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Cannabis Therapeutics and the Future of Neurology

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.

Introduction

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 ​ Table1 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.

Table 1

Neurological conditions for which cannabis-based treatments have been employed (revised, reformatted and supplemented from MacCallum and Russo, 2018).

Condition Preparation Level of evidence Type of evidence
Multiple sclerosis (MS) spasticity Nabiximols Conclusive Phase III RCTs, Regulatory approval
Epilepsy (Dravet and Lennox-Gastaut syndromes) Cannabidiol (Epidiolex ® ) Conclusive Phase III RCTs, Regulatory approval
Chronic pain THC, nabiximols Substantial Phase II RCTs
Schizophrenia, positive and negative symptoms CBD Substantial Phase II RCTs
Sleep disturbance secondary to neurological symptoms THC, nabilone, nabiximols Moderate Phase II–III RCTs
Glaucoma THC, cannabis Moderate Phase II RCTs
Lower urinary tract symptoms (LUTS) in MS Nabiximols Moderate Phase II RCTs
Tourette syndrome THC, cannabis Moderate Phase II RCTs, observational studies
Dementia with agitation THC, cannabis Limited Observational studies
Parkinson disease symptoms THC, CBD, cannabis Limited Observational studies
Post-traumatic stress disorder Cannabis Limited Observational studies
Social anxiety CBD Limited Phase II RCT, observational studies

This author has previously addressed the pathophysiology of migraine (Sarchielli et al., 2007), post-traumatic stress (Hill et al., 2013), Parkinson disease (PD; Pisani et al., 2005) and other conditions as putative clinical endocannabinoid deficiency disorders wherein disturbances in endocannabinoid tone have been demonstrated objectively (Russo, 2004, 2016b).

Various synthetic fatty acid amidohydrolase (FAAH) inhibitors have been investigated for neurological therapeutics (Nozaki et al., 2015), but none have advanced to Phase III clinical trials. This is a mechanism of action seemingly shared with cannabidiol (Bisogno et al., 2001).

Cannabis and Epilepsy

After elucidation of phytocannabinoid structures in the 1960s, their pharmacology was slowly revealed (reviewed by Cascio and Pertwee, 2014; Pertwee and Cascio, 2014; Russo and Marcu, 2017; Figure ​ Figure1). 1 ). Various components were tested for anticonvulsant activities with findings of ED50 in mice of 80 mg/kg for tetrahydrocannabinol (THC), 120 mg/kg for cannabidiol (CBD) and 200 mg/kg for tetrahydrocannabinolic acid A (THCA-A), the carboxylic acid precursor to THC found in raw cannabis flowers (Karler and Turkanis, 1979). 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, 2017a).

The pharmacology of phytocannabinoids pertinent to treatment of neurodegenerative disorders (molecular structures drawn by ER with ACD/ChemSketch 2015.2.5).

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.

Sporadic case reports of successful utilization of THC in seizures associated with severe neurological conditions in children in Germany followed (Lorenz, 2004; Gottschling, 2011), but the prime focus returned to CBD due to strong anticonvulsant results in laboratory investigation (Jones et al., 2010), which led directly to a pharmaceutical development program. 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, 2014). Positive survey results (Porter and Jacobson, 2013) were tempered, however, by studies suggesting strong ascertainment bias in parental reporting of seizure frequency: response rate for families moving to the state of Colorado for cannabidiol treatment was 47% vs. only 22% for those already living there, and were three-fold higher for those reporting >50% response (Press et al., 2015). More careful observational studies with a standardized cannabidiol oral extract with THC removed (Epidiolex ® ) provided more compelling results (Devinsky et al., 2016) with a 55% median reduction in seizures in Dravet and Lennox-Gastaut Syndrome (LGS) patients at high dose. Subsequent Phase III results in Dravet syndrome at CBD 20 mg/kg/d showed strong statistical significance in seizure frequency and Caregiver Global Impression of Change (Devinsky et al., 2017). More recent studies have bolstered evidence for safety and efficacy of the preparation in both conditions (Devinsky et al., 2018; Thiele et al., 2018). As a result, it received US Food and Drug Administration approval in June 2018.

Interestingly, extensive observations from other practitioners (Russo et al., 2015) seemed to indicate similar therapeutic successes with much lower doses of CBD when utilized in cannabis-based preparations with small concomitant amounts of THC, THCA and linalool, a terpenoid component of cannabis (Russo, 2017a; Sulak et al., 2017; Pamplona et al., 2018). Selective cannabis breeding via Mendelian techniques raises the possibility of producing chemovars with multiple anticonvulsant components that may produce synergistic benefits (Lewis et al., 2018). THCA is an intriguing issue, in that there is debate about whether it harbors CB1 activity, or rather is due to spontaneous decarboxylation to THC (McPartland et al., 2017; Figure ​ Figure1). 1 ). Cannabidiolic acid (CBDA) was also recently reported to demonstrate anticonvulsant activity (Bonni Goldstein, personal communication), possibly attributable to its serotonergic activity (Bagdy et al., 2007), in that CBDA demonstrates 100-fold greater affinity for the 5-HT1A receptor (Bolognini et al., 2013) as compared to CBD (Russo et al., 2005).

