Cannabis Therapeutics and the Future of Neurology
Ethan B. RUSSO
Frontiers in Integrative Neuroscience, 18 October 2018
Neurological therapeutics have been hampered by its inability to advance beyond symptomatic treatment of neurodegenerative disorders into the realm of actual palliation, arrest or reversal of the attendant pathological processes. While cannabis-based medicines have demonstrated safety, efficacy and consistency sufficient for regulatory approval in spasticity in multiple sclerosis (MS), and in Dravet and Lennox-Gastaut Syndromes (LGS), many therapeutic challenges remain. This review will examine the intriguing promise that recent discoveries regarding cannabis-based medicines offer to neurological therapeutics by incorporating the neutral phytocannabinoids tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors, tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), and cannabis terpenoids in the putative treatment of five syndromes, currently labeled recalcitrant to therapeutic success, and wherein improved pharmacological intervention is required: intractable epilepsy, brain tumors, Parkinson disease (PD), Alzheimer disease (AD) and traumatic brain injury (TBI)/chronic traumatic encephalopathy (CTE). Current basic science and clinical investigations support the safety and efficacy of such interventions in treatment of these currently intractable conditions, that in some cases share pathological processes, and the plausibility of interventions that harness endocannabinoid mechanisms, whether mediated via direct activity on CB1 and CB2 (tetrahydrocannabinol, THC, caryophyllene), peroxisome proliferator-activated receptor-gamma (PPARγ; THCA), 5-HT1A (CBD, CBDA) or even nutritional approaches utilizing prebiotics and probiotics. The inherent polypharmaceutical properties of cannabis botanicals offer distinct advantages over the current single-target pharmaceutical model and portend to revolutionize neurological treatment into a new reality of effective interventional and even preventative treatment.
Cannabis burst across the Western medicine horizon after its introduction by William O’Shaughnessy in 1838 (O’Shaughnessy, 1838–1840; Russo, 2017b), who described remarkable successes in treating epilepsy, rheumatic pains, and even universally fatal tetanus with the “new” drug. Cannabis, or “Indian hemp,” was rapidly adopted by European physicians noting benefits on migraine by Clendinning in England (Clendinning, 1843; Russo, 2001) and neuropathic pain, including trigeminal neuralgia by Donovan in Ireland (Donovan, 1845; Russo, 2017b). These developments did not escape notice of the giants of neurology on both sides of the Atlantic, who similarly adopted its use in these indications: Silas Weir Mitchell, Seguin, Gowers and Osler (Mitchell, 1874; Seguin, 1877; Gowers, 1888; Osler and McCrae, 1915). While medicinal cannabis suffered a period of obscurity and quiescence, mainly attributable to quality control issues and political barriers, modern data on migraine (Russo, 2004, 2016b; Rhyne et al., 2016) and neuropathic pain, whether central or peripheral support its common application by affected patients (Rog et al., 2005; Nurmikko et al., 2007; Russo and Hohmann, 2013; Serpell et al., 2014), additionally supported by the National Academies of Science, Engineering and Medicine (National Academies of Sciences Engineering and Medicine (U.S.). Committee on the Health Effects of Marijuana: An Evidence Review and Research Agenda, 2017).
It has been noted for some time that muscle tone on the central level is mediated by the endocannabinoid system (Baker et al., 2003), but some additional years were necessary to bring this “aspirin of the 21st century” through Phase I–III Randomized Clinical Trials (RCTs; Novotna et al., 2011) and post-marketing assessment to demonstrate its safety, efficacy and consistency (Rekand, 2014; Fife et al., 2015; Maccarrone et al., 2017). That preparation, nabiximols (US Adopted Name; Sativex®) has currently attained regulatory approval in 30 countries for spasticity associated with multiple sclerosis (MS), and in Canada for central neuropathic pain in MS (Rog et al., 2005), and for opioid-resistant cancer pain (Johnson et al., 2010). Recent surveys find usage rates for cannabis of 20%–60% among MS patients (Rudroff and Honce, 2017). An earlier attempt to demonstrate neuroprotection in head trauma after intravenous administration of single doses of the non-intoxicating cannabinoid analog, dexanabinol, failed (Maas et al., 2006), but hope remains for other preparations in stroke and other brain insults (Latorre and Schmidt, 2015; Russo, 2015; Pacher et al., 2018). Table 1 summarizes the current status of cannabis-based drugs in neurological conditions not discussed at length herein, including sleep disturbance (Russo et al., 2007; Babson et al., 2017), glaucoma (Merritt et al., 1980), lower urinary tract symptoms (LUTS; Brady et al., 2004; Kavia et al., 2010), social anxiety (Bergamaschi et al., 2011), Tourette syndrome (Müller-Vahl et al., 2002, 2003) and schizophrenia (Leweke et al., 2012; McGuire et al., 2018). This Perspective article will rather focus on several neurological syndromes that overlap in their pathophysiology or have yet to receive concerted attention in clinical trials of cannabis-based medicines.fnint-12-00051