Therapeutic Use of Cannabis: Indications in Neurology

• Spasticity
  • Pathophysiology
  • Available Treatments
  • Antispasmodic Mechanism of Action of Cannabis and Cannabinoids
    • Animal Studies
    • Endocannabinoid System and Spasticity
  • Cannabis and Cannabinoids in the Treatment of Spasticity
    • Case Reports and Patient Series
    • Clinical Trials
      • Bibliographic Search Strategy
      • Selection of Studies
      • Data Extraction
      • Summary Table: Multiple Sclerosis
      • Summary Table: Spinal Cord Injuries
    • Other Studies
• Ongoing Clinical Trials
• Place in Therapy
• Multiple Sclerosis and Spinal Cord Injuries
• Recent Advances and Future Directions
• Conclusions
• Bibliography

Spasticity

Pathophysiology

Spasticity is when your muscles don’t respond normally to passive muscle stretch. In other words, it’s when your muscles resist the stretch more than they should. It is usually accompanied by increased muscle tone, decreased stretch reflexes, muscle weakness, and painful muscle spasms. It can make it hard to move around and do daily things like dressing, eating, and bathing. It can also make it hard to work. Some other possible consequences of spasticity include sleep disturbances, pressure ulcers, and muscle contractures. [1], [2]

We don’t fully understand why this happens, but we know that it’s caused by an injury to or dysfunction of the upper motor neuron. This disrupts the spinal cord’s inhibitory pathways, leading to overactivity of the alpha motor neurons. [3] There is also an imbalance in the chemicals in the brain, with more stimulation of glutamatergic excitatory neurons and less activity of GABAergic inhibitory neurons. [2] The ceruleospinal pathway, which controls the activity of adrenergic spinal motor neurons, is also involved. [4]

Conditions that may cause spasticity include disorders affecting the brain and/or the spinal cord, such as multiple sclerosis (MS), cerebral palsy, traumatic brain injury, cerebrovascular disease, and spinal cord injury (SCI) of traumatic or non-traumatic origin. [5]

The symptoms and treatment response vary depending on where and how much the lesion is in the spinal cord, brainstem, or brain. Many patients with MS and SCI also have muscle spasms, clonus, ataxia, tremor, and paroxysmal pain. [2]

Available Treatments

Spasticity is managed symptomatically. The main goal is to reduce excessive muscle tone in affected limbs, thereby improving the patient’s functional capacity and reducing discomfort. [3] Non-pharmacological interventions include rehabilitation, physiotherapy, orthopedic measures, electrical stimulation techniques (such as transcutaneous nerve stimulation), and surgery (for example, anterior or posterior rhizotomy and tendon relaxation procedures). Neuronal blockade with local anesthetics or alcohol is also used, though surgical complications may include anesthesia-related risks, denervation atrophy, or skeletal muscle paralysis. [6]

Pharmacologically, several agents have been used—classified as having central or peripheral actions. Central-acting drugs include baclofen, tizanidine, benzodiazepines (primarily diazepam and clonazepam), gabapentin, clonidine, and cannabis (with its derivatives). Peripheral agents include dantrolene and botulinum toxin A. Regulatory approval has been granted only for baclofen, diazepam, dantrolene, and tizanidine for spasticity treatment. [3] (Note: Dantrolene was withdrawn from the Spanish market in 1996 due to low commercial profitability, although it remains available elsewhere.)

Studies have shown that baclofen, dantrolene, diazepam, and tizanidine are more effective than placebo and have similar efficacy among themselves, though their adverse effect profiles differ. They can moderately reduce hypertonia and painful spasms, but they do not significantly change overall disability or quality of life. [3], [7] Common adverse effects include sedation, drowsiness, and muscle weakness; these may compromise patient independence. Gabapentin has shown a promising adverse effect profile in one clinical trial for this indication. [3]

Antispasmodic Mechanism of Action of Cannabis and Cannabinoids

The precise mechanism by which cannabis and its derivatives exert antispasmodic effects is not fully elucidated. However, evidence suggests that the endocannabinoid system plays an important role.