Cannabis and Brain Tumors

Strong scientific evidence of cytotoxic benefit of phytocannabinoids has been available since 1975 (Munson et al., 1975) and highlighted three decades later (Ligresti et al., 2006), but the historical record suggests ancient use by Egyptian Copts (THC and/or THCA; Reymond, 1976; Russo, 2007) with similar claims by Renaissance herbalists in Europe (CBD and/or CBDA; Russo, 2007). Brain tumors are the subject of an excellent current review (Dumitru et al., 2018). To summarize available research, specific pro-apoptotic activity of THC in C6 glioma was reported (Sánchez et al., 1998), and shrinkage of in situ human glioma cell line tumors was observed with CBD (Massi et al., 2004). Intra-tumoral THC administration in glioblastoma multiforme (GBM) produced slight life prolongation over expectations in nine human patients (Guzmán et al., 2006). Case reports from Canada documented total regression of residua in two pilocytic astrocytomata in children after smoked cannabis (Foroughi et al., 2011). Careful laboratory analysis has established synergistic benefits of combinations of THC, CBD and standard chemotherapy with temozolomide on glioma (Torres et al., 2011). Clinical application of the concept has been reported online in a Phase II randomized controlled trial (RCT) of 21 patients with recurrent GBM on temozolomide plus nabiximols up to 12 sprays per day (32.4 mg THC plus 30 mg CBD plus terpenoids) vs. placebo with an 83% 1-year survival vs. 53% in controls (p = 0.042) and survival exceeding 550 days vs. 369 for controls, and only two withdrawals in each group due to adverse events (AEs) 2 .

Such encouraging results are supplemented by a recent report that THCA is a peroxisome proliferator-activated receptor-gamma (PPARγ) agonist (IC50 = 470 nM, Ki = 209 nM) > CBGA (517.7 nM) and ≫ than CBDA, CBD or THC (Nadal et al., 2017). THCA improved neuronal viability in an animal model of Huntington disease (HD), and decreased striatal neurodegeneration (blocked by PPARγ antagonist), and it was suggested as a therapeutic agent in HD. This finding, however, has much larger implications and could explain claims of therapeutic efficacy in epilepsy noted above (Sun et al., 2008), as well tumors, and perhaps even in major depression (Colle et al., 2017a,b). In contrast to other neutral cannabinoids and terpenoids, THCA is reported not to cross the blood-brain barrier (BBB), but if true, that hindrance may not be applicable in the context of chronic epilepsy (Oby and Janigro, 2006), or in brain tumors wherein that barrier is compromised.

As reviewed (Elrod and Sun, 2008), PPARs are ligand-binding transcription factors on nuclear membranes that affect adipogenesis, apoptosis and many other functions. PPARγ stimulation may kill cancer cells without toxicity to normal cells, such as astrocytes, and their effects are additive with other cytotoxic agents. Butyrate and capsaicin may be natural ligands. PPARγ has been identified in many cancers including those affecting the brain, where it regulates target gene transcription (Shen et al., 2016), and its activation inhibits tumor cell growth. These authors suggested that PPARγ agonist may prove useful in treating brain tumors, and may extend as well to “benign” lesions, such as meningioma, wherein pioglitazone demonstrated activity (Gehring et al., 2011; Shen et al., 2016).

Thus, a Type II cannabis preparation, with equal THC and CBD concentration, combining THC, CBD, THCA and even CBDA along with cytotoxic terpenoids such as limonene may prove extremely useful in cancer treatment (Lewis et al., 2018).

Cannabis and Parkinson Disease (PD)

As early as 1888, Gowers noted benefits of “Indian hemp” on a parkinsonian syndrome (Gowers, 1888; Russo, 2007). Because of the density of cannabinoid receptors in basal ganglia, PD has been an area of active research, but with mixed results therapeutically. An oral THC:CBD extract showed no significant benefits on dyskinesia or other signs in 17 patients (Carroll et al., 2004), but CBD was helpful in five PD patients with psychosis (Zuardi et al., 2009) and 21 patients with more general symptoms (Chagas et al., 2014b) and more specifically on rapid eye movement sleep disorder in four patients (Chagas et al., 2014a). An observational study showed 22/28 patients tolerated smoked cannabis (presumably THC-predominant) and showed acute benefits on tremor, rigidity and bradykinesia (Lotan et al., 2014). Five of nine patients using cannabis reported great improvement, particularly on mood and sleep (Finseth et al., 2015).

A carefully crafted survey of 339 Czech patients using oral cannabis leaves reported significant alleviations of multiple symptoms (Venderová et al., 2004), particularly those using the treatment for three or more months, with improvement in general function (p < 0.001), resting tremor (p < 0.01), bradykinesia (p < 0.01), and rigidity (p < 0.01) with few side effects.

Whereas PD is commonly attributed to cell loss in the substantia nigra, with chronicity, widespread pathology is the norm. In common with Alzheimer disease (AD), tau proteins that regulate microtubule assembly, cytoskeletal integrity and axonal transport in neurons develop neurofibrillary tangles (Lei et al., 2010). Interestingly, nabiximols reduced such tangles in parkin-null human tau-expressing mice with improvement in dopamine metabolism, glial function and oxidative stress, as well as reducing anxiety and self-injury (Casarejos et al., 2013).

