Identification of Psychoactive Degradants of Cannabidiol in Simulated Gastric and Physiological Fluid

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“The flowering plants of the genus Cannabis, which mainly comprises the sativa and indica species, have been recognized for medical treatment for millennia.

Although Cannabis contains nearly 500 compounds from 18 chemical classes, its physiological effects derive mainly from a family of naturally occurring compounds known as plant cannabinoids or phytocannabinoids. Of the more than 100 phytocannabinoids that have been identified in Cannabis, among the most important and widely studied are its main psychoactive constituent, Δ9-tetrahydrocannabinol (Δ9-THC), and the most important nonpsychoactive component, cannabidiol (CBD). Other biologically active phytocannabinoids that have been isolated in Cannabis include Δ8-THC, cannabinol, Δ9-tetrahydrocannabivarin, and cannabidivarin.

In recent research, orally administered cannabidiol (CBD) showed a relatively high incidence of somnolence in a pediatric population. Previous work has suggested that when CBD is exposed to an acidic environment, it degrades to Δ9-tetrahydrocannabinol (THC) and other psychoactive cannabinoids. To gain a better understanding of quantitative exposure, we completed an in vitro study by evaluating the formation of psychoactive cannabinoids when CBD is exposed to simulated gastric fluid (SGF).

SGF converts CBD into the psychoactive components Δ9-THC and Δ8-THC. The first-order kinetics observed in this study allowed estimated levels to be calculated and indicated that the acidic environment during normal gastrointestinal transit can expose orally CBD-treated patients to levels of THC and other psychoactive cannabinoids that may exceed the threshold for a physiological response. Delivery methods that decrease the potential for formation of psychoactive cannabinoids should be explored.

Despite persistent challenges with dosing and administration, CBD-based therapies have a good safety profile and a potential for efficacy in the treatment of a variety of medical conditions. The rapidly evolving sciences of drug delivery and cannabinoid pharmacology may soon lead to breakthroughs that will improve access to the benefits of this pharmacological class of agents. In addition, current technologies, such as transdermal-based therapy, may be able to eliminate the potential for psychotropic effects due to this acid-catalyzed cyclization by delivering CBD through the skin and into the neutral, nonreactive environment of the systemic circulation.”

http://online.liebertpub.com/doi/10.1089/can.2015.0004

Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy

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“Severe childhood epilepsies are characterized by frequent seizures, neurodevelopmental delays and impaired quality of life. In these treatment-resistant epilepsies, families often seek alternative treatments.

This survey explored the use of cannabidiol-enriched cannabis in children with treatment-resistant epilepsy. The survey was presented to parents belonging to a Facebook group dedicated to sharing information about the use of cannabidiol-enriched cannabis to treat their child’s seizures.

Nineteen responses met the inclusion criteria for the study: a diagnosis of epilepsy and current use of cannabidiol-enriched cannabis. Thirteen children had Dravet syndrome, four had Doose syndrome, and one each had Lennox-Gastaut syndrome and idiopathic epilepsy.

The average number of anti-epileptic drugs (AEDs) tried before using cannabidiol-enriched cannabis was 12. Sixteen (84%) of the 19 parents reported a reduction in their child’s seizure frequency while taking cannabidiol-enriched cannabis. Of these, two (11%) reported complete seizure freedom, eight (42%) reported a greater than 80% reduction in seizure frequency, and six (32%) reported a 25-60% seizure reduction.

Other beneficial effects included increased alertness, better mood and improved sleep. Side effects included drowsiness and fatigue.

Our survey shows that parents are using cannabidiol-enriched cannabis as a treatment for children with treatment-resistant epilepsy. Because of the increasing number of states that allow access to medical cannabis, its use will likely be a growing concern for the epilepsy community. Safety and tolerability data for cannabidiol-enriched cannabis use among children is not available. Objective measurements of a standardized preparation of pure cannabidiol are needed to determine whether it is safe, well tolerated and efficacious at controlling seizures in this difficult-to-treat pediatric population.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157067/

Cannabidiol monotherapy for treatment-resistant schizophrenia

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“Cannabidiol (CBD), one of the major products of the marijuana plant, is devoid of marijuana’s typical psychological effects. In contrast, potential antipsychotic efficacy has been suggested based on preclinical and clinical data.

In this report, we further investigated the efficacy and safety of CBD monotherapy in three patients with treatment-resistant schizophrenia (TRS).

Efficacy, tolerability and side effects were assessed.

All patients tolerated CBD very well and no side effects were reported.

These preliminary data suggest that CBD monotherapy may not be effective for TRS.”

http://jop.sagepub.com/content/20/5/683.short

Hypothermia induced by delta9-tetrahydrocannabinol in rats with electrolytic lesions of preoptic region.

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“The preoptic region (POR) is a primary central site for thermoregulation. Bilateral lesions of POR disrupt thermoregulation, and in rats, produce a characteristic syndrome including hyperthermia.

delta9-Tetrahydrocannabinol (delta9-THC), a potent hypothermic agent, appears to mediate this effect via some central mechanism. The studies reported here suggest that delta9-THC induces hypothermia at a site other than POR.

