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review of the neurological benefits of phytocannabinoids

Methods: In 1980, Cunha et al. reported anticonvulsant benefits in 7/8 subjects with medically uncontrolled epilepsy using marijuana extracts in a phase I clinical trial. Since then neurological applications have been the major focus of renewed research using medical marijuana and phytocannabinoid extracts.

Keywords: Cannabidiol; delta-9-tetrahydrocannabinol; endocannabinoid system; neurological disease; phytocannabinoids.

Conflict of interest statement

Background: Numerous physical, psychological, and emotional benefits have been attributed to marijuana since its first reported use in 2,600 BC in a Chinese pharmacopoeia. The phytocannabinoids, cannabidiol (CBD), and delta-9-tetrahydrocannabinol (Δ9-THC) are the most studied extracts from cannabis sativa subspecies hemp and marijuana. CBD and Δ9-THC interact uniquely with the endocannabinoid system (ECS). Through direct and indirect actions, intrinsic endocannabinoids and plant-based phytocannabinoids modulate and influence a variety of physiological systems influenced by the ECS.

Conclusions: In this review we will provide animal and human research data on the current clinical neurological uses for CBD individually and in combination with Δ9-THC. We will emphasize the neuroprotective, antiinflammatory, and immunomodulatory benefits of phytocannabinoids and their applications in various clinical syndromes.

Results: Recent neurological uses include adjunctive treatment for malignant brain tumors, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, neuropathic pain, and the childhood seizure disorders Lennox-Gastaut and Dravet syndromes. In addition, psychiatric and mood disorders, such as schizophrenia, anxiety, depression, addiction, postconcussion syndrome, and posttraumatic stress disorders are being studied using phytocannabinoids.

Keywords: cannabis, pain, brain tumor, epilepsy, Alzheimer disease, Parkinson disease, traumatic brain injury, microbiome

Pisani, A., Fezza, F., Galati, S., Battista, N., Napolitano, S., Finazzi-Agro, A., et al. (2005). High endogenous cannabinoid levels in the cerebrospinal fluid of untreated Parkinson’s disease patients. Ann. Neurol. 57, 777–779. doi: 10.1002/ana.20462

Russo, E. B., Mead, A. P., and Sulak, D. (2015). Current status and future of cannabis research. Clin. Res. 58–63. doi: 10.14524/CR-15-0004

Footnotes

Emery, D. C., Shoemark, D. K., Batstone, T. E., Waterfall, C. M., Coghill, J. A., Cerajewska, T. L., et al. (2017). 16S rRNA next generation sequencing analysis shows bacteria in Alzheimer’s post-mortem brain. Front. Aging Neurosci. 9:195. doi: 10.3389/fnagi.2017.00195

Legitimate concerns surround the psychoactive sequelae of THC, but as amply demonstrated by the nabiximols RCTs and supported by mitigating effects of cannabidiol and cannabis terpenoids (Russo, 2011; Russo and Marcu, 2017; Lewis et al., 2018; MacCallum and Russo, 2018), cannabis-based drugs portend to provide future safe and effective treatments for heretofore recalcitrant neurological conditions.

Devinsky, O., Cross, J. H., Laux, L., Marsh, E., Miller, I., Nabbout, R., et al. (2017). Trial of cannabidiol for drug-resistant seizures in the dravet syndrome. N. Engl. J. Med. 376, 2011–2020. doi: 10.1056/NEJMoa1611618

Subsequent investigation demonstrated that seizure threshold is mediated by the endocannabinoid system (Wallace et al., 2003), and that THC produced a 100% reduction in seizures, whereas phenobarbital and diphenylhydantoin did not. Additionally, animal studies demonstrated both acute increases in endocannabinoid production and a long-term up-regulation of CB1 production as apparent compensatory effects counteracting glutamate excitotoxicity, and that anticonvulsant effect was present at sub-sedating levels.

In an animal model of AD, treatment with Δ9-THC (3 mg/kg) once daily for 4 weeks with addition of a COX-2 inhibitor reduced the number of beta-amyloid plaques and degenerated neurons. Δ9-THC has been used for AD symptom control. Treatment with 2.5 mg dronabinol (a synthetic analog of Δ9-THC) daily for 2 weeks significantly improved the neuropsychiatric inventory total score for agitation and aberrant motor and nighttime behaviors.[121]

The FDA has approved the synthetic drugs Cesamet®, Marinol®, and Syndros® for therapeutic uses in the U.S. FDA-posted indications include nausea and the treatment of anorexia associated with weight loss in AIDS patients. Marinol® and Syndros® include the active ingredient dronabinol, a synthetic delta-9-THC. Cesamet® contains the active ingredient nabilone that has a chemical structure similar to THC and is also synthetically derived. Although these medications are often cited in human clinical research, their general use is limited based both on side effects and indication constraints.

Cannabidiol

Numerous physical, psychological, and emotional benefits have been attributed to marijuana since its first reported use in 2,600 BC in a Chinese pharmacopoeia. The phytocannabinoids, cannabidiol (CBD), and delta-9-tetrahydrocannabinol (Δ9-THC) are the most studied extracts from cannabis sativa subspecies hemp and marijuana. CBD and Δ9-THC interact uniquely with the endocannabinoid system (ECS). Through direct and indirect actions, intrinsic endocannabinoids and plant-based phytocannabinoids modulate and influence a variety of physiological systems influenced by the ECS.

CBD, and to a lesser degree Δ9-THC, can have both direct and indirect effects on isoforms of peroxisome proliferator-activated receptors (PPARs α, β, and γ). Activation of PPAR, along with CB1 and CB2, mediates numerous analgesic, neuroprotective, neuronal function modulation, antiinflammatory, metabolic, antitumor, gastrointestinal, and cardiovascular effects, both in and outside the ECS. In addition, PPAR-γ (gamma) agonists have been used in the treatment of hyperlipidemia and hyperglycemia. PPAR-γ decreases the inflammatory response of many cardiovascular cells, particularly endothelial cells, thereby reducing atherosclerosis. Phytocannabinoids can increase the transcriptional activity of and exert effects that are inhibited by selective antagonists of PPAR-γ, thus increasing production.[33]

In this review we will provide animal and human research data on the current clinical neurological uses for CBD individually and in combination with Δ9-THC. We will emphasize the neuroprotective, antiinflammatory, and immunomodulatory benefits of phytocannabinoids and their applications in various clinical syndromes.