Apothecaries were not worth a pin,

If Hemp seed did not bring their commings in;

Oyles, Vnguents, Sirrops, Minerals, and Baulmes,

(All Natures treasures, and th' Almighties almes,)

Emplasters, Simples, Compounds, sundry drugs

With Necromanticke names like fearefull Bugs,

Fumes, Vomits, purges, that both cures, and kils,

Extractions, conserues, preserues, potions, pils,

Ellixers, simples, compounds, distillations,

Gums in abundance, brought from foreigne nations.

John Taylor (1580–1653)

For several millennia, many civilizations have used Cannabis sativa for assorted purposes [1]. This magical plant was eulogized for its recreational use and its tremendous beneficial effects in painless surgeries [2, 3]. To date, >100 terpenophenolic cannabinoids have been isolated from C. sativa, among these, Δ9-tetrahydrocannabinol (Δ9-THC), as the primary and main psychoactive constituent, cannabidiol (CBD), cannabinol, cannabichromene, and cannabigerol are of particular interest [4–6]. In the light of previous studies, the cannabis plant has been shown to play a role as an antiemetic, appetite stimulant, analgesic, euphoriant, anti-inflammatory agent, anticonvulsant, and as a sedative [2, 4, 7–20]. It has also been noted that cannabis can impair memory and cognition [21, 22]. However, the clinical applications of cannabis remain circumscribed, largely owing to the known psychoactive effects of Δ9-THC [23, 24]. Cannabinoids exert their pharmacological and physiological activities predominantly through G protein-coupled cannabinoid CB1 and CB2 receptors (CB1R and CB2R, respectively) [25, 26]. Following the discovery of cannabinoid receptors in rat brain in 1980, the location of these receptors was mapped in mammalian species, including humans, and were shown to be ubiquitous in hippocampus, basal ganglia, and cerebellum. Some years later, in 1990 and 1993, CB1R and CB2R, respectively, were cloned [27–29]. The predominant expression of these receptors, in particular CB1R, and the presence of endocannabinoids in brain areas responsible for the management of movements, such as basal ganglia and cerebellum, together with the conspicuous changes in endocannabinoid transmission in the brains of individuals affected by motor disorders, provides a compelling conceptual argument that cannabinoid-based compounds may have the potential to alleviate symptoms of these diseases and provide a novel area of research [30, 31]. The aim of the current paper is to review the literature on the effects of cannabinoids in motor disorders associated with tremor, with the goal of highlighting possible therapeutic applications. Tremor is a rhythmic, unintentional, oscillatory, and twitching movement, and a clinical manifestation of numerous disorders such as multiple sclerosis (MS), Parkinson’s disease (PD), and Huntington’s disease (HD), which all affect central areas associated with motor control [32–34]. Tremor has been categorized, based on its etiology, origin, and clinical presentations, into 6 main groups [35]. Despite significant efforts to find an effective pharmacological intervention, as yet there is limited availability of efficient treatments to reduce tremor markedly [36]. However, new insights into the molecular basis of diseases associated with tremor might lead to such a discovery. As argued below, cannabinoids could represent a promising avenue of future research.

Cannabinoid Receptors and Signaling in relations to Central Nervous System Dysfunction Associated with Tremor

Endocannabinoids are produced “on demand” and act as a retrograde messenger on presynaptic cannabinoid receptors. Although additional molecular targets may be involved, cannabinoid receptors have been divided into 2 major subtypes, CB1R and CB2R [26, 37]. While CB2R are mostly found in the immune system, CB1R are highly expressed and localized to several regions of the brain, with reported expression in neurons, oligodendrocytes, astrocytes, and neural stem cells [38–46]. Owing to this abundance, the potentially greater significance of CB1Rs will be the focus of this review (Table 1).