Animal Studies

In animal models of autoimmune neurological disorders such as MS, THC and some synthetic cannabinoids—as well as endogenous cannabinoids—have demonstrated antispasmodic effects and improvements in tremor control. Some studies even suggest potential beneficial effects on disease progression. [8], [9], [10], [11], [12]

For example, in a model using mice with experimental chronic relapsing allergic encephalomyelitis (CRAE) induced by an injection of homogenized mouse spinal cord in complete Freund’s adjuvant, demyelination and axonal loss occur, mimicking many aspects of MS (including relapsing–remitting paralysis, tremor, and spasticity). In one study, intravenous administration of THC and the potent synthetic cannabinoid agonist Win-55,212-2 reduced both the frequency and amplitude of spasticity and tremor in these mice. [8]

These findings were important because they represented the first well-controlled positive results in animal models and pointed toward new therapeutic strategies for tremor and spasticity in MS—conditions that have historically been difficult to treat.

However, questions remain regarding the exact contributions of CB1 versus CB2 receptor activation, their influence on neurotransmitter release, and whether the antispasmodic effects are related to enhanced GABAergic tone in areas such as the substantia nigra (a finding observed in animal models of Parkinson’s disease). [13], [14], [15]

Endocannabinoid System and Spasticity

Some endocannabinoids—such as metanandamide (a stable metabolite of anandamide) and palmitoylethanolamide—have shown antispasmodic effects in the CRAE model. [8] Metanandamide has a very low potential for dependence [16] and has been proposed as a possible treatment for spasticity in MS patients. [17] Palmitoylethanolamide, which does not bind to CB1 or CB2 receptors, may act via a third, as-yet-unidentified receptor (sometimes referred to as “CB2-like”). [18]

These data indicate that the endocannabinoid system may be a natural modulator of spasticity and tremor. For example, blocking CB1 receptors with the antagonist SR141716A worsened spasticity and tremor in mice with CRAE during remission but not in healthy mice or those in the acute phase, suggesting that endocannabinoids produced during tissue injury act as compensatory agents. [9]

Other experimental studies have suggested that cannabinoids might also slow disease progression in autoimmune neurological disorders such as MS, although clinical confirmation of these findings is still pending. [10]

Cannabis and Cannabinoids in the Treatment of Spasticity

Case Reports and Patient Series

The lack of an effective conventional treatment for MS has led many patients to seek alternative therapies. Numerous anonymous interviews with a total of 270 patients with MS and SCI reported improvements in spasticity, muscle spasms, tremor, urinary symptoms, and pain. [18], [19], [20], [21] For example, the United Kingdom Multiple Sclerosis Society estimates that at least 1,000 of 85,000 MS patients use marijuana to alleviate their symptoms. [22] An Australian survey also identified cannabis—as well as cold baths, meditation, and dietary changes—as among the most beneficial factors reported by MS patients. [23]

In addition, many anecdotal reports describe improvements in spasticity and related symptoms in both MS and SCI patients who have used cannabis. [24], [25] Some of these case reports have been published in medical journals and were later incorporated into systematic reviews on the antispasmodic efficacy of cannabis and cannabinoids.

One publication described two patients—one with MS and one with progressive myelopathy—who received oral THC (10–15 mg four times daily for four days) followed, after a 14-day washout, by rectal THC hemisuccinate (5 to 2.5 mg four times daily for four days). Both patients experienced reduced spasticity (as measured by the Ashworth scale), reduced rigidity, and improved mobility (assessed via a 5‑minute walk test) with both formulations. [26]

In another case, a 59‑year‑old man with MS and pendular nystagmus—resistant to baclofen, clonazepam, and gabapentin—experienced suppression of nystagmus within 30 minutes after smoking two cannabis cigarettes. This effect was reproducible on three occasions; however, he did not respond to 6 mg of nabilone or to an oily cannabis extract containing 40 mg of THC. [27]

Additionally, a 30‑year‑old patient with disabling progressive MS (characterized by spastic tetraparesis, limb ataxia, urinary retention, and sexual dysfunction) demonstrated objective improvement in all symptoms with both smoked cannabis and orally administered cannabis cookies. [28]

Clinical Trials with Cannabis and Cannabinoids in the Treatment of Spasticity

Bibliographic Search Strategy

To evaluate the antispasmodic efficacy of cannabis and cannabinoids, a search was performed in the PubMed database and in the Cochrane Library, using various combinations of MeSH terms and free text (including “cannabis,” “cannabinoids,” “marijuana smoking,” “nabilone,” “levonantradol,” “muscle spasticity,” “multiple sclerosis,” “spinal cord injuries,” and “clinical trial”), from the inception of each database until April 2004. (More recent searches have extended this period; see “Recent Advances” below.)

