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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 122034 approval in spasticity in multiple sclerosis MSand in Dravet and Lennox-Gastaut Syndromes LGSmany therapeutic challenges remain.
This review will examine the intriguing promise that recent discoveries regarding cannabis-based medicines offer to neurological lej by incorporating the neutral phytocannabinoids tetrahydrocannabinol THCcannabidiol CBDtheir acidic precursors, tetrahydrocannabinolic acid THCA and cannabidiolic acid CBDAand cannabis terpenoids in the putative treatment of five syndromes, currently labeled recalcitrant to therapeutic success, and wherein improved pharmacological intervention is required: 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.
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: While medicinal cannabis suffered a period of obscurity and quiescence, mainly attributable to quality control issues and political barriers, modern data on migraine Russo,b ; Rhyne et al. Committee on the Health Effects of Marijuana: An Evidence Review and Research Agenda, It has been noted for some time that muscle tone on the central level is mediated by the endocannabinoid system Baker et al.
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. Table 1 summarizes the current status of cannabis-based drugs in neurological conditions not discussed at length herein, including sleep disturbance Russo et al.
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. Neurological conditions for which cannabis-based treatments have been employed revised, reformatted and supplemented from MacCallum and Russo, This author has previously addressed the pathophysiology of migraine Sarchielli et al. Various synthetic fatty acid amidohydrolase FAAH inhibitors have been investigated for neurological therapeutics Nozaki et al.
This is a mechanism of action seemingly shared with cannabidiol Bisogno et al. After elucidation of phytocannabinoid structures in the s, their pharmacology was slowly revealed reviewed by Cascio and Pertwee, ; Pertwee and Cascio, ; Russo and Marcu, ; Figure 1.
Although dose-response was tested, it is unclear that very low doses were assessed and given the biphasic tendencies of cannabinoids, it is possible that positive lower dose effects may have remained unnoticed. CBD was considered an excellent candidate for development based on its lack of untoward psychoactive sequelae. However, little work was done until a series of small human trials in Brazil in following decades reviewed by Russo, a.
Subsequent investigation demonstrated that seizure threshold is mediated by the endocannabinoid system Wallace et al. Additionally, animal studies demonstrated both acute increases in endocannabinoid production and a long-term up-regulation of CB 1 production as apparent compensatory effects counteracting glutamate excitotoxicity, and that anticonvulsant effect was present at sub-sedating levels.
Sporadic case reports of successful utilization of THC in seizures associated with severe neurological conditions in children in Germany followed Lorenz, ; Gottschling,but the prime focus returned to CBD due to strong anticonvulsant results in laboratory investigation Jones et al.
The lay public quickly became aware of these developments, with promotion of the concept by Project CBD 1 and publicity associated with the case of Charlotte Figi and significant improvement in seizures associated with Dravet syndrome, as portrayed on the Weeds documentary on Cable News Network Maa and Figi, Positive survey results Porter and Jacobson, were tempered, however, by studies suggesting strong ascertainment bias in parental reporting of seizure frequency: More recent studies have bolstered evidence for safety and efficacy of the preparation in both conditions Devinsky et al.
Interestingly, extensive observations from other practitioners Russo et al.
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Selective cannabis breeding via Mendelian techniques raises the possibility of producing chemovars with multiple anticonvulsant components that may produce synergistic benefits Lewis et al. Cannabidiolic acid CBDA was also recently reported to demonstrate anticonvulsant activity Bonni Goldstein, personal communicationpossibly attributable to its serotonergic activity Bagdy et al.
Strong pei evidence of cytotoxic benefit of phytocannabinoids has been available since Munson et al. Brain tumors are the subject of an excellent current review Dumitru et al. Case reports from Canada documented total regression of residua in two pilocytic astrocytomata in children after smoked cannabis Foroughi et al.
Careful laboratory analysis has established synergistic benefits of combinations of THC, CBD and standard chemotherapy with temozolomide on glioma Torres et al. Clinical application of the concept has been reported online in a Phase II randomized controlled trial RCT of 21 patients with recurrent GBM fe temozolomide plus nabiximols up to 12 sprays per day This finding, however, has much larger implications and could explain claims of therapeutic efficacy in epilepsy noted above Sun et al.
In contrast to other neutral cannabinoids and terpenoids, THCA is reported not to cross the blood-brain barrier BBBbut if true, that hindrance may le be applicable in the context of chronic epilepsy Oby and Janigro,or in brain tumors wherein that barrier is compromised.
Ldi reviewed Elrod and Sun,PPARs are ligand-binding transcription factors on nuclear membranes that affect adipogenesis, apoptosis and many other functions.
Butyrate and capsaicin may be natural ligands. Because of the density of cannabinoid receptors in basal ganglia, PD has been an area of active research, but with mixed results therapeutically.
CBD extract showed no significant benefits on dyskinesia or other signs in 17 patients Carroll et al. Five of nine patients using cannabis reported great improvement, particularly on mood and sleep Finseth fe al.