Cannabis and Alzheimer Disease (AD)

Recent reviews (Aso and Ferrer, 2014; Ahmed et al., 2015) have nicely summarized the pathophysiology of AD: a neurodegenerative disease with senile plaques formed of fibrillar β-amyloid (Aβ) from cleavage of the Aβ precursor protein (APP) by β- and γ-secretases and by presence of neurofibrillary tangles composed of hyper-phosphorylated and nitrated tau protein. The latter precedes Aβ deposition in sporadic cases. Once the process begins, deterioration is inexorable. Additional pathology includes functional mitochondrial defects, increased reactive oxygen species (ROS) and reactive nitrogen species (RNS), and 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: protein misfolding, neuroinflammation, excitotoxicity, mitochondrial dysfunction and oxidative stress. CB2 levels increase in AD especially in microglia around senile plaques, and its stimulation stimulates Aβ removal by macrophages.

The epidemiology of AD is fascinating (Mayeux and Stern, 2012). North America and Western Europe have highest rates (6.4% and 5.4% at age 60), then Latin America (4.9%), and China (4%; ascertainment bias vs. mirroring economic development and Western diet?). Prevalence is lower for Africans in homelands, as opposed to higher rates in the Western European and American diaspora. Head trauma increases Aβ deposition and neuronal tau expression, and diabetes, obesity, trans-fats and head trauma all increase AD risk. Mediterranean diet (increased monounsaturated olive oil, and omega-3 from fish), education 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., 2007), with an FDA “Black Box Warning.” Four acetylcholinesterase inhibitors are approved in the USA to improve memory: galantamine, donepezil, tacrine and rivastigmine. 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 1998 (Hampson et al., 1998), and the subject of USA patent US09674028, CBD is a neuroprotective antioxidant, more potent than ascorbate or tocopherol, that works on the same NMDA target without attendant toxicity. Subsequently (Iuvone et al., 2004), CBD inhibited Aβ plaque formation, prevented ROS production and peroxidation of lipids in PC12 cells exposed to Aβ, limited neuronal apoptosis from caspase 3 reduction, and counteracted increases in intracellular Ca ++ from Aβ. In an in vivo model (Esposito et al., 2006), CBD was anti-inflammatory via reduction in inducible nitric oxide synthase (iNOS) and IL-1β expression and release. It also inhibited tau protein hyper-phosphorylation in Aβ-stimulated PC12 neurons. Subsequently, it was shown that CBD’s MOA seemed to be selectively mediated via PPARγ (Esposito et al., 2011): dose dependently antagonizing pro-inflammatory NO, tumor necrosis factor-alpha (TNF-α), and IL-1β. That effect was blocked by GW9662 (PPARγ antagonist), reducing reactive gliosis via selective PPARγ-related NFκB inhibition. Both AEA and CBD promoted neurogenesis after Aβ exposure.

In addition to its neuroprotective antioxidant effects (Iuvone et al., 2004), THC competitively inhibited acetylcholinesterase, increasing levels, and prevented Aβ aggregation via binding to the enzyme in a critical region affecting amyloid production (Eubanks et al., 2006).

On the clinical side, various trials of THC in AD have produced positive results. In 1997 (Volicer et al., 1997), in 15 institutionalized dementia patients refusing nutrition, an RCT 6-week crossover trial of THC (Marinol ® ) 2.5 mg twice daily led to increased body-mass index (BMI), with decreased Cohen-Mansfield Agitation Inventory (CMAI) scores, improved negative affect scores, and a notable carry-over effect when THC was administered first. In 2006 (Walther et al., 2006), an open-label 2-week study of five AD and one vascular dementia patient taking THC 2.5 mg at 19:00 h showed benefit noted on nocturnal motor activity, agitation, appetite, and irritability with no AEs. A 2015 study (van den Elsen et al., 2015) failed, however: an RCT in 50 demented patients with neuropsychiatric symptoms received 1.5 mg THC vs. placebo thrice daily for 3 weeks with no benefit noted to THC. 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, 2017). Patients were treated with a variety of preparations: THC-predominant (2.5–30 mg/dose), CBD predominant, and THCA, mainly in tinctures and confections. 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.

Based on its pharmacology (Russo and Marcu, 2017), cannabis components may provide myriad benefits on target symptoms in this complex disorder:

Agitation: THC, CBD, linalool

Anxiety: CBD, THC (low dose), linalool

Insomnia/Restlessness: THC, linalool

Aggression: THC, CBD, linalool

Depression: THC, limonene, CBD

Memory: alpha-pinene (Russo, 2011; Russo and Marcu, 2017) + THC

Neuroprotection: CBD, THC

Reduced Aβ plaque formation: THC, CBD, THCA

Thus, an extract of a Type II chemovar of cannabis (THC/CBD) with a sufficient pinene fraction would seem to be an excellent candidate for clinical trials (Lewis et al., 2018).

