Medical Marijuana and Movement Disorders

Although medical marijuana (cannabis) may not be commonly used or top of mind in neurology, use is increasing, and data from oncology and psychiatry exist to guide use for managing nonmotor symptoms of movement disorders. There is also research suggesting that medical marijuana or its derivatives (eg, tetrahydrocannabinol [THC] or cannabidiol [CBD]) have potential for treating motor symptoms. Concerns about safety and efficacy remain and data are significantly limited by the difficulty inherent in conducting research of scheduled substances.¹ .

About Medical Marijuana

Understanding medical marijuana and medicinal use of substances derived from the cannabis plant is complicated by complex and contradictory laws at the state and federal level. Most US states (39 of 50) have legalized medicinal marijuana. Although the Drug Enforcement Administration (DEA) continues to classify marijuana and its derivatives as Schedule I drugs with no medical value and high abuse potential (making them illegal at the federal level), Congress prevents enforcement by stipulating that no federal funds may be used to prevent states from implementing laws legalizing use of medicinal marijuana.² In addition, the 2018 Farm Bill defines Cannabis species with less than 0.3% THC as hemp, which is legal to grow and use.³ Other contradictions include the DEA scheduling synthetic THCs dronabinol and nabilone as Schedule III and II, respectively, and descheduling CBD oil with less than 0.1% THC when used in medicine approved by the Food and Drug Administration (FDA).^4,5

Cannabis plants contain more than 400 chemical compounds and the balance of these in any species can result in markedly different effects. In particular, the THC to CBD ratio influences whether the effects are anxiety-inducing, calming, or hallucinogenic. CBD is typically used as a chronic pain modulator and is also used as an approved antiseizure medication when highly purified. THC is primarily used for its antianxiolytic effects and has been likened, at high doses, to a benzodiazepine with hallucinogenic effects; synthetic THC is also used as an appetite promoter in people with anorexia caused by chemotherapy.¹

Both CBD and THC are active at endogenous cannabinoid receptors (CB1 and CB2) with interacting and synergistic effects. Additionally, other compounds in the cannabis plant also are active at these receptors. CB1 and CB2 receptors are present in the periphery and the central nervous system (CNS), with CB2 predominating in the periphery and CB1 predominant in the CNS. CB2 receptors are found in the basal ganglia. Anti-inflammatory effects have been observed with both THC and CBD, although this effect is much stronger with CBD.⁶

Medical Marijuana for Movement Disorders

A recent systematic review⁷ identified only 7 randomized controlled trials of cannabinoids in people with movement disorders, including 2 for Parkinson disease (PD), 2 for Tourette syndrome (TS) and tics, and 3 for Huntington disease (HD). This review and others note the great need for further research^1,7,8 Only 5 clinical trials of cannabinoids for movement disorders are registered at clinicaltrials.gov (Table).

Nonmotor Symptoms

Awareness of the importance of treating nonmotor symptoms of PD and other movement disorders has been increasing and palliative care skills and knowledge can be helpful in this regard.⁹ The palliative care needs among people with PD or HD and their care partners differ from those receiving oncologic care. Both the substantially longer disease course and neuropsychiatric symptoms that can be identity-altering create a different signature of palliative needs, including prolonged care-partner burden and risk of burnout.

Nonmotor symptoms of PD that may be ameliorated by medical marijuana include sleep difficulties (including restless leg syndrome) and fatigue, trouble eating, pain, cognitive difficulties, anxiety, depression, as well as speech and communication problems. An observational trial involving 503 participants demonstrated that 30% of subjects used cannabis and 45% of those individuals reported subjective symptom improvement.¹⁰ Open-label case series have demonstrated improvements in anxiety, sleep, and pain using the Unified Parkinson’s Disease Rating Scale (UPDRS) and other validated measures.^11-15 A phase 2 trial of nabilone involving 47 participants demonstrated improvement on UPDRS part 1, primarily in anxiety and sleep, and a crossover, double-blind study involving 24 participants with PD treated with nabilone also demonstrated reductions in anxiety.^16,17 Neuropsychiatric symptom improvement after nabilone treatment was noted in 1 study involving people with HD.¹⁸ Studies of cannabinoids in people with nonneurologic disorders have demonstrated efficacy for improvement of pain, anxiety, and nausea.^19,20 Multiple randomized controlled studies also support use of cannabinoids for pain, sleep, anxiety, and agitation in other neurologic conditions.^21-23 The quality of evidence in these trials is low to moderate, however, and heterogeneity of compounds used makes drawing firm conclusions difficult. Of the 5 relevant planned or ongoing registered clinical trials (Table), 2 are for pain in PD and 1 is for nonmotor symptoms of PD. A study for TS is also measuring nonmotor symptoms as secondary outcomes.

Motor Symptoms

Some studies suggest that cannabinoids may be helpful for motor symptoms, particularly tics, and perhaps levodopa-induced dyskinesia, anxiety-related tremor, and rapid eye movement sleep behavior disorder (RBD).

