Cannabidiol : Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders

Orrin Devinsky, Maria Roberta Cilio, Helen Cross, Javier Fernandez-Ruiz, Jacqueline French, Charlotte Hill, Russell Katz, Vincenzo Di Marzo, Didier Jutras-Aswad, William George Notcutt, Jose Martinez-Orgado, Philip J. Robson, Brian G. Rohrback, Elizabeth Thiele, Benjamin Whalley, and Daniel Friedman

Epilepsia, 2014, 55, 6, 791–802,

doi: 10.1111/epi.12631

 

SUMMARY

To present a summary of current scientific evidence about the cannabinoid, cannabidiol (CBD) with regard to its relevance to epilepsy and other selected neuropsychiatric disorders.Wesummarize the presentations from a conference in which invited participants reviewed relevant aspects of the physiology, mechanisms of action, pharmacology, and data from studies with animal models and human subjects. Cannabis has been used to treat disease since ancient times. D9-Tetrahydrocannabinol (D9-THC) is the major psychoactive ingredient and CBD is the major nonpsychoactive ingredient in
cannabis. Cannabis and D9-THC are anticonvulsant in most animal models but can be proconvulsant in some healthy animals. The psychotropic effects of D9-THC limit tolerability. CBD is anticonvulsant in many acute animal models, but there are limited data in chronic models. The antiepileptic mechanisms of CBD are not known, but may include effects on the equilibrative nucleoside transporter; the orphan G-protein-coupled receptor GPR55; the transient receptor potential of vanilloid type-1 channel; the 5-HT1a receptor; and the a3 and a1 glycine receptors. CBD has neuroprotective and anti-inflammatory effects, and it appears to be well tolerated in humans, but small and methodologically limited studies of CBD in human epilepsy have been inconclusive. More recent anecdotal reports of high-ratio CBD:D9-THC medical marijuana have claimed efficacy, but studies were not controlled. CBD bears investigation in epilepsy and other neuropsychiatric disorders, including anxiety, schizophrenia, addiction, and
neonatal hypoxic-ischemic encephalopathy. However, we lack data from well-powered double-blind randomized, controlled studies on the efficacy of pure CBD for any disorder. Initial dose-tolerability and double-blind randomized, controlled studies focusing on target intractable epilepsy populations such as patients with Dravet and Lennox- Gastaut syndromes are being planned. Trials in other treatment resistant epilepsies may also be warranted.

KEY WORDS : Cannabidiol, Cannabis, Tetrahydroacannabinol, Dravet syndrome, GPR55, Medical marijuana.

Cannabis sativa and its sister species Cannabis indica have been used to treat epilepsy for centuries. Recent years have seen a resurgence in interest in the therapeutic potential of compounds derived from these plants. Specifically, the nonpsychoactive compound cannabidiol (CBD) has shown promise as an anticonvulsant with novel mechanisms of action and a favorable side-effect profile. Cannabinoid-based
therapies are already approved for conditions as diverse as spasticity, nausea, and pain. An abundance of preclinical evidence and anecdotal human data support the use of cannabinoids in the treatment of epilepsy. In this article, we survey the history of cannabis and its derivatives in the treatment of epilepsy from ancient times to the present day; review the clinical pharmacology of the neuroactive components of cannabis; summarize research into the potential of cannabinoids in other neurologic and psychiatric disorders; and discuss avenues for future clinical trials.

Cannabinoids : A Brief History of Their Medicinal Uses

The Cannabis genus of flowering plants mainly comprises the sativa and indica species. Indigenous to Central and South Asia, cannabis was used for millennia to produce hemp fiber for rope, clothing, bowstrings, and paper; for its seeds and seed oils; as livestock feed; and for medicine, religious ceremonies, and recreation. Hemp is now a worldwide crop used to make cordage, construction material, paper, and textiles, as well as for edible seeds, milk, and oil.

The two major neuroactive components in cannabis are the psychoactive D9-tetrahydrocannabinol (D9-THC) and the nonpsychoactive cannabidiol. We use nonpsychoactive to indicate a lack of psychotropic effects that produce a “high” similar to that of D9-THC; however, CBD can have some antianxiety and other behavioral effects.1 Cannabis sativa usually has higher D9-THC:CBD ratios than Cannabis indica. Sativa strains often have more psychotropic effects, and are more stimulating, whereas indica strains are typically more sedating.2 D9-THC activates the endocannabinoid system, which consists of G-protein-coupled cannabinoid (CB) receptors, synthetic and degradative enzymes, and transporters. In the central nervous system, this system influences synaptic communication and modulates eating, anxiety, learning and memory, and growth and development.3

Medicinal preparations from the flowers and resin of C. sativa have been used in China since ~2,700 BCE to treat menstrual disorders, gout, rheumatism, malaria, constipation, and absent-mindedness.4 In medieval times, Islamic physicians used cannabis to treat nausea and vomiting, epilepsy, inflammation, pain, and fever. Western medicine used cannabis widely in the 1800s; before aspirin, it was a common analgesic drug. More recently, cannabis has been used to treat glaucoma, pain, nausea and vomiting, muscle spasms, insomnia, anxiety, and epilepsy. Evidence for efficacy varies substantially for different indications, with the best data in painful HIV-associated sensory neuropathy,5 chronic pain,6 chemotherapy-induced nausea and vomiting, 7 and spasms in patients with multiple sclerosis.8 Other medicinal uses for cannabis have been proposed (discussed later in this article), but none has been examined in wellcontrolled clinical trials.

Use in epilepsy in the modern era

In the late 19th century, prominent English neurologists including Reynolds9 and Gowers10 used cannabis to treat epilepsy (see Box 1). However, the use of cannabis for epilepsy remained very limited, and despite anecdotal successes, cannabis received scant or no mention from Englishlanguage
epilepsy texts in the late 19th and early to mid- 20th centuries.

Four controlled studies, mainly in the 1970s, examined the effect of CBD on seizures (Table 1, reviewed in Gloss & Vickrey11). However, although two of the studies found limited improvements, all four suffered from methodological flaws, including small sample size and, in some cases, inadequate blinding.

One epidemiologic study of illicit drug use and new-onset seizures found that cannabis use appeared to be a protective factor against first seizures in men.12 The adjusted odds ratio (OR) was 0.42 for every cannabis use and 0.36 for cannabis use within 90 days of hospitalization. No effect was observed in women. The authors suggested that cannabis is protective of both provoked and unprovoked seizures, for
men.

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