Cannabis and Traumatic Brain Injury (TBI)/Chronic Traumatic Encephalopathy (CTE)

The neuroprotective antioxidant effects of the cannabinoids (Hampson et al., 1998) are particularly relevant in their ability to counteract “glutamate excitoxicity,” which leads to neuronal demise after traumatic brain injury (TBI). Anecdotally, cannabis, particularly chemovars combining THC and CBD, have been extremely helpful in treatment of chronic traumatic encephalopathy (CTE) symptoms: headache, nausea, insomnia, dizziness, agitation, substance abuse, and psychotic symptoms. CTE, previously known as dementia pugilistica, or “punch-drunk syndrome” has garnered a great deal of attention due to its apparent frequency among long-term players of American football but including victims of repetitive head injury from causes as diverse as other contact sports, warfare and even “heading” in soccer. A recent study (Mez et al., 2017) showed 87% of autopsied American football players demonstrated CTE with tau aggregates in neurons and astrocytes, neurofibrillary tangles in superficial cortical layers and hippocampus, α-synuclein and Aβ deposition. 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. CSF examination in CTE patients were elevated compared to controls and AD patients (p = 0.028), and correlated to years of football played (p = 0.04; Cherry et al., 2017), indicating CCL11 may be a premortem biomarker for the syndrome. Additionally, PET imaging binding levels in a CTE patient before death correlated with postmortem tau deposition (p = 0.02). The greatest tau concentration was observed in parasagittal and paraventricular cortical and brainstem areas (Omalu et al., 2018), allowing pre-mortem diagnosis and distinction from AD. Neuroprotective benefits of phytocannabinoids, particularly CBD, further outlined below, provide support for trials of these agents in post-traumatic syndrome and CTE prevention.

Human Nutrition, Cannabis, the ECS, “Acne of the Brain” and the “Gut-Skin-Brain Axis”

Human gut harbors 100 trillion micro-organisms at a concentration of 10 12 bacteria/ml, and exceeding the human genome 100-fold (Musso et al., 2010). This is termed the microbiome. Obese humans have lower Bacteroidetes and higher Firmicutes counts. Recent review (Clarke et al., 2012; Russo, 2016b) supports the efficacy of probiotics (supplemental beneficial gut lactic acid bacteria) in treating irritable bowel syndrome without AEs. Microbiota regulate 5-HT1A, BDNF and NMDA expression (Sampson et al., 2016), and experimental transplantation of the microbiome of Parkinson patients to mice was demonstrated to increase their motor deficits, supporting the finding of a pro-inflammatory dysbiosis (microbiome imbalance) in that disorder (Keshavarzian et al., 2015).

Another recent review elucidates additional findings of pertinence to the current discussion (He and Shi, 2017). The combination of prebiotics (dietary fiber that serves as bacterial feedstock, reviewed by Russo, 2016a), and deficient in modern Western diets (Calame et al., 2008; Slavin, 2013) and probiotics may be termed, “synbiotics.” Translocation of bacterial fragments produces “metabolic endotoxemia” from bacterial lipopolysaccharides (LPS). Probiotics may help control PPARγ, “the master regulator of adipogenesis” and TNF-α in inflammation. Additional research supports that prebiotic galacto-oligosaccharides (as from beans) decrease TNF-α, and interleukin production (He and Shi, 2017). GPR41 and GPR43 are orphan receptors for short-chain fatty acids (SCFA) that can increase release of 5-HT and other factors. Additionally, prebiotics change microbiota to reduce adipogenesis and stabilize the gut barrier. Furthermore, CB2 levels correlate to Lactobacillus concentrations and negatively with potentially pathogenic Clostridium species.

Other experiments relate the microbiome to the ECS. A direct effect of Lactobacillus acidophilus NCFM strain via oral administration to induce CNR2 (gene encoding the CB2 receptor) mRNA expression above that of resting human HT-29 epithelial cells (p < 0.01) was demonstrated. An enhancement of morphine antinociceptive effect in rats (p < 0.001) was also demonstrated which was inhibited by administration of the CB2 antagonist, AM-630 (p < 0.001; Rousseaux et al., 2007). Additionally, THC altered the microbiome balance in obese DIO mice affecting the Firmicutes: Bacteroidetes ratio (p = 0.021). Furthermore, THC prevented weight gain despite a high-fat diet (Cluny et al., 2015). This explains, perhaps, how the stereotype of the “skinny hippie” is more accurate than that of the lazy, obese “stoner.”

Additional dietary factors include the function of bitter taste receptors (Tepper et al., 2014), present not only on the tongue, but in the gut, and hypothalamus (Herrera Moro Chao et al., 2016), wherein interaction with ECS appetite mechanisms seem to be operative.

Diet is also a key factor in acne vulgaris, whose pathophysiology and epidemiology are surprisingly relevant to this discussion. Acne was not observed in Inuit populations living a traditional lifestyle over 30 years, but became common with adoption of a Western diet and lifestyle (Cordain et al., 2002). 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., 2017) demonstrating that neuroinflammation is a stimulus to AD development and is triggered by infectious insults. Additionally, AD brains demonstrated 5–10× greater bacterial loads, especially with Actinobacteria, particularly Propionibacterium acnes, a gram-positive an aerobic resident of skin, mouth and gut and pathological agent of acne. P. acnes has been cultured from AD brains, can grow there, and stimulate alpha synuclein fibrillar formation in PD, amyloid fibrillization in AD, and biofilm formation, which is opposed by cannabinoids, and cannabis terpenoids limonene, alpha-pinene (Soni et al., 2015; Subramenium et al., 2015; Russo and Marcu, 2017).