Data from animal studies have demonstrated that the endocannabinoid system is involved in motor control and movement,²⁴ suggesting that exogenous cannabinoids could have potential for treatment of motor symptoms in movement disorders. For example, changes in the expression pattern of basal ganglia CB2 receptors were observed in primates after induction of experimental PD.²⁵ Other alterations in the endocannabinoid system in experimental models of PD can be reversed with levodopa treatment.²⁶ Agents that inhibit CB1 agonists, however, have been shown both to increase and decrease bradykinesia in animal models of PD, which could reflect the complex pharmacology of these receptors.²⁷ Agents that antagonize CB1 receptors more consistently improve motor symptoms without increasing dyskinesia.^28,29

In the systematic review described earlier,⁷ no improvement of motor symptoms was seen in the 2 trials of cannabinoids for PD. In contrast, tic reduction was observed in both trials for TS. Symptomatic relief was seen in 1 of the trials for PD. No reduction of dystonia was seen in the 2 trials measuring this symptom; in the 3 trials that measured levodopa-induced dyskinesia, only 1 showed reduction. All trials were small and used different cannabinoids, making it difficult to reach any conclusions. In 2 open-label case series, reductions in RBD-related events and improved clinical impression occurred.1 Of the 5 planned or active clinical trials, 1 is evaluating tic severity in TS and 1 includes dyskinesia as a secondary outcome (Table).

Patient Counseling

Despite the lack of evidence from clinical trials, in part because of marijuana’s status as a Schedule I substance, medical marijuana can be prescribed for movement disorders and other conditions in many states. In this context, neurologists need to be aware of the limits of current knowledge as well as the safety profile of this treatment when patients have questions. Medical marijuana can be considered when patients and care partners report high levels of pain, anxiety, or insomnia.

Person-centered medicine and palliative care approaches can be useful in these discussions. Asking permission to speak about medical marijuana and assessing patient interest are important first steps, considering the stigma of scheduled drugs. For patients who are open to a conversation about medical marijuana products or raise the issue themselves, a discussion weighing published evidence that does not fully endorse use and real-world efficacy and safety experience would be appropriate to foster shared clinical decision-making.

Formulations and Modes of Administration

Available formulations and accepted uses differ from state to state because of the complex patchwork of federal, state, and local laws. In New York state, a tincture (ie, sublingual oil) is available that has onset of action within 10 minutes, which can be particularly helpful when patients have high levels of anxiety are occurring. Vaping marijuana may have the fastest onset of action; however, the dose cannot be regulated, which limits consistent potential efficacy. For treatment of pain, orally ingested CBD tablets have longer effects over many hours. For localized pain, transdermal patches, ointments, or creams can be applied locally without significant CNS effects.

In New York state, when medicinal marijuana is prescribed, it is filled at a pharmacy or a dispensary, where trained professionals complete an evaluation and provide counseling on different formulations and administration methods. Often a formulation that has a balanced ratio of THC to CBD is tried first.

A concern is that obtaining medical marijuana from such dispensaries can be cost-prohibitive, depending on the amount a person needs to take. It is important to discuss with patients that obtaining marijuana products outside of dispensaries and pharmacies without using the prescribing system carries risks in that the quality and composition of those products is highly variable and less reliable.

Contraindications and Safety Considerations

There are no known contraindications for marijuana products based on the limited number of studies completed. Its use may be inappropriate for patients with severe substance use disorders. For individuals who have hallucinations or delusions, products high in THC should be avoided and compounds that can be applied locally should be preferred.

Epidemiologic studies show a correlation with marijuana use and cognitive processing changes in healthy adolescents,³⁰ leading many to suggest these products should be avoided by young people. However, these studies may not be applicable and have no analagous evidence in adults with PD. Formulations that are high in THC can cause euphoria and hallucinations, which are typically not seen with formulations high in CBD. Acute side effects seen in 2 studies of older individuals treated with dronabinol were sedation, anxiety, mood changes, fatigue, somnolence, and euphoria. Studies of real-word recreational use suggest that serious adverse events, when they occur, include nausea, vomiting, and intoxication.³¹ Stopping use abruptly may cause mood change, sleep disturbances, changes in appetite or weight, headaches, sweating, nausea, or abdominal pain.³² Caution should be exercised in that regard as both THC and CBD are metabolized through the P450 enzyme system.³³

Summary

Medical marijuana has potential to improve nonmotor symptoms, improve quality of life, and reduce burden of disease for people with movement disorders and their care partners. There may also be potential to reduce motor symptoms, although more research is needed. Products containing THC may be more useful for symptoms of anxiety and sleep difficulties and those high in CBD may be more useful for treating pain. Real-world experience and widespread knowledge of these products make it important for physicians to be able to discuss the possible benefits and risks of medical marijuana for people with movement disorders.