Table 1 A brief outlook on tremor and cannabinoid-based compounds
Full size table

The notably high expression of CB1R in the cerebellum, in particular on inputs into Purkinje cells from inhibitory basket and stellate interneurons and excitatory climbing fibers arising from granule cells, is indicative of the crucial role of CB1R in cerebellar function. Moreover, it has been shown that CB1R knockout mice, as well as chronic marijuana users or animals administered CB1R agonists, have clear impairment of eyeblink conditioning, an epitome of cerebellar cortex function [47–51]. 2-Arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA), 2 arachidonic acid derivatives, are the chief endocannabinoids in the brain; cerebellum CB1R are predominantly activated by 2-AG. An increase in the concentration of postsynaptic Ca2+ either by entry via voltage-gated Ca2+ channels or activation of type 1 metabotropic glutamate receptors brings about the release of 2-AG synthesized from diacylglycerol, a reaction catalyzed by diacylglycerol lipase-alpha in Purkinje cells, with the overall effect of activation of presynaptic CB1R [52–56]. In addition, several studies have reported the high density of CB1Rs in striatum and the presence of AEA throughout the basal ganglia, in particular in the globus pallidus and substantia nigra [31, 57, 58]. The crosstalk between dopaminergic transmission and endocannabinoids signaling in the striatum nigra is also well established and there is a growing body of evidence that CB1R activation by endocannabinoid retrograde signaling has the potential to decrease glutamate release in a dopaminergic D2 receptor-dependent manner [59–61].

Cannabinoids and Tremor in PD

PD is a progressive neurodegenerative disease affecting basal ganglia and characterized by tremor, rigidity, bradykinesia, and muscle stiffness [62–64]. The piecemeal loss of melanin-containing nigral neurons leads to aberrant dopaminergic transmission, with tremor emerging as a consequence of subthalamic overactivity [64–69]. The increase in the levels of endocannabinoids and alteration in both CB1R and CB2R expression in different stages of PD opens the possibility of manipulation of receptor function in the management of disease [64, 70]. Studies have demonstrated that, in the early stages of PD, CB1R are downregulated, while in advanced and symptomatic phases there is a switch to CB1R upregulation [71]. These findings may suggest a basis for use of cannabinoid antagonists in order to alleviate the motor deficits associated with advanced PD. Despite findings supporting this suggestion, Meschler et al. [72] failed to show the proficiency of the CB1R antagonist SR141716A (rimonabant) in the mitigation of symptoms in a nonhuman primate model of PD. In another study using tacrin, an acetylcholinesterase inhibitor, to induce Parkinsonian tremor, pretreatment with rimonabant was without significant effect on tremor bursts, whereas, in combination with the adenosine A2A receptor antagonist, SCH58261, a marked reduced in tremor bursts was seen [73]; however, it is of note that SCH58261 per se produced a pronounced decrease in tremor bursts. Moreover, an early clinic report suggests no advantageous effects of cannabis on tremor among 5 unresponsive patients to anticholinergics and beta blockers [74]. By contrast, a questionnaire-based study revealed a 30.6 % improvement in rest tremor in tremulous patients with PD [75]. A plausible argument for using cannabinoid agonists as therapeutic agents has arisen from studies describing the inhibitory effect of CB1R activation on glutamate release and its capability to oppose subthalamonigral neuronal overactivity and subsequently reduce tremor [64, 76, 77]. It has also been suggested that cannabinoid agonists and endocannabinoids can block dopamine transporters and thereby inhibit dopamine reuptake to ameliorate dyskinesia [78–80]. However, there are other studies asserting no beneficial effects of cannabinoid agonists in alleviation of motor symptoms [75, 81–83].

Unfortunately, there are currently only few double-blind controlled studies and those that have been performed are often paradoxical. In a recent small, open-labeled observational study, the efficacy of cannabis treatment on patients who had experienced severe PD-related pain and tremor, and whose symptoms were insufficiently controlled with current anti-Parkinson medications, was assessed [84]; the results indicated a significant improvement in tremor and rigidity, with a lesser beneficial effect on bradykinesia, among cannabis smokers. Currently, an observational prospective clinical trial is underway to scrutinize the impact of cannabis on PD tremor (ClinicalTrials.gov identifier: NCT02028858); such trials should help advance, and resolve, controversies in this field. Despite these conflicting results, cannabinoid-based compounds should not be neglected as a treatment strategy. It seems that alterations to the endocannabinoid system may play a role in Parkinsonian tremor pathogenesis and that more studies are requisite to consider a further range of individual cannabinoids as potential therapeutic agents for managing signs and symptoms of PD, in particular, tremor.