An additional parallel pertains to the TRPV4 receptor (Zhang et al., 2013). TRPV4 is expressed in cerebral endothelial cells where it mediates Ca ++ and influx acetylcholine-induced dilation. Cerebral hypoperfusion with impaired vessel dilation is a pathogenetic factor in AD. That function is impaired in a mouse model of AD and is sensitive to oxidative stress from Aβ, which is alleviated by antioxidants. The authors suggested TRPV4 as a target for AD treatment.

Cannabidiol, in addition to its anti-inflammatory and bacteriostatic effects, is a TRPV4 agonist that works as a sebostatic agent in acne (Oláh et al., 2014), while cannabis terpenoids limonene, linalool potently inhibited P. acnes and consequent TNF-α production (Kim et al., 2008). Alpha-pinene was also a potent inhibitor of the bacterium (Raman et al., 1995; reviewed by Russo, 2011).

The importance of these relationships becomes apparent as efforts are made to integrate disparate threads (Bowe and Logan, 2011). Mental health impairment scores in acne patients surprisingly exceed those with epilepsy and diabetes. Oral probiotics regulate inflammatory cytokines in skin. Intestinal microbiota, skin inflammation and psychiatric symptoms are thus intertwined in a “gut-brain-skin axis.” The author posits that acne-induced processes could also affect PD, AD and CTE pathophysiology (Figure ​ (Figure2 2 ).

Cannabis, the endocannabinoid system and the gut-brain-skin axis (diagrams of brain, gut by Mikael Hagstrom, face by Mouagip, all public domain).

Future Trends

It is the opinion of many that neurology is facing therapeutic brick walls. The current single target receptor model of pharmacotherapy has not proven universally salutary in the face of complex neurodegenerative diseases. Rather, reconsideration must be given to an older proven model of botanical synergy that may enable polytherapy in single preparations (Russo, 2011; Brodie et al., 2015; Russo and Marcu, 2017; Lewis et al., 2018). Such approaches, combined with nutritional and lifestyle management may make neurology a more preventative and therapeutic specialty, rather than merely diagnostic, and provide better treatment for epilepsy, tumors, AD, PD and TBI/CTE. Suggested strategies include:

Aerobic activity (Raichlen et al., 2012; Schenkman et al., 2018)

Education as a lifestyle

Anti-inflammatory, prebiotic and probiotic diet emphasizing saturated and monounsaturated and omega-3 EFAs, bioflavonoids (berries), fermented foods, protein and minimizing carbohydrates (Fallon and Enig, 1999; Perlmutter and Loberg, 2015)

Supplementation with cannabis extracts providing THC, CBD, THCA, CBDA, caryophyllene and other select terpenoids (Figure ​ (Figure1; 1 ; Russo and Marcu, 2017; Lewis et al., 2018).

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.

Author Contributions

The author confirms being the sole contributor to this work and has approved it for publication.

Conflict of Interest Statement

ER is Director of Research and Development for the International Cannabis and Cannabinoids Institute (ICCI), Prague, Czechia.

Acknowledgments

The assistance of the Inter-Library Loan staff of Mansfield Library of the University of Montana in providing research materials is greatly appreciated.

Funding. This study was performed without outside funding.

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This is the first study to use novel assessment techniques including high-density electroencephalography (EEG) with structural brain MRI to comprehensively examine and localise differences in brain activation during sleep and wake periods in participants with insomnia disorder.

This study uses a randomised, controlled trial design to investigate the effects of a pharmaceutical-grade oral oil solution containing 10mg Δ 9 -tetrahydrocannabinol (THC) and 200mg cannabidiol (CBD) on sleep and daytime function in a clinical population.

Participants will have sleep physician-confirmed insomnia disorder and will be thoroughly screened to rule out other sleep disorders.

This study is a single-dose design investigating only the acute effects of a cannabis-based medicine over a 24-hour period in a controlled in-laboratory environment.

This study cannot assess the individual contribution of THC and CBD.

Introduction

Insomnia is a common sleep disorder that can present in isolation or comorbid to other medical or psychiatric conditions.1 Despite often emerging as a transient response to stress or change to one’s normal sleep–wake cycle,2 approximately 30% of individuals with insomnia display chronic symptoms.3 Chronic insomnia is characterised by sleep disturbances (difficulties with falling asleep, maintaining sleep, or inability to return to sleep on awakening) occurring at least three nights per week and for at least 3 months.4 5 The sleep disturbance is often coupled with clinically significant daytime impairments in social life, occupational function and/or educational achievement.4 5 It is often the perceived daytime impairments, as opposed to the noctural insomnia symptoms per se, that prompt patients to seek treatment.6 Chronic insomnia tends to either ‘wax and wane’ or persist over a lifetime, with the latter course predicted by more severe insomnia symptoms at baseline, female gender and older age.7 8There are emerging associations between chronic insomnia and increased health risks such as cardiovascular disease,9 depression10–12 and dementia,13 14 as well as high rates of absenteeism15 16 and healthcare utilisation.17 Indeed, longitudinal studies with follow-up period ranging from 1 to 34 years have found a substantial risk for developing depression (both first onset and recurrent major depressive disorder) in patients with insomnia, an association that is bidirectional.18 As such, there is a strong need for early clinical intervention.