Selection of Studies

Phase III clinical trials with random assignment comparing placebo and/or active treatment that evaluated the antispasmodic efficacy and/or safety of cannabis or its derivatives in patients with any spasticity-inducing condition were selected. Additional studies identified from the references of these trials were also included.

Data Extraction

One author (MD) extracted the data from the selected studies, and a second reviewer (DC) verified the data. Discrepancies were resolved by consensus. Variables recorded included study quality, patient characteristics, baseline treatment, cannabinoids and doses used, control treatments, efficacy outcomes, toxicity, and study duration.

The quality of the clinical trials was assessed using the 5‑item Jadad scale, which awards points for randomization, double-blinding, and reporting of withdrawals (with additional points if randomization and blinding were conducted appropriately). [29]

Seventeen publications on the use of cannabis and its derivatives for spasticity were initially identified. After excluding three reviews [30], [31], [32], an open study without a control group [26], three anecdotal case descriptions [27], [28] (one of which focused on pain rather than spasticity) [33], and two trials that did not measure antispasmodic efficacy as the primary outcome [34], [35], eight clinical trials remained for inclusion.

Of these eight trials, six evaluated the antispasmodic efficacy of cannabinoids in a total of 726 MS patients. [36], [37], [38], [39], [40], [41] One trial involved a single patient (n=1) with spasticity and pain due to an ependymoma. [42] The eighth trial included five patients with traumatic spinal cord injuries. [43] Although the trials were heterogeneous with respect to patient type (MS and SCI), cannabinoid preparation and dose, treatment duration, and outcome measures, a qualitative review was conducted.

Summary Table: Multiple Sclerosis

Study (Reference)	Design & Duration	Patient Characteristics	Cannabinoid(s) Evaluated	Control	Outcome Measures	Results	Adverse Effects & Withdrawals	Jadad Score
Petro et al. [36]	Crossover, double-blind, randomized 3 days	Age: 21–55; 5 males, 5 females MS; No previous cannabis use	THC 5 mg/day; THC 10 mg/day (Single dose)	Placebo	Objective: Tendon reflexes, resistance to stretch, deep tendon reflexes Subjective: Clinical evaluation by physician and patient	Spasticity scale (sum of all variables): THC > Placebo (p<0.01)	THC 10 mg: euphoria in one patient; Placebo: euphoria in one patient No withdrawals; 7/9 correctly identified placebo treatment	3
Ungerleider et al. [38]	Crossover, double-blind, randomized 12 days	Age: 26–64; 5 males, 8 females MS with intolerance to standard antispasmodics; 9/13 with previous cannabis use	THC 2.5–15 mg once or twice daily (for 5 days)	Placebo	Objective: Spasticity scale Subjective: Patient clinical evaluation	Objective: THC = Placebo Subjective: 7.5–20 mg THC > Placebo	Mild adverse effects (dry mouth, sedation, dizziness, perceptual changes in 7/8 patients); 4 withdrawals not treatment-related	3
Martyn et al. [39]	Double-blind, randomized (n=1) 16 weeks	Age: 45; Male Relapsing–remitting MS with severe spasticity; Prior nabilone use	Nabilone 1 mg every 48 hours for 2 weeks	Placebo	Subjective: Frequency of painful spasms, general condition, nocturia	All variables: Nabilone > Placebo	Mild sedation (beneficial)	5
Killestein et al. [40]	Crossover, double-blind, randomized 20 weeks	Age: 46; Sex not specified Progressive MS with baseline spasticity (Ashworth ≥2); 6 with cannabis experience	THC 5–10 mg/day; Cannabis extract (Dose escalation: 2 weeks, maintenance: 2 weeks, washout: 4 weeks)	Placebo	Objective: EI, Ashworth scale, EDSS Subjective: MFSS, clinical evaluation, quality-of-life questionnaires, VAS (overall impression)	Muscle tone: THC and extract = Placebo Mobility & overall impression: THC and extract < Placebo (p=0.01) Quality of life: THC > Placebo (p=0.02)	Mild adverse effects; one case of severe acute psychosis with extract; most patients correctly identified active treatment; no withdrawals	4
Zajicek et al. [36]	Parallel-group, double-blind, randomized 15 weeks	Mean age: 50; 413 males, 217 females MS (progressive and relapsing–remitting) with spasticity (Ashworth ≥2 in two muscle groups); 6 with cannabis experience	THC 5–25 mg/day; Cannabis extract (2–10 capsules/day)	Placebo	Objective: Ashworth scale, EDSS, 10‑minute walk test Subjective: Quality-of-life questionnaires, VAS differences (pain, spasticity, spasms, urinary issues, tremor, sleep, depression, irritability, weakness)	Muscle tone: THC = extract = Placebo Mobility: THC > Placebo and extract (p=0.015) VAS: THC and extract > Placebo (p=0.03)	Extract = THC = Placebo; 9 withdrawals due to adverse effects	5
Vaney et al. [41]	Crossover, double-blind, randomized 1 month	Age and sex not specified MS with previous cannabis use	Oral cannabis extract (15 mg/day, divided into three doses)	Placebo	Objective: Ashworth scale, digit span, SF36, Rivermead Index, MSFC Subjective: Daily spasm scale, symptom diary (pain, spasticity, spasms, urinary issues, tremor, sleep, depression, irritability, weakness)	Spasm frequency: Extract > Placebo (p=0.05); Ashworth scale: Extract = Placebo	Not specified	Not specified

