Medical Evidence of the Health Benefits of Cannabis
AD, the leading form of dementia in the elderly, is a progressive, age-related disorder characterized by cognitive and memory deterioration. AD has several neuro- pathological markers, including neuritic plaques and neuro- fibrillary tangles. Although several researchers have suggested dronabinol and Nabilone may act on these mechanisms to confer therapeutic effects for patients with AD, a recent Cochrane systematic review found no evidence that dronabinol was effective in re- ducing symptoms of dementia. The authors of a placebo-controlled crossover study of 15 patients with AD who were refusing to eat suggest that dronabinol increases weight gain and decreases disturbed behavior, but there is insufficient quantitative data to support this conclusion, and one study participant had a grand mal seizure following dronabinol administration. Another pilot study of two patients with dementia found that dronabinol reduced nocturnal motor activity . No studies have examined the effects of smoked marijuana in patients with AD. In sum, there is insufficient evidence to recommend marijuana for the treatment of AD. Future directions should include conducting randomized controlled trials (RCTs) comparing both smoked and oral marijuana to placebo and existing treatments, with sample sizes large enough to detect treatment effects and the safety and tolerability of marijuana.
Amyotrophic lateral sclerosis
ALS is a fatal neurological disease with symptoms that include weakness, spasticity, and respiratory difficulties. Cannabinoids are hypothesized to act in the regions of established pathophysiology for ALS and could be used for symptom management (e.g., pain, spasticity, wast- ing, respiratory failure, dysphagia, negative mood, and dysautonomia). Although there is limited evidence from a survey of patients with ALS that marijuana consumed in a variety of forms (i.e., oral, smoked, vaporized, and eaten) improves speech and swallowing, the antisalivatory components of marijuana may reduce the risk of aspiration pneumonia, while also increasing patient comfort . These survey findings indicate that up to 10 percent of patients use marijuana for symptom management, and these self-reports suggest efficacy in increasing appetite and mood and decreasing pain, spasticity, and drooling. However, as is consistent with the half-life of smoked marijuana, the beneficial effects of marijuana on symp- toms of ALS were fewer than 3 hours in duration . The only randomized, double-blind, placebo-controlled crossover trial of marijuana in patients with ALS has a small sample size (N = 27) and indicates that while 5 mg of dronabinol is well-tolerated, there was no effect on number or intensity of cramps, quality of life, appetite, sleep, or mood. There is currently insufficient clinical evidence in humans with ALS to recommend cannabinoids as primary or adjunctive therapy.
CD is an inflammatory bowel disease (IBD) that has no cure; treatment targets include reducing inflammation and secondary symptoms. Between 16 percent and 50 percent of patients use marijuana to relieve symptoms of IBD, and patients using marijuana for 6 months or longer are five times more likely to have had surgery for their IBD; whether marijuana exacerbates dis- ease progression or more severe disease results in self- medication is unclear. Only one placebo-controlled study of the effects of marijuana in patients with CD has been conducted . This study found that there was no difference between placebo and smoked marijuana on CD remission (defined as a CD Activity Index (CDAI) of less than 100), and that marijuana was superior to placebo in promoting clinical response (a decrease in CDAI score greater than 100), reducing steroid use, and improving sleep and appetite. Importantly, this study did not include objective measurement of inflammatory activity, and there was no significant difference in placebo and treatment groups 2 weeks after treatment cessation . Until clinical trials with objective measurement of treatment effects over an extended period of time are conducted to examine the safety and efficacy of marijuana for the treatment of IBD, there is insufficient evidence for the use of marijuana for the treatment of IBD.
Glaucoma is a neurodegenerative eye disease that can cause blindness by damaging retinal ganglion cells and axons of the optic nerve. Intraocular pressure (IOP) can influence both onset and progression of glaucoma and is often a target for intervention. Small samples have demonstrated reduced IOP following smoked marijuana, but the effect is only present in 60–65 percent of individualsand lasts for 3–4 hours, requiring repeated dosing throughout the day. Furthermore, patients discontinue marijuana use due to side effects (e.g., dizziness, anxiety, dry mouth, sedation, depression, confusion, weight gain, and distortion of perception), and this treatment discontinuity may exacerbate optic nerve damage and obviate the benefits of reduced IOP. Limited research and documented toxicity have resulted in the American Glaucoma Society, Canadian Opthalmological Society, and the American Academy of Ophthalmology’s Complementary Therapies Task Force determining that there is insufficient evidence to indicate that marijuana is safer or more effective than existing pharmacotherapy or surgery for the reduction of IOP. Development of eye drops for topical application of THC would minimize psychoactive and other side effects but is complicated by the high lipophilicity and low water solubility of cannabinoids. Additionally, the distance from the application site to the retina may be too great to afford neuroprotective benefits, given that only 5 percent of an applied dose penetrates the cornea to the intraocular space.