The goal of treatment for insomnia is to improve sleep (both duration and quality) and alleviate daytime impairments. Psychological therapies such as cognitive behavioural therapy for insomnia (CBT-I) and psychoeducation regarding sleep hygiene can be effective.19 However, these often require access to a therapist and can involve substantial effort, time and financial commitment.20 Furthermore, the perceived benefits from these approaches are typically delayed. Thus, patients with persistent symptoms often seek strategies offering short-term relief to maintain normal daytime functioning; highlighting a specific role for adjunctive use of pharmacological treatments such as benzodiazepines, sedating antidepressants, and Z-drugs.21 However, these are associated with undesirable side effects such as cognitive impairment, tolerance/dependence and impaired driving due to sedative effects that can persist into the following day.22 Moreover, many of these medications disturb sleep architecture; increasing sleep fragmentation and one’s sense of having non-restorative sleep and ultimately impair the ability to undertake normal daily activities.23 Thus, novel approaches are needed to address the needs of people with chronic insomnia disorder.

Anecdotally, consumers of cannabis commonly report that the drug promotes uninterrupted sleep.24 The plant Cannabis sativa contains >100 different cannabinoids—the most abundant of which are the main psychoactive component, Δ 9 -tetrahydrocannabinol (THC), and the non-intoxicating cannabinoid, cannabidiol (CBD).25 Both CBD and THC affect components of the endogenous cannabinoid system which are involved in the regulation of the circadian sleep–wake cycle, including the maintenance and promotion of sleep.26 27 THC is a partial agonist of the cannabinoid 1 (CB1) receptor, found primarily within the central nervous system28 and the cannabinoid 2 (CB2) receptor, found primarily in the immune system and on peripheral organs.29 THC is known to have sedating properties via its action at the CB1 receptor, which is notably dense in areas of the central nervous system such as the thalamus, hypothalamus, hippocampus, basal ganglia and cortex, suggesting a diverse role in the modulation of physiological functions including sleep.30 31 CBD is an indirect CB1 and CB2 receptor agonist, and has shown to increase concentrations of the major endogenous cannabinoid, anandamide, by inhibiting its degradative enzyme, fatty acid amid hydrolase (FAAH).32 33 Increasing endogenous anandamide via FAAH inhibition normalised deficits in stage N3 sleep in cannabis-dependent men experiencing withdrawal,34 consistent with preclinical data showing that anandamide promotes slow wave sleep, possibly through increases in extracellular adenosine concentrations.35–37 This effect can be blocked by administration of the CB1 antagonist, rimonabant.38 Indeed, clinical trials of rimonabant have reported an increased risk of sleep disturbances,39 suggesting a role for the CB1 receptor in mediating sleep. CBD is also a negative allosteric modulator of CB1 receptor40 and may reduce the effects of THC and anandamide on the brain.41 42 There is an emerging viewpoint that coadministration of CBD with THC may enhance therapeutic outcomes by attenuating the adverse effects of THC (e.g., on emotion recognition,43 next-day memory performance,44 appetitive effects45 and acute psychotic symptoms46 47); however, findings are inconsistent with a recent study showing CBD exacerbating THC-induced impairment on driving and cognition, possibly via a pharmacokinetic interaction.48 Furthermore, CBD is a promiscuous molecule that exhibits activity on a wide array of molecular targets beyond CB1 and CB2 receptors such as inhibitory GABAA receptors,49 which may also influence sleep. Administration of THC alone (15 mg) in the evening was associated with next-day changes in mood, sleepiness and memory in healthy adults,44 emphasising the need for careful consideration of dose and ratio of cannabinoids when administered in clinical insomnia populations.

To date, there have been no well-designed randomised controlled trials employing objective measures assessing the effects of cannabis on sleep duration and quality in a clinical insomnia population.50–52 Previous studies have shown potential benefits in the therapeutic use of nabiximols (Sativex), an oromucosal spray containing equal parts THC and CBD, in the relief of pain and other chronic symptoms including improved sleep, with the latter only assessed as a secondary outcome using subjective rating scales.53 Other studies using synthetic THC (nabilone) showed improvements in subjective sleep quality in patients with post-traumatic stress disorder (PTSD)54 55 and fibromyalgia,56 while CBD was found to be effective in reducing the frequency of rapid eye movement sleep behaviour disorder events in Parkinson’s disease.57 One case study showed that 25 mg CBD daily reduced anxiety symptoms and improved sleep disturbances in a young child with PTSD.58 Indeed, preclinical evidence has demonstrated anxiolytic effects of CBD, likely dependant on CB1 and 5-HT1A receptor action, with early human experimental evidence supporting preclinical findings.59 To address the lack of studies in a clinical insomnia population, we will investigate the acute effects of a plant-derived, pharmaceutical-grade, oral formulation containing 10 mg THC and 200 mg CBD relative to placebo on sleep and next-day function (cognitive function, alertness, simulated driving performance) in participants with physician-confirmed chronic insomnia disorder. This study will be the first to employ 256-channel high-density electroencephalography (EEG) coupled with structural MRI brain scans to examine and localise differences in sleep depth and brain activation during both sleep and wakefulness in this clinical population.