Summary Table: Spinal Cord Injuries

Study (Reference)	Design & Duration	Patient Characteristics	Cannabinoid(s) Evaluated	Control	Outcome Measures	Results	Adverse Effects & Withdrawals	Jadad Score
Maurer et al. [42]	n=1; Double-blind, randomized 8 months	Male, 28 years SCI due to ependymoma; neuropathic pain; on baclofen, clonazepam, carbamazepine	THC, 5 mg × 18 doses over 5 months	Placebo; Codeine 50 mg	Subjective: VAS (pain, spasticity, mood, concentration, sleep, nocturia)	Spasticity: THC > Placebo and Codeine Mood, sleep, concentration, nocturia: THC and Codeine > Placebo	No adverse effects related to decreased mood, sleep, concentration, or level of consciousness with THC	3
Hanigan et al. [43] (abstract)	n=5; Double-blind, crossover 20 days	Age and sex not specified Traumatic paraplegia; spasticity resistant to multiple treatments	THC, 35 mg per day	Placebo	Objective: Deep tendon reflexes, muscle stretch Subjective: VAS for spasticity (patients and nursing staff)	In 2/5 patients: decreased objective measures with THC In 1/5: improvement in subjective measures In 1/5: THC = all variables	One patient withdrew due to psychiatric adverse effects; 2/5 correctly identified active treatment	1

^a All treatments were administered orally.

Other Studies

Additional clinical trials that did not measure spasticity as the primary outcome have evaluated other relevant symptoms in MS patients, such as posture, tremor, and urinary dysfunction. For example:

• In one study with 8 MS patients, 5 reported subjective improvement in tremor with smoked hemp, and in 2 patients this was confirmed objectively. [34]
• A placebo-controlled crossover trial found that an oral cannabis extract was not effective in improving tremor in 14 MS patients. [44]
• In another trial with 10 MS patients, most reported subjective improvement compared with placebo, although objective measures of muscle balance and posture worsened. [35]
• A pilot trial in 10 MS patients found that sublingual administration of a standardized cannabis extract improved bladder hyperactivity (assessed by cystometry) more than placebo. [45]

Ongoing Clinical Trials

Ongoing studies have been identified from the PubMed and Cochrane Library databases, as well as from the references of the selected trials. Additional information has been requested directly from investigators.

Since the original review, several new trials have been initiated. Notably, GW Pharmaceuticals has developed cannabis extracts (e.g., nabiximols, commercially known as Sativex) from selected clones of Cannabis sativa and has conducted multiple phase III trials. These studies include between 50 and 160 patients, are randomized, double-blind, and parallel-group, and feature extension phases of 12 to 24 months to assess long-term safety. Results from these and other recent trials (including meta-analyses and systematic reviews) have contributed to regulatory approvals in various countries and provide updated evidence regarding efficacy and tolerability.

Place in Therapy

As with any symptomatic treatment, management of spasticity must be individualized. Traditional agents (baclofen, tizanidine, dantrolene, diazepam) have demonstrated efficacy over placebo in patients with non-progressive neurological diseases and in MS; however, clinical trials are limited by small sample sizes, short follow-up durations, and heterogeneous outcome measures. [47], [48] Adverse effects such as drowsiness, hypotonia, and muscle weakness may further complicate treatment.

