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

Does Cannabidiol Protect Against Adverse Psychological Effects of THC?

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“Tetrahydrocannabinol (THC) is the main psychoactive substance in cannabis. Cannabidiol (CBD) is a cannabinoid that appears in cannabis resin but rarely in herbal cannabis. In recent years, many positive attributes have been ascribed to CBD. Is cannabis that contains CBD less harmful than cannabis without CBD? Are people who smoke cannabis resin, therefore, less susceptible to psychosis or less likely to become addicted than are people who smoke herbal marijuana?

Delta-9-tetrahydrocannabinol (THC) is the main psychoactive constituent of cannabis, and most, if not all, of the effects associated with the use of cannabis are caused by THC. Recent studies have suggested a possible protective effect of another cannabinoid, cannabidiol (CBD).

Most recreational users will never be faced with persistent mental illness, but in some individuals cannabis use leads to undesirable effects: cognitive impairment, anxiety, paranoia, and increased risks of developing chronic psychosis or drug addiction.

Studies examining the protective effects of CBD have shown that CBD can counteract the negative effects of THC.

Few or no adverse effects of CBD have been proffered, and where CBD has been found to have an effect, it is usually in a “positive” (i.e., salubrious) direction. The evidence favoring a beneficial effect of CBD therefore merits further investigation in studies in which the amounts and ratios of CBD and THC correspond to the daily practices of recreational cannabis use.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797438/

“Studies examining the protective effects of CBD have shown that CBD can counteract the negative effects of THC.” https://www.ncbi.nlm.nih.gov/pubmed/24137134

“CBD may also potentiate some of Δ9-THC’s beneficial effects as it reduces Δ9-THC’s psychoactivity to enhance its tolerability and widen its therapeutic window.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707667/

Can we make cannabis safer?

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“Cannabis use and related problems are on the rise globally alongside an increase in the potency of cannabis sold on both black and legal markets. Additionally, there has been a shift towards abandoning prohibition for a less punitive and more permissive legal stance on cannabis, such as decriminalisation and legalisation. It is therefore crucial that we explore new and innovative ways to reduce harm.

Research has found cannabis with high concentrations of its main active ingredient, δ-9-tetrahydrocannabinol (THC), to be more harmful (in terms of causing the main risks associated with cannabis use, such as addiction, psychosis, and cognitive impairment) than cannabis with lower concentrations of THC. By contrast, cannabidiol, which is a non-intoxicating and potentially therapeutic component of cannabis, has been found to reduce the negative effects of cannabis use.

Here, we briefly review findings from studies investigating various types of cannabis and discuss how future research can help to better understand and reduce the risks of cannabis use.”  https://www.ncbi.nlm.nih.gov/pubmed/28259650

“Studies examining the protective effects of CBD have shown that CBD can counteract the negative effects of THC.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797438/

“CBD may also potentiate some of Δ9-THC’s beneficial effects as it reduces Δ9-THC’s psychoactivity to enhance its tolerability and widen its therapeutic window.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707667/

EFFECTS OF CANNABIDIOL IN HUNTINGTON’S DISEASE

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“Cannabidiol (CBD) is a major nonpsychoactive cannabinoid of marijuana.

Based on reports indicating possible efficacy of CBD in dystonic movements, we tried CBD in three patients with Huntington’s disease (HD).

The patients;, aged 30 to 56, had HD of 7 to 12 years’ duration. Their condition has been slowly progressive and unresponsive to prior therapy with neuroleptics. Orally administered CBD was initiated at 300 mg/d and increased 1 week later to 600 mg/d for the next 3 weeks.

Mild improvement ( 5 to 15%) in the choreic movements was documented using the tongueprotrusion test and a chorea severity evaluation scale after the first week. Further improvement (20 to 40%) was noticed after the second week of CBD, and this remained stable for the following 2 weeks.

Except for transient, mild hypotension, no side effects were recorded, and laboratory tests were normal. Withdrawal of CBD after 48 hours resulted in return of choreic movements to the pre-CBD state.”

http://www.druglibrary.org/schaffer/hemp/medical/hunting1.htm

The current status of artisanal cannabis for the treatment of epilepsy in the United States.

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“The widespread patient use of artisanal cannabis preparations has preceded quality validation of cannabis use for epilepsy. Neurologists and cannabinoid specialists are increasingly in a position to monitor and guide the use of herbal cannabis in epilepsy patients. We report the retrospective data on efficacy and adverse effects of artisanal cannabis in Patients with medically refractory epilepsy with mixed etiologies in Washington State, California, and Maine. Clinical considerations, including potential risks and benefits, challenges related to artisanal preparations, and cannabinoid dosing, are discussed.

RESULTS:

Of 272 combined patients from Washington State and California, 37 (14%) found cannabis ineffective at reducing seizures, 29 (15%) experienced a 1-25% reduction in seizures, 60 (18%) experienced a 26-50% reduction in seizures, 45 (17%) experienced a 51-75% reduction in seizures, 75 (28%) experienced a 76-99% reduction in seizures, and 26 (10%) experienced a complete clinical response. Overall, adverse effects were mild and infrequent, and beneficial side effects such as increased alertness were reported. The majority of patients used cannabidiol (CBD)-enriched artisanal formulas, some with the addition of delta-9-tetrahydrocannabinol (THC) and tetrahydrocannabinolic acid (THCA). Four case reports are included that illustrate clinical responses at doses <0.1mg/kg/day, biphasic dose-response effects, the use of THCA for seizure prevention, the use of THC for seizure rescue, and the synergy of cannabinoids and terpenoids in artisanal preparations. This article is part of a Special Issue entitled “Cannabinoids and Epilepsy”.”

https://www.ncbi.nlm.nih.gov/pubmed/28254350

Potential of Cannabidiol for the Treatment of Viral Hepatitis.