Methods and analysis

Study design

A double-blind, randomised, placebo-controlled, crossover study design will be used to evaluate the effects of 10 mg THC and 200 mg CBD on sleep and daytime function in participants diagnosed with chronic insomnia disorder. Participants will be recruited over an 18-month period commencing August 2019. The recruitment target is 20 participants, which will provide the proof-of-concept evaluation of the study drug to determine whether future larger studies in insomnia disorder are warranted. The study site and sponsor is the Woolcock Institute of Medical Research; a research institute and specialist sleep clinic in inner suburban Sydney, Australia. Participants will undergo two separate overnight study assessment visits. Each study assessment visit will be scheduled at least one week apart to avoid any carryover effects, as informed by previous studies of this nature.60 61 The protocol (Version 2.3, July 2019) has been prepared in accordance with the SPIRIT statement (see online supplementary file 1).62

Supplemental material

Recruitment and enrolment

The study population will be adults aged 35–60 years with chronic insomnia disorder as per International Classification of Sleep Disorders–Third Edition (ICSD-3) criteria.63 This age range was chosen to limit age-related variability in sleep architecture for better interpretation of EEG changes.64 Participation will be voluntary under conditions of informed consent. A list of the inclusion and exclusion criteria is presented in box 1. Participants will be recruited through the following strategies: (1) referral from sleep physicians and psychologists at the Woolcock Institute of Medical Research, Australia; (2) via two databases that host the details of people who have provided consent to be contacted about future clinical trials (”Woolcock Volunteer Database” and the “Lambert Initiative for Cannabinoid Therapeutics Expression of Interest database”); (3) physical study advertisements displayed around the local University area; and (4) study advertisements posted on social and news media. All participants will receive financial compensation for their time commitment to the study.

Inclusion and exclusion criteria

Inclusion criteria

Aged 35–60 years

Diagnosis of insomnia disorder made by a physician or a psychologist

Insomnia Severity Index (ISI) score≥15

Insomnia symptoms for >3 times per week and present longer than 3 months

Exclusion criteria

Medical condition (e.g., chronic pain) or medication that is the cause of the insomnia

Sleep apnoea (defined as Apnoea Hypopnoea Index (AHI)>15 and Oxygen Desaturation Index (ODI)>10) or sleep-related movement disorder based on in-laboratory polysomnography

Advanced or delayed sleep–wake phase disorder based on actigraphy

Used any modality of treatment for insomnia, including cognitive–behavioural therapy (CBT) and CNS-active drugs, within 3 months before screening or at the medical doctor’s discretion

Transmeridian travel (two time zones) in the past month

Use of medications that may influence cannabinoid metabolism (e.g. inhibitors/inducers of the CYP450 pathway)

Clinically relevant cardiovascular abnormalities (as determined by 12-lead ECG at screening)

Pregnancy or lactation (females)

History of a major psychiatric disorder within the past 12 months (except clinically-managed mild depression or anxiety) as per the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 or at the medical doctor’s discretion

History of attempted suicide or current suicidal ideation as determined by a score >0 on Q9 of the Patient Health Questionnaire (PHQ)-9

History of drug or alcohol abuse/dependency within the past 2 years

Urinary drug screen positive for drugs (benzodiazepines, opiates, cannabis, amphetamines, cocaine)

Known hypersensitivity to cannabis

Cannabis use within the past 3 months (confirmed by negative urine drug screen)

Unable to undergo brain MRI due to implanted device or other reason

Excessive caffeine use that, in the opinion of the medical doctor contributes to the participant’s insomnia, or is unable to abstain from caffeine use ≥24 hours prior to each overnight study assessment visit

Inability to refrain from alcohol consumption ≥24 hours prior to each overnight study assessment visit

Medical conditions that result in frequent need to get out of bed (e.g., nocturia)

Required to complete mandatory drug testing for cannabis (e.g., workplace testing, court order)

Study intervention

The investigational product (‘ETC120’) is a plant-derived oral formulation containing a 1:20 ratio of THC to CBD suspended in medium-chain triglycerides (MCT) oil. ETC120 will be purchased from Linnea (Ticino, Switzerland). Participants will be administered a single fixed dose of ETC120 (2 mL containing 10 mg THC and 200 mg CBD) or matched placebo (2 mL containing no cannabinoids). The 1:20 ratio of THC to CBD was chosen to harness the sedating properties of THC while including some of the potential anti-anxiety properties of CBD,65 given that anxiety is a very common comorbidity in people with insomnia disorder.66 67 As noted above, there is also possibility that this dose of CBD might reduce some of the possible adverse effects of THC (e.g., anxiety, memory impairment). The chosen ratio also mimics naturalistic findings in recent surveys where individuals reported using cannabis with higher CBD concentrations in addition to THC to effectively manage insomnia symptoms.68 69 The THC dose (10 mg) was chosen as being the maximum dose that is likely to induce subjective drug effects of feeling ‘sleepy/tired’ without impairing cognitive performance (e.g., reaction time tasks) or producing significant intoxication in naïve or occasional cannabis users.60 A significant intoxicating effect might inadvertently cause a stimulatory response and interfere with sleep induction.60 70