Hepatitis C Virus
There have been no RCTs examining the use of cannabi- noids on HCV infection. Of the studies that have been conducted, one longitudinal study demonstrates that smoked marijuana has no effect on HCV progression in individuals with HIV . In contrast, individuals with HCV who smoke marijuana have a higher fibrosis pro- gression rate and more severe steatosis , with daily smokers having a more rapid rate of progression and greater severity than occasional marijuana users . Marijuana may have independent negative effects on steatosis, but because none of these findings were in the context of a clinical trial, these correlations are not causal and it is possible that individuals who use marijuana do so to manage greater symptom severity .
There may be secondary effects of cannabinoids on HCV treatment side effects: dronabinol and Nabilone stabilized treatment-induced weight-loss; and dronabinol, Nabilone, and marijuana procured from a marijuana club (dose and method of administration unspecified) increased HCV treatment duration and reduced post- treatment virological relapse . However, there is also a potential drug-drug interaction between ribavirin, a traditional HCV treatment, and marijuana due to shared cytochrome 450 metabolism. Because 90 percent of HCV infections are the result of injection drug use, treatment of symptoms with marijuana may be contra- indicated for this subpopulation, particularly because marijuana use in the context of other substance use (i.e., alcohol) has multiplicative effects on the odds of fibrosis severity. Given that newer treatments for HCV (e.g., sofosbuvir) are replacing ribavirin, there will likely be less need for use of marijuana in management of treatment- related side effects. In sum, there is currently insufficient empirical support to recommend marijuana for the treatment of HCV.
Marijuana use in HIV-infected patients is typically for the management of side effects (e.g., nausea) of older antiretroviral treatments and AIDS-related symptoms, including weight-loss and HIV-associated neuropathy (covered in cachexia and pain sections, respectively). Survey studies indicate that 23 percent of patients with HIV/AIDS smoked marijuana in the past month and do so largely to improve mood and appetite and reduce pain ; these patients may exhibit tolerance and need higher doses of THC than are currently approved by the FDA for use in clinical trials to experience treatment effects. The few RCTs that have been conducted in a small number of patients with HIV/AIDS largely examined the effects of marijuana (synthetic or natural marijuana that is smoked or ingested) on symptoms (e.g., nausea and appetite) over a short treatment window (21–84 days）. Studies examining the effects of marijuana on the pharmacokinetics of antiretroviral medication demonstrated that neither smoked marijuana nor dronabinol affects short-term clinical outcomes (e.g., viral load, CD4 and CD8 counts), influences the efficacy of antiretro-viral medication, or indicates that dose adjustments for protease inhibitors are necessary. However, individuals who are dependent on marijuana have demonstrated poorer medication adherence and greater HIV symptoms and side effects than nonusers and nondependent users. Furthermore, while some studies have no participant withdrawal due to adverse events, others reported treatment-limiting adverse events. Finally, because drug use is a risk factor for HIV infection, treatment of symptoms with marijuana may be contraindicated for this subpopulation. In sum, there is variability in short-term outcomes and insufficient long-term data addressing the safety and efficacy of marijuana when used to manage symptoms of HIV/AIDS and its role in those also using newer, better- tolerated antiretroviral agents.
Nabiximols (THC:CBD extract) has been the primary cannabis agent studied for the treatment of spasticity in patients with multiple sclerosis. Spasticity is commonly associated with painful spasms and sleep disturbance and contributes to increased morbidity. Endogenous and exogenous cannabinoids have been shown to be effective for multiple sclerosis spasticity in animal models, primarily through effects at the CB1 receptor. Nabiximols has been shown to be effective as monotherapy and as add-on therapy for patients not fully relieved with other anti- spasticity therapy.
One large multi-center parallel-group, double- blind, randomized placebo-controlled study included 160 patients with multiple sclerosis who were experiencing primary symptoms of spasticity, spasms, bladder problems, tremor, or pain. 58 Treatment evaluated was oromucosal sprays of matched placebo or whole plant canna- bis–based medicinal extract (CBME) containing equal amounts of THC and CBD at a dosage of 2.5–120 mg/day, in divided doses. A visual analog scale score for each patient’s most trouble- some symptom was used. This primary symptom score improved in both groups with no statistically significant difference; the scores of patients CBME reduced from a meanstandard of 74.36 +/- 11.1 to 48.89 +/-22.0, and using placebo from 74.31 +/- 12.5 to 54.79 +/- 26.3. Spasticity scores were significantly reduced with CBME in comparison to placebo (p=0.001). No significant adverse effects on cognition or mood were reported, and intoxication was generally mild.
In another double-blind study evaluating nabiximols, 189 patients with diagnosed multiple sclerosis and spasticity were randomized to receive daily doses of active preparation (124 patients) or placebo (65 patients) over 6 weeks. 59 The primary efficacy analysis on the intent-to- treat population (184 patients) showed the active preparation to be significantly superior (p=0.048) as measured with a numeric rating scale of spasticity. For the responders, 40% of patients receiving active preparation achieved greater than 30% benefit (p=0.014). Eight withdrawals were attributed to adverse events: six received active preparation and two received placebo.