Cannabinoids and MS-related Tremor

There is much anecdotal evidence that patients self-medicate with marijuana with the intention of palliating pain, tremor, spasticity, ataxia, and other symptoms associated with MS, an autoimmune disease typified by demyelination and remyelination, and associated with neuroaxonal damage and inflammation [67, 69, 85, 86]. More recent controlled studies, both in animal models of MS and in humans, have begun to validate these preclinical and uncontrolled observations. Involvement of the endocannabinoid system acting at CB1R in the pathogenesis of MS have been supported by several studies [87–90]. There are now several lines of evidence indicative of therapeutic potentials of cannabinoids in the control of MS-related symptoms, including tremor, which remains difficult to manage with current medications (e.g., carbamazepine, propranolol, primidone, and gluthetimide) [12, 89, 91, 92]. Following this premise, De Lago et al. [93] have shown that the nonselective cannabinoid agonist WIN 55,212-2 ameliorated neurological disability, tremor, and spasticity in the chronic relapsing experimental autoimmune encephalomyelitis murine model of MS [92]. Correspondingly, this study revealed the prominent role of CB1R activation in the relief of tremor and spasticity, as a selective CB1R, but not a CB2R, antagonist reversed the positive effects of preadministered cannabinoids; moreover, no beneficial effects were observed by administering a selective CB2 agonist [93, 94]. An earlier study reported that cannabinoid agonists Δ9-THC, methanandamide, R(+)WIN 55,212-2, and JWH-133 all diminished tremor and spasticity in the experimental autoimmune encephalomyelitis model, and that aggravation of the symptoms occurred after using CB2R and, in particular, CB1R antagonists [12].

There is also an animal study that supports previous findings which report that chronic, but not acute, Δ9-THC-rich extracts are effective in reducing tremor and spasticity [95]. The “cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis” (CAMS) study, where 611 of 630 patients were followed, reported 48 %, 40 %, and 33 % recuperation in tremor of patients consuming cannabis extract, Δ9-THC, and placebo, respectively; however, the difference in perception of tremor improvement was not statistically significant [96]. A double-blind randomized placebo controlled study failed to show any favorable effects of a cannabis-based medicinal extract on tremor in a subgroup of 13 patients [97, 98]. In addition, although placebo recipients showed faster finger tapping than that of cannabis extract recipients in a randomized double-blind crossover trial amongst 14 tremulous patients, the study was unable to show any overall marked improvement on measures of objective tremor [99]. In a systematic review published by Koppel et al. [100], oral cannabis extract and Δ9-THC was considered, at present, “probably ineffective” and Sativex (nabiximols) “possibly ineffective” for easing MS-related tremors [100]. Although a decrease in CB1R density has been found in caudate–putamen and cortical regions, there are still lack of convincing data on changes to CB1R and CB2R expression and endocannabinoid transmission in both animals and postmortem brain of patients suffering from MS [12, 101].

Cannabinoids and HD-related Tremor

HD is an autosomal dominant, progressive neurodegenerative disorder primarily affecting cortical and striatal neurons [102, 103]; HD is characterized by chorea, that is, jerky involuntary movements (from the Greek word khoreia meaning “dancing in unison”). The loss of CB1R during the progression of HD, most specifically in the lateral pallidum, in transgenic mouse models of HD and in postmortem basal ganglia of patients who suffered from HD, represents a possible justification to investigate the use of cannabinoid agonists in HD [104–107]. While a beneficial response in reducing chorea has been reported for CBD [108], a controlled clinical trial among 15 patients with HD showed no significant improvements in chorea severity after 6 weeks of CBD administration at an average daily dose of 700 mg/day [109, 110]. In 2 uncontrolled single-patient, single-dose studies, nabilone produced opposing effects, worsening the symptoms and increasing choreatic movements in one study, but improving symptoms in the other [111–113]. A recent randomized, double-blind, placebo-controlled, crossover study also indicated the effectiveness of nabilone in the improvement in chorea [114]. It should be pointed out that none of these studies has investigated disease progression and they have all used a single cannabinoid. Therefore, data from animal models suggest either that combinations of different cannabinoids or a broad-spectrum cannabinoid may be needed to justify the lack of positive findings in some of the mentioned studies [115, 116].

