Cannabichromene, Related Phytocannabinoids, and 5-Fluoro-cannabichromene Have Anticonvulsant Properties in a Mouse Model of Dravet Syndrome

Abstract

Cannabis-based products are increasingly being used to treat refractory childhood epilepsies such as Dravet syndrome. Cannabis contains at least 140 terpenophenolic compounds known as phytocannabinoids. These include the known anticonvulsant compound cannabidiol (CBD) and several molecules showing emergent anticonvulsant properties in animal models. Cannabichromene (CBC) is a phytocannabinoid frequently detected in artisanal cannabis oils used in the community by childhood epilepsy patients. Here we examined the brain and plasma pharmacokinetic profiles of CBC, cannabichromenic acid (CBCA), cannabichromevarin (CBCV), and cannabichromevarinic acid (CBCVA) following intraperitoneal administration in mice. The anticonvulsant potential of each was then tested against hyperthermia-induced seizures in the Scn1a +/– mouse model of Dravet syndrome. All phytocannabinoids within the CBC series were readily absorbed and showed substantial brain penetration (brain–plasma ratios ranging from 0.2 to 5.8). Anticonvulsant efficacy was evident with CBC, CBCA, and CBCVA, each significantly increasing the temperature threshold at which Scn1a +/– mice had a generalized tonic–clonic seizure. We synthesized a fluorinated derivative of CBC (5-fluoro-CBC), which showed improved brain penetration relative to the parent CBC molecule but not any greater anticonvulsant effect. Since CBC and derivatives are anticonvulsant in a model of intractable pediatric epilepsy, they may constitute part of the mechanism through which artisanal cannabis oils are anticonvulsant in patients.

Systematic evaluation of a panel of 30 synthetic cannabinoid receptor agonists structurally related to MMB‐4en‐PICA, MDMB‐4en‐PINACA, ADB‐4en‐PINACA, and MMB‐4CN‐BUTINACA using a combination of binding and different CB1 receptor activation assays—Part II: Structure activity relationship assessment via a β‐arrestin recruitment assay

“…However, it should be emphasized that the findings reported here primarily reflect the intrinsic potential of these compounds to activate CB 1 . Ideally, in vivo studies examining conventional cannabinoid effects, like body temperature and heart rate changes, 30 hyperthermia‐induced seizures, 35 the cold plate test, 36 or the tetra test (assessing locomotion, catalepsy, body temperature, and analgesia) 37 are used to further substantiate these findings. In this context, it needs to be mentioned that in vivo, the net impact of these compounds will be determined by many factors, including bioavailability, metabolic stability, the formation of active metabolites, blood brain barrier penetration, and off‐target effects.…”

A primer on medicinal cannabis safety and potential adverse effects

“…Other products contain CBD and/or THC with a 'full-spectrum' of cannabis plant constituents including other phytocannabinoids (eg cannabichromene, cannabigerol, ∆ 9 -tetrahydrocannabinolic acid or cannabidiolic acid) as well as terpenes and flavonoids, all of which may have therapeutic effects. [7][8][9][10] To ascertain exactly what is contained in a given medicinal cannabis product, a request can be made to the manufacturer for a certificate of analysis. Therapeutic daily doses of CBD are typically between 50 mg and 1500 mg, which are greater than those for THC, which are between 5 mg and 20 mg. 1 When evaluating the safety profile of medicinal cannabis products, it is important to consider the relative THC and CBD content, as CBD generally has fewer safety concerns than THC.…”

Cannabinoids in the Treatment of Epilepsy: A Review

“…70 Cannabichromene and its related phytocannabinoids were recently demonstrated to have anticonvulsant properties in a DS mouse model. 71 Other cannabinoids including cannabinol, cannabidiolic acid, and tetrahydrocannabinolic acid that have been researched for neuroprotective and therapeutic potential in other neurologic conditions have yet to be studied in epilepsy. 72 There is also evidence to suggest benefit from combinations of cannabinoids.…”