A meta-analysis of three studies (two of which were described here earlier) evaluated 666 patients with multiple sclerosis and spasticity. These were randomized, placebo-controlled, double-blind parallel-group studies of nabiximols. On a 0–11 numeric rating scale, the adjusted mean decrease from baseline was 1.30 with nabiximols compared to 0.97 with placebo. Using a linear model, the treatment difference was 0.32 (95% CI 0.61 to 0.04, p=0.026). A greater proportion of the treated patients were responders (OR 1.62; 95% CI 1.15–2.28, p=0.0073) and they also reported greater improvement (OR 1.67; 95% CI 1.05–2.65, p=0.030). Many patients experienced at least one adverse event (288 of 363 patients for nabiximols, 169 of 303 patients for placebo), although most events were mild to moderate in severity and all serious adverse events resolved. Forty (11%) and 11 (3.6%) patients withdrew from the study due to adverse events in the nabiximols and placebo groups, respectively.
A consecutive series of randomized, double- blind placebo-controlled single-patient crossover trials evaluated muscle spasms as one outcome for 24 patients (18 with multiple sclerosis) with plant extracts of THC and CBD and a 1:1 mixture of THC:CBD in a sublingual spray.60 The THC and THC:CBD groups both reported significant improvement in the spasticity severity rat- ing versus placebo (p<0.05). Three patients experienced transient hypotension and intoxication with rapid initial dosing of CBME. The authors acknowledged that this was a preliminary study and that larger well-controlled studies were needed.
Oral cannabis has been evaluated in several trials for spasticity due to multiple sclerosis. In a double-blind crossover placebo-controlled randomized trial of 50 patients, the intent-to-treat analysis showed no significant difference in Ashworth spasticity scores compared to placebo. However, in the 37 patients who received more than 90% of the treatment (per protocol analysis), there was a significant improvement in the number of spasms and spasticity scores (p=0.013) and mobility (p=0.01). In a large multicenter double-blind randomized controlled trial of 630 patients with multiple sclerosis, 576 responded to questions about their spasticity. There was a significant improvement in patient-reported pain and spas- ticity (p=0.003) with a reduction in spasticity of 61% for the 197 patients receiving cannabis extract (95% CI 54.6–68.2) and of 60% for the 181 patients receiving oral THC (95% CI 52.5– 66.8). Of note, of the 198 patients receiv- ing placebo, 46% reported improvement in spasticity (95% CI 39.0–52.9). A double-blind placebo-controlled crossover study in 13 patients showed significant improvement in patient-reported subjective spasticity scores after receiving THC at doses ranging from 7.5 to 15 mg/day for 5 days. No objective outcomes were measured.
In one double-blind crossover placebo-con- trolled randomized trial of 12 patients, nabilone twice/day was given for 4 weeks to determine if it improved spasticity caused by spinal cord injury. There was a significant reduction in the Ashworth scale and total Ashworth score (p=0.003 and p=0.001, respectively).
Overall, cannabis-derived pharmaceuticals appear effective for muscle spasticity related to multiple sclerosis. Nabiximols is approved for this purpose in 10 different countries. Limited data exist on the use of other forms and doses of medical cannabis for muscle spasms. Further- more, most states list “muscle spasm” as an indication for medical cannabis use but do not require that the diagnosis of multiple sclerosis be present. The evidence of effectiveness of med- ical cannabis in muscle spasm not related to multiple sclerosis is scarce. Limitations of published studies include differences in spasticity assessment between patients (subjective) and providers (objective with Ashworth scale scoring), presence of other multiple sclerosis symptoms, lack of comparative trials for various formulations and routes of administration, self- selection bias, blinding participants to potentially psychoactive substances, and having many studies (especially those evaluating nabiximols) sponsored by the manufacturer or the medical marijuana industry. Most of these studies evaluated patients with inadequate spasticity relief using existing treatments, suggesting that the included patient populations would likely respond well to medical cannabis. Nabiximols or medical cannabis may be best reserved for the patient population who have not shown efficacy or are intolerant to other standard therapies for muscle spasm.
Marinol is made with synthetic THC and is used for the control of nausea and vomiting caused by chemotherapy and to stimulate appetite in AIDS patients. In 1999 Marinol was placed in Schedule III of the CSA.
Sativex is the first natural cannabis plant derivative to gain full market approval in any country. It is an effective drug for multiple sclerosis symptom management by British biopharmaceutical company, GW Pharmaceuticals. Sativex has been launched in 15 countries, including the UK, Spain, Germany, and Italy. The drug is also pending approval for pain associated with cancer.
GW Pharmaceuticals latest development, Epidolex, is an investigational drug made with cannabidiol to treat children with Dravet and Lennox-Gastaut syndromes, which are severe forms of epilepsy. Although the drug has not been approved for use by the FDA, the FDA recently granted Epidolex orphan drug designation and Fast Track for Dravet syndrome.