised to directly modulate stress-integrative heterogeneous CRF afferents in the LC, some of which arise from limbic sources.”

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The Direct Actions of Cannabidiol and 2-Arachidonoyl Glycerol at GABAA Receptors.

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“Cannabidiol (CBD) is a major non-intoxicating component of cannabis and possesses anti-epileptic, anxiolytic and anti-hyperalgesic properties.

Despite evidence that some endogenous and synthetic cannabinoids interact with GABAA receptors, no-one has yet investigated the effects of CBD.

Here we used two-electrode voltage clamp electrophysiology to compare the actions of CBD with those of the major central endocannabinoid, 2-arachidonoyl glycerol (2-AG) on human recombinant GABAA receptors (synaptic α1-6βg2 and extrasynaptic α4β2δ) expressed on Xenopus oocytes.

Taken together these results reveal a mode of action of CBD on specifically configured GABAA receptors that may be relevant to the anticonvulsant and anxiolytic effects of the compound.”

https://www.ncbi.nlm.nih.gov/pubmed/28249817

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Fatty acid amide hydrolase inhibitors produce rapid anti-anxiety responses through amygdala long-term depression in male rodents.

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“Pathological anxiety is the most common type of psychiatric disorder. The current first-line anti-anxiety treatment, selective serotonin/noradrenalin reuptake inhibitors, produces a delayed onset of action with modest therapeutic and substantial adverse effects, and long-term use of the fast-acting anti-anxiety benzodiazepines causes severe adverse effects.

Inhibition of the fatty acid amide hydrolase (FAAH), the endocannabinoid N-arachidonoylethanolamine (AEA) degradative enzyme, produces anti-anxiety effects without substantial “unwanted effects” of cannabinoids, but its anti-anxiety mechanism is unclear.

CONCLUSION:

We propose that the rapid anti-anxiety effects of FAAH inhibition are due to AEA activation of astroglial CB1R and subsequent basolateral amygdala LTD in vivo.”

https://www.ncbi.nlm.nih.gov/pubmed/28234213

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