These data demonstrate that delta9-THC is able to induce a hypothermic response in rats whose body temperatures were elevated by POR ablation. Although delta9-THC does not appear to act primarily at POR to induce hypothermia, it is evident than an intact POR plays a role in modifying the duration and magnitude of delta9-THC induced hypothermia.”

http://www.ncbi.nlm.nih.gov/pubmed/996043

Pharmacological hypothermia: a potential for future stroke therapy?

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“Mild physical hypothermia after stroke has been associated with positive outcomes.

Pharmacologically induced hypothermia has been explored as a possible treatment option following stroke in animal models.

Currently, there are eight classes of pharmacological agents/agonists with hypothermic effects affecting a multitude of systems including cannabinoid, opioid, transient receptor potential vanilloid 1 (TRPV1), neurotensin, thyroxine derivatives, dopamine, gas, and adenosine derivatives.

This review offers the opinion that these agents may be useful in combination therapies with physical hypothermia to achieve faster and more stable temperature control in hypothermia.”

http://www.ncbi.nlm.nih.gov/pubmed/27320243

No Link Between Marijuana Use and Stroke Risk

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“There was no evidence that marijuana use was associated with an increased risk of ischemic stroke in adolescents and young adults, a researcher said here.

“Our data did not support” a link between the drug and stroke risk”

http://www.medpagetoday.com/meetingcoverage/aan/45577

“Cannabinoids in experimental stroke: a systematic review and meta-analysis. Cannabinoids (CBs) show promise as neuroprotectants with some agents already licensed in humans for other conditions. Cannabinoids reduced infarct volume in transient and permanent ischemia and in all subclasses: endocannabinoids, CB1/CB2 ligands, CB2 ligands, cannabidiol, Δ9-tetrahydrocannabinol, and HU-211. Overall, CBs significantly reduced infarct volume and improve functional outcome in experimental stroke.” http://www.ncbi.nlm.nih.gov/pubmed/25492113

http://www.thctotalhealthcare.com/category/stroke-2/

Pot a Common Remedy to Ease Back Pain

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“Use of marijuana to ease back pain was common among patients at a university spine clinic in Colorado where pot has been legal for medical purposes since 2000, but most of the users did not have a prescription, according to research presented here.

Among 184 patients at a Colorado spine center, 19% said they used marijuana for pain relief, but less than half, 46%, actually had a prescription for the drug, according to study co-author Michael Finn, MD, an assistant professor of neurosurgery at the University of Colorado in Denver.

The most common way to use the drug was smoking it, 90%, followed by oral ingestion, 45%, and vaporization, 29%.

According to the users, marijuana worked. A total of 89% said it greatly or moderately relived their pain, and 81% said it worked as well as or better than narcotic painkillers.”

http://www.medpagetoday.com/MeetingCoverage/AdditionalMeetings/42228

β-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease.

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“Parkinson disease (PD) is a neurodegenerative disease characterized by progressive dopaminergic neurodegeneration in the substantia nigra pars compacta (SNc) area.

The present study was undertaken to evaluate the neuroprotective effect of β-caryophyllene (BCP) against rotenone-induced oxidative stress and neuroinflammation in a rat model of PD.

The findings demonstrate that BCP provides neuroprotection against rotenone-induced PD and the neuroprotective effects can be ascribed to its potent antioxidant and anti-inflammatory activities.”

http://www.ncbi.nlm.nih.gov/pubmed/27316720

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”  http://www.ncbi.nlm.nih.gov/pubmed/23138934

http://www.thctotalhealthcare.com/category/parkinsons-disease/

Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinsońs disease.

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“Elements of the endocannabinoid system are strongly expressed in the basal ganglia where they suffer profound rearrangements after dopamine depletion.

Modulation of the levels of the endocannabinoid 2-arachidonoyl glycerol by inhibiting monoacylglycerol lipase alters glial phenotypes and provides neuroprotection in a mouse model of Parkinsońs disease.

In this study, we assessed whether inhibiting fatty acid amide hydrolase could also provide beneficial effects on the time course of this disease.

Together, these results demonstrate an effect of fatty acid amide hydrolase inhibition on the motor symptoms of Parkinsońs disease in two distinct experimental models that is mediated by cannabinoid receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27318096

Cannabinoid receptor agonism suppresses tremor, cognition disturbances and anxiety-like behaviors in a rat model of essential tremor.

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“Cognitive and motor disturbances are serious consequences of tremor induced by motor disorders. Despite a lack of effective clinical treatment, some potential therapeutic agents have been used to alleviate the cognitive symptoms in the animal models of tremor.

In the current study, the effects of WIN55, 212-2 (WIN), a cannabinoid receptor (CBR) agonist, on harmaline-induced motor and cognitive impairments was studied.

The neuroprotective and anxiolytic effects of WIN demonstrated in the current study can be offered cannabinoid receptor (CBR) agonism as a potential neuroprotective agent in the treatment of patients with tremor that manifest mental dysfunctions.”

http://www.ncbi.nlm.nih.gov/pubmed/27317835