Ataxia

Ataxias are a group of related neurological movement disorders that affect coordination, balance, and speech, and can also be associated with tremor. It is well known that cannabinoid agonists can induce motor dysfunction in the cerebellum to give an ataxic phenotype in animals, with effects ameliorated by selective CB1R antagonists [117, 118]. To date, there have been no published clinical trials on effects of cannabinoids in ataxia and potential effects on ataxia are confined to case report data in patients with MS with associated ataxia. Here, oral Δ9-THC or marijuana have been reported to improve motor coordination in some patients with MS [89, 92]. These reports contrast with the clear exacerbating effects of CB1R agonists in animals and suggest that investigations with different cannabinoids in patient populations with specific ataxias are needed. In one preclinical model, namely, the “ducky” du 2J mouse model of ataxia and absence epilepsy, it was found that the prominent CB1R-mediated inhibition of GABAergic transmission at interneuron–Purkinje cell synapses seen in the wild type was completely absent in heterozygous and homozygous du 2J mice, despite CB1R expression being unchanged [119] . du 2J mice are deficit in the auxiliary Ca2+ channel subunit α2δ2, and these data are consistent with this deficit leading to aberrant CB1R signaling downstream of receptor activation; it is also possible that deficits in endocannabinoid modulation of inhibitory transmission in the cerebellum contribute to the ataxic phenotype seen here.

Concluding Remarks

Cannabinoids, proposed to act predominantly via CB1R and CB2R activation, have been evaluated for different medical purposes. Cannabinoid receptors and endocannabinoids are highly abundant in the brain areas involved in the management of motor function, and their significant role in modulating many motor functions has been detailed. Although the exact molecular mechanisms of cannabinoid signaling in the pathogenesis of motor-related diseases has not been fully elucidated, and there are significant gaps in our understandings of their influence on motor pathways, medical cannabis appears to have benefits among some patients enduring tremor-associated diseases. However, no studies have so far investigated the role of cannabinoids in essential tremor. At present, despite much anecdotal evidence, observations from case studies and controlled human trials remain poorly matched with those in animal models of diseases. In order to better bridge this gap, it will be important to elucidate mechanisms of cannabinoid action and use comprehensive controlled studies to determine the impact of different cannabinoid-based compounds on tremor-related diseases in both animal models and humans. Furthermore, many clinical studies have reported psychoactive side effects of cannabinoids and hence their introduction in clinical use remains somewhat controversial. Therefore, there is a need to improve and develop novel therapeutic strategies using cannabinoid-based medicines with fewer side effects. In this regard, non-Δ9-THC cannabinoids may provide an attractive alternative. Moreover, while the above mentioned studies have largely focused on exogenous cannabinoid and endocannabinoid effects on CB1R in the central nervous system, it is important to point out that cannabinoid compounds may also act at alternative molecular targets [120]; in particular, the major phytocannabinoid, CBD, has only low, pharmacologically irrelevant, affinity at CB1R and is not associated with psychoactive effects. CBD was recent given orphan drug status for Dravet syndrome and warrants further investigation here, as do other non-Δ9-THC phytocannabinoids, to determine which may be friends and which may be foes in the aim of combating tremor. Given the foregoing considerations, it is reasonable to conclude that cannabinoids represent potential candidates for the management of tremor in some patients with motor-related diseases but that more studies should be done in order to elucidate alterations in cell signaling in both basal ganglia and cerebellum of animal models treated with cannabinoids with the aim of reducing tremors.