In a single trial, gabapentin showed a favorable safety profile, but direct comparisons between antispasmodics are rare. [3], [48], [49] Overall, current options remain suboptimal, underscoring the need for methodologically robust, long-term, head-to-head studies.

The evidence available to date for the potential efficacy and role of cannabis and cannabinoids in treating spasticity is limited by the small number and heterogeneity of trials. Nevertheless, both experimental data and recent clinical studies (including those with nabiximols) suggest that cannabis-based medicines can improve patient-reported symptoms such as stiffness, pain, and sleep quality—even if objective measures (e.g., Ashworth scale) do not always show significant change. These agents may offer an alternative for patients who do not respond adequately to conventional therapies.

Multiple Sclerosis and Spinal Cord Injuries

Multiple Sclerosis (MS)
MS is an autoimmune inflammatory disease of the central nervous system characterized by primary myelin destruction. It affects approximately 2.5 million people worldwide, with a lifetime risk of about 1 in 400, and is the most common cause of neurological disability in young adults. [50] Motor symptoms vary widely; mild cases may involve exercise-induced weakness, while rapidly progressive cases can lead to paraplegia within days. Approximately 60% of MS patients experience spasticity. Symptomatic treatment in MS primarily targets spasticity, pain, fatigue, tremor, and urinary dysfunction. [48]

Although early trials with oral THC and cannabis extracts did not always show significant antispasmodic efficacy on objective scales (such as the Ashworth scale), many patients reported improvements in spasticity, pain, and sleep quality. These findings have been corroborated by subsequent systematic reviews and clinical trials, leading to the approval of cannabis-based medicines such as nabiximols (Sativex) in several countries.

Spinal Cord Injuries (SCI)
Spasticity is also common in patients with SCI—whether traumatic or due to other causes. Although the clinical evidence for cannabis and cannabinoids in SCI is less extensive than in MS, available studies suggest potential benefits for both spasticity and associated pain. Ongoing trials aim to better define their role in this patient population.

Recent Advances and Future Directions

Since the early 2000s, research on cannabinoids has expanded significantly. Key developments include:

• Nabiximols (Sativex): Several phase III trials have demonstrated that nabiximols—a cannabis-based oromucosal spray containing THC and cannabidiol (CBD)—can reduce patient-reported spasticity and improve quality of life in MS. Regulatory approval has been granted in multiple countries, and real-world data continue to support its use.
• Meta-analyses and Systematic Reviews: Recent comprehensive reviews (published post-2010) have confirmed that cannabis-based medicines offer modest improvements in subjective measures of spasticity, pain, and sleep disturbances, with an acceptable safety profile.
• Advances in Mechanistic Understanding: Ongoing preclinical studies have further elucidated the roles of CB1 and CB2 receptors as well as potential non-cannabinoid receptor targets. Novel compounds—including selective CB2 agonists and inhibitors of endocannabinoid metabolism—are under investigation, with the aim of achieving antispasmodic effects while minimizing psychoactive side effects.
• Personalized Therapy: Emerging research is exploring biomarkers and clinical characteristics that may predict responsiveness to cannabinoid-based treatments, paving the way for more personalized therapeutic approaches.

Future research will focus on long-term safety, optimal dosing strategies, and head-to-head comparisons with conventional antispasmodics. The integration of patient-reported outcomes with objective measures will also be key in understanding the full clinical impact of these therapies.

Conclusions

Spasticity is a common and serious symptom in patients with multiple sclerosis and spinal cord injuries. The main goal of treatment is to reduce muscle tension, which can improve function and reduce discomfort. Studies on animals and in the lab have shown that cannabinoids, the natural chemicals in the cannabis plant, can help with spasticity by interacting with certain receptors in the body. Early clinical trials had mixed results, but patient reports of improvements in stiffness, pain, and sleep quality have led to the acceptance of cannabis-based medicines as a viable therapeutic option.

In recent years, more clinical trials—including those that led to the approval of nabiximols—have shown the potential role of cannabinoids in managing spasticity. However, the studies so far have been small and used different methods, so more research is needed. However, more well-designed, long-term studies are needed to determine the exact place of cannabis-based treatments in therapy.

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