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“Viral hepatitis B (HBV) and hepatitis C (HCV) pose a major health problem globally and if untreated, both viruses lead to severe liver damage resulting in liver cirrhosis and cancer. While HBV has a vaccine, HCV has none at the moment. The risk of drug resistance, combined with the high cost of current therapies, makes it a necessity for cost-effective therapeutics to be discovered and developed.

The recent surge in interest in Medical Cannabis has led to interest in evaluating and validating the therapeutic potentials of Cannabis and its metabolites against various diseases including viruses. Preliminary screening of cannabidiol (CBD) revealed that CBD is active against HCV but not against HBV in vitro. CBD inhibited HCV replication by 86.4% at a single concentration of 10 μM with EC50 of 3.163 μM in a dose-response assay.

These findings suggest that CBD could be further developed and used therapeutically against HCV. Cannabidiol exhibited in vitro activity against viral hepatitis C.”  https://www.ncbi.nlm.nih.gov/pubmed/28250664

“Cannabidiol (CBD) is a nonpsychoactive cannabinoid found in the Cannabis plants and is credited for several pharmacological properties. It is also known to have beneficial effects against inflammation/pain, neurological conditions, cancer, and other ailments. In general, with regard to antiviral activity, medical Cannabis was reported to be used as an accompanying remedy by HIV/AIDS patients to alleviate neuropathic pain, wasting, nausea, and vomiting. Given the increasing use and application of medical Cannabis along with its nonpsychoactive metabolite (CBD), and in line with our continuous effort to evaluate and validate the potential therapeutic properties of CBD, the major aim of this study was as such to evaluate the anti-HBV and anti-HCV activities of CBD in vitro. We report here for the first time in vitro studies to demonstrate the antiviral activity of CBD against HCV. CBD was shown to have activity against HCV in vitro but not against HBV. A review of the literature seems to suggest that CBD may also have activity in vivo based on its interaction with the CB2 receptor and as such using a host mechanism to indirectly slow the pathogenic process of the HBV virus. Based on these findings, CBD as such has potential to be further developed as a treatment for viral hepatitis, especially as a combination therapy with the currently existing therapies.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330095/

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

Social correlates of health status, quality of life, and mood states in patients treated with cannabidiol for epilepsy.

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“Social characteristics, such as socioeconomic status and race/ethnicity, play a role in the treatment and outcomes of patients with epilepsy (PWE), but little is known about how these factors affect patients receiving cannabidiol (CBD) to treat seizures. This exploratory study examined the sociodemographic profile of patients treated with CBD (n=80) and associations between social factors and patient-centered outcomes – overall health status, Quality of Life in Epilepsy-89 (QOLIE-89), and Profile of Mood States (POMS) – in this population.

Associations were examined using Pearson correlations and multiple ordinary-least-squares regression (alpha=0.1). The sample was predominantly white (96%) and non-Hispanic/Latino (96%); 76% of patients had family incomes of $40,000+/year. Some patients/families reported experiencing food scarcity (13%), not being able to make ends meet (6%), or not being able to afford antiepileptic medications (8%). The patients’ health ratings declined with age and income (p≤0.014), and there was a statistically significant interaction (p<0.055) between these variables: for example, a higher-income 10-year-old had a predicted health rating of 3 (“very good”), followed by a higher-income 40-year-old with a rating of 2 (“good”), a low-income 10-year-old with a rating of 1 (“fair”), and a low-income 40-year-old with a rating of 0 (“poor”).

This is the first study reporting the social profile of patients taking pharmaceutical grade CBD for the treatment of epilepsy. The results suggest that despite free access to this treatment some patients may not be accessing CBD because of their socioeconomic situation or race/ethnicity. Larger, diverse samples and longitudinal data are needed to more accurately model social factors and patient-centered outcomes in PWE receiving CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/28236578

Cannabidiol: State of the art and new challenges for therapeutic applications.

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“Over the past years, several lines of evidence support a therapeutic potential of Cannabis derivatives and in particular phytocannabinoids. Δ9-THC and cannabidiol (CBD) are the most abundant phytocannabinoids in Cannabis plants and therapeutic application for both compounds have been suggested. However, CBD is recently emerging as a therapeutic agent in numerous pathological conditions since devoid of the psychoactive side effects exhibited instead by Δ9-THC. In this review, we highlight the pharmacological activities of CBD, its cannabinoid receptor-dependent and -independent action, its biological effects focusing on immunomodulation, angiogenetic properties, and modulation of neuronal and cardiovascular function. Furthermore, the therapeutic potential of cannabidiol is also highlighted, in particular in nuerological diseases and cancer.”

https://www.ncbi.nlm.nih.gov/pubmed/28232276

Anti-inflammatory role of cannabidiol and O-1602 in cerulein-induced acute pancreatitis in mice.

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“The anti-inflammatory effects of O-1602 and cannabidiol (CBD), the ligands of G protein-coupled receptor 55 (GPR55), on experimental acute pancreatitis (AP) were investigated.

Cannabidiol or O-1602 treatment significantly improved the pathological changes of mice with AP and decreased the enzyme activities, IL-6 and tumor necrosis factor α; levels, and the myeloperoxidase activities in plasma and in the organ tissues.

G protein-coupled receptor 55 mRNA and protein expressed in the pancreatic tissue, and the expressions were decreased in the mice with AP, and either CBD or O-1602 attenuated these changes to a certain extent.

CONCLUSION:

Cannabidiol and O-1602 showed anti-inflammatory effects in mice with AP and improved the expression of GPR55 in the pancreatic tissue as well.”

https://www.ncbi.nlm.nih.gov/pubmed/22850623