Whereas PD is commonly attributed to cell loss in the substantia nigra, with chronicity, widespread pathology is 22009 norm. In common with Alzheimer disease ADtau proteins that regulate microtubule assembly, cytoskeletal integrity and axonal transport in neurons develop neurofibrillary tangles Lei et al. Interestingly, nabiximols reduced such tangles in parkin-null human tau-expressing mice with improvement in dopamine metabolism, glial function and oxidative stress, as dw as reducing anxiety and self-injury Casarejos et fe.
Recent reviews Aso and Ferrer, ; Ahmed et al. Once the process begins, deterioration is inexorable. Additional pathology includes functional mitochondrial defects, increased reactive oxygen species ROS and reactive nitrogen species RNSand failure of enzymes involved in energy production that, in turn, produces nerve cell exhaustion.
Eventually, synapses and dendritic branching fail, with consequent progressive neuronal wastage. Dementia and cognitive decline develop, and no treatment arrests the process. Intervention must begin at an early preclinical stage to have any hope of success. Endocannabinoid function modulates the primary pathological processes of AD during the silent phase of neurodegeneration: The epidemiology of AD is fascinating Mayeux and Stern, North America and Western Europe have highest rates 6.
Prevalence is lower for Africans in homelands, as opposed to higher rates in the Western European and American diaspora. Mediterranean diet increased monounsaturated olive oil, and omega-3 from fisheducation and physical activity reduce it. No current pharmacotherapy is approved for agitation in AD.
Commonly used anti-psychotics, antidepressants, anxiolytics and hypnotics are often associated with increased mortality in demented patients Kales et al.
None show strong evidence of efficacy and are of limited benefit on a temporary basis. Various NMDA receptor antagonists in development have proven largely ineffective on disease progression or have proven toxic. In contrast, treatment with cannabinoids appears both more promising and benign. As demonstrated in Hampson et al. Subsequently Iuvone et al.
In an in vivo model Esposito et al.
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In addition to its neuroprotective antioxidant effects Iuvone et al. In Volicer et al. In Walther et al. A study van den Elsen et al. A total lack of AEs indicated to the even the authors that the administered dosage was inadequate and that higher doses might be required.
Initial trials of herbal cannabis for AD have begun sporadically, with a more focused effort in a California nursing home Hergenrather, Patients were treated with a variety of preparations: Marked benefit was reported on neuroleptic drug sparing, decreased agitation, increased appetite, aggression, sleep quality, objective mood, nursing care demands, self-mutilation and pain control.
1234 on its pharmacology Russo and Marcu,cannabis components may provide myriad benefits on target symptoms in this complex disorder:. The neuroprotective antioxidant effects of the cannabinoids Hampson et al.
A recent study Mez et al. Microglia were present early in the course, whose premonitory symptoms include dementia, personality change, rage, and attention problems.
Ninety-six percent demonstrated a degenerative course. Heretofore, this has been considered a post-mortem pathological diagnosis, but two current studies support the ability for pre-mortem identification. CCL11 protein is a chemokine associated with cognitive decline and enhances microglial production of ROS and excitotoxic cell death.
The greatest tau concentration was observed in parasagittal and paraventricular cortical and brainstem areas Omalu et al. Neuroprotective benefits of phytocannabinoids, particularly CBD, further outlined below, provide support for trials of these agents in post-traumatic syndrome and CTE prevention. This is termed the microbiome. Obese humans have lower Bacteroidetes and higher Firmicutes counts.
Recent review Clarke et al. Another recent review elucidates additional findings of pertinence to the current discussion He and Shi, The combination of prebiotics dietary fiber that serves as bacterial feedstock, reviewed by Russo, aand deficient in modern Western diets Calame et al. Additionally, prebiotics change microbiota to reduce adipogenesis and stabilize the gut barrier. Furthermore, CB 2 levels correlate to Lactobacillus concentrations and negatively with potentially pathogenic Clostridium species.
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Other experiments relate the microbiome to the ECS. 12043, THC prevented weight gain despite a high-fat diet Cluny et al. Additional dietary factors include the function of bitter taste receptors Fe et al. Diet is also a key factor in acne vulgariswhose pathophysiology and epidemiology are surprisingly relevant to this discussion.
Acne was not observed in Ve populations living a traditional lifestyle over 30 years, but became common with adoption of a Western diet and lifestyle Cordain et al. Similarly, no acne was observed in Papua New Guinea or Paraguay among traditional indigenous peoples. Neither population demonstrated markers of insulin resistance, nor leptin elevations.
The author then suggests that in many respects, the epidemiology of acne parallels that of AD. The relationship becomes more salient in light of recent findings Emery et al.
Cerebral hypoperfusion with impaired vessel dilation is a pathogenetic factor in AD. Alpha-pinene was also a potent inhibitor of the bacterium Raman et al. The importance of these relationships becomes apparent as efforts are made to integrate disparate threads Bowe and Logan,