Randomisation and allocation concealment

Each participant will be randomly allocated to one of two treatment sequences: (1) ETC120–placebo, or (2) placebo–ETC120. As this is a blinded study, the participant, the study staff (including the medical doctor) and the outcome assessors will not be aware of which treatment order participants have been allocated to. Method of allocation concealment will involve central randomisation by computer prepared by the trial statistician (NSM) and identical containers numbered according to the randomisation sequence prepared by the drug distributor. Neither the drug distributer or the trial statistician will meet any prospective or enrolled participants or be involved in any day-to-day trial process. The sequence will be computer-generated using a simple 1:1 randomisation ratio by the trial statistician, and by the order of participant enrolment. The sequence will be stored in a password-protected data management system and cannot be accessed by blinded study staff who have contact with participants. The order of treatment will only be known by the drug distributer and the trial statistician. In the event of a serious adverse event (SAE) or reaction, the allocation list will be retrieved from the unblinded trial statistician or drug distributer to reveal the participant’s allocated treatment during the trial.

Study objectives

The primary outcome of the study is to assess the effect of 10 mg THC and 200 mg CBD on sleep continuity (wake after sleep onset) and quantity (total sleep time) assessed using attended overnight full polysomnography in participants with chronic insomnia disorder.

Secondary objectives include:

To determine changes in sleep microarchitecture metrics measured using high-density EEG and source modelling in participants with chronic insomnia disorder treated with ETC120 relative to placebo.

To assess next-day neurobehavioural functioning (cognition, alertness and simulated driving performance) in participants with chronic insomnia disorder treated with ETC120 relative to placebo.

To demonstrate feasibility of a cannabinoid study in chronic insomnia and establish clinical trial procedures for future trials in this area.

The ANZCTR trial registry has a comprehensive list of the trial’s primary and secondary outcomes. See online supplementary file 2 for WHO Trial Registration Data Set.

Supplemental material

Study visits and procedures

Screening

A flowchart of the study is depicted in figure 1. Initial suitability assessment via a brief online questionnaire and a follow-up telephone screen will be conducted by the study investigator. Written informed consent will be obtained by the study medical doctor before conducting an interview to ascertain sleep difficulties and diagnose ICSD-3 chronic insomnia disorder (Visits 1–2). Individuals will then undergo comprehensive screening to be completed within one month of study entry, which will include a diagnostic sleep study at the Woolcock Clinic to exclude sleep disorders other than insomnia disorder (unless one has already been conducted in the past 12 months). The Insomnia Severity Index71 (ISI; measure of nature, severity, and impact of insomnia), the Pittsburgh Sleep Quality Inventory72 (PSQI; measure of sleep quality and sleep habits), the Epworth Sleepiness Scale73 (ESS; measure of daytime sleepiness), the Hospital Anxiety Depression Scale74 (HADS; measure of anxiety and depression) and the Patient Health Questionnaire75 (PHQ-9; multi-purpose tool for assessing severity of depression) will be administered to phenotype insomnia symptoms and to assess suitability for study inclusion. All participants will be screened for prior cannabis use history (ie, whether they have consumed cannabis in the past, the form(s) in which it was consumed, and frequency of use) as well as for past or present cannabis use disorder as per the ICD-10 criteria.76 A urine specimen will be screened (DrugCheck NxStep OnSite Drug Test, Minnesota, USA) to rule out recent drug use. Participants testing positive for any drug (cannabis, cocaine, benzodiazepines, opiates or amphetamines/MDMA/methamphetamines) will result in exclusion or rescheduled at the studymedical doctor’s discretion. A standard 12-lead electrocardiogram (ECG) will be recorded to screen for any clinically relevant cardiovascular abnormalities. Rapid urine pregnancy test (Alere HCG Combo Cassette, Massachusetts, USA) will be administered to female participants, and identification of pregnancy will result in exclusion. Participants will then be instructed to maintain a sleep diary and wear a wrist-worn commercially available device (Actiwatch 2, Philips Respironics) to monitor sleep and wake periods for one week. These data will allow the study team to estimate the participant’s individual typical sleep-onset and wake-onset times for the study assessment visits as well as rule out advanced or delayed sleep-wake phase syndrome.

Study flow diagram.

Following screening, the participants will undergo a structural brain MRI at a medical imaging clinic (Visit 3). Then, participants will attend the sleep clinic for an orientation session (Visit 4) to practise wearing the high-density EEG sensor cap during a short nap opportunity as well as complete a familiarisation and practice drive on the driving simulator. Participants will then be asked to maintain consistent sleep-onset and wake-onset times, confirmed by at-home sleep diary and actigraphy for one week prior to each study assessment visit. Participants will be instructed to abstain from illicit drug use for the duration of the study (ie, from pre-enrolment until after the final study assessment visit) and to refrain from consuming alcohol and caffeine for 24 hours prior to and during the study assessment visits, but to continue use of any regular prescribed medications (except those listed in the exclusion criteria). Standardised meals and snacks will be provided for participants at each study assessment visit. Table 1 depicts the schedule of visits and procedures from pre-enrolment to study completion.