06.23.2015
by Sarah Wickline Wallan
Staff Writer, MedPage Today

Various cannabinoid compounds did not improve nausea, vomiting, or appetite, and only slightly improved chronic pain and spasticity, in patients with various long-term health conditions, a review of randomized clinical trials found.

The greatest reductions in chronic pain were reported by patients who smoked tetrahydrocannabinol (THC) in eight of the trials, but the majority of the 79 trials in the meta-analysis demonstrated cannabinoids had little effect on HIV/AIDS patients with low-appetite and actually worsened chemotherapy-related nausea and vomiting, Penny F. Whiting, PhD, of University Hospitals Bristol NHS in England, and colleagues reported in the Journal of the American Medical Association.

Whiting’s group searched for randomized, controlled trials testing cannabis, or cannabinoid-based medications, across 28 databases through April 2015 and settled on 79 trials with 6,462 participants for this meta-analysis. Most of the trials included patients who had chemotherapy-related nausea and vomiting, HIV/AIDS-stunted appetite, chronic pain, or paraplegia, or spasms related to multiple sclerosis (MS).

A few trials had patients with Tourette syndrome, glaucoma, sleep disorders, psychosis, depression or anxiety, but none of them provided reliable research, the authors noted.

Whiting’s group determined that only 5% had a low risk of bias, and 70% were considered high risk. Some of this bias was due to lack of double-blinding and placebo controls.

Medical marijuana laws differ by state, but medical marijuana is not approved by the FDA to treat any medical condition. As a result, state approval has been based on “low-quality scientific evidence, anecdotal reports, individual testimonials, legislative initiatives, and public opinion,” wrote Deepak Cyril D’Souza, MBBS, MD, and Mohini Ranganathan, MBBS, of Yale University, in an accompanying editorial. “Imagine if other drugs were approved through a similar approach.”

Marijuana “is a complex of more than 400 compounds including flavonoids and terpenoids and approximately 70 cannabinoids other than delta-9-tetrahydrocannabinol (THC),” they wrote, stating that cannabis research isn’t comparable to other FDA-approved drugs, which contain one or two active ingredients. “These cannabinoids have individual, interactive, and even entourage effects (effects of a compound that are only appreciable in the presence of other compounds) that are not fully understood and that contribute to the net effect of marijuana.”

“If the states’ initiative to legalize medical marijuana is merely a veiled step toward allowing access to recreational marijuana, then the medical community should be left out of the process, and instead marijuana should be decriminalized,” they wrote. “Evidence justifying marijuana use for various medical conditions will require the conduct of adequately powered, double-blind, randomized, placebo/active controlled clinical trials to test its short- and long-term efficacy and safety.”

 

Study Details

Overall, 28 of the trials tested compounds to treat nausea and vomiting in chemotherapy patients. These trials tried several different cannabinoid compounds, such as nabilone, dronabinol, nabiximols, levonantradol, and THC, up against comparator drugs like prochlorperazine, chlorpromazine, domperidone, alizapride, hydroxyzine, metoclopramide, and ondansetron.

But the risk of bias was high for 23 of these trials and unclear for the other five, according to the authors.

Compared with placebo in three of the trials, chemotherapy patients who were in the cannabinoid arms of dronabinol or nabiximols were more likely to have nausea or vomiting (47% versus 20%, odds ratio 3.82, 95% CI 1.55-9.42).

In four of the trials, HIV/AIDS patients with low appetite were assessed and three of the trials used a placebo, one included marijuana, and one used megestrol acetate in the control arm.

The authors suggested that all four trials had a high risk of bias and “limited findings.”

In 28 of the trials, smoked or vaporized cannabis, or various cannabinoid compounds, were tested to treat chronic pain. With the exception of one trial, which compared nabilone with amitriptyline, all of the other trials were placebo-controlled.

Patients in these trials had chronic pain associated with several different conditions, including cancer, diabetic peripheral neuropathy, and other neuropathic pain.

Whiting’s team reported that only two of the studies had a low risk for bias, and 17 had a high risk.

Most of the studies reported modest improvements in pain with cannabinoids, but most individual studies did not reach statistical significance.

In eight of the trials, patients who reported a reduction in pain of at least 30% were more likely to be in a cannabinoid group compared with a placebo group (OR 1.41, 95% CI 0.99-2.00).

Patients who smoked THC reported the greatest reduction in pain (OR 3.43, 95% CI 1.03-11.48). The largest improvements were reported in neuropathic pain (weighted mean difference -3.89, 95% CI -7.32 to -0.47), which was assessed in five placebo-controlled trials.

D’Souza and Ranganathan argued that for chronic pain patients, there is some evidence of cross-tolerance between cannabinoids and opioids that should be considered in attempting to partially or fully substitute opioids with marijuana in the treatment of pain syndromes.

“Perhaps medical marijuana should also be included in monitoring databases as has been done for opioids and benzodiazepines, so physicians could have a more complete understanding of the medication profile of their patients,” they wrote.

In multiple sclerosis and paraplegia, 14 trials assessed the use of cannabinoids to reduce spasticity.

Based on the Ashworth scale for spasticity, cannabinoid use improved spasticity compared with placebo in five trials. But improvements in most of these studies failed to reach statistical significance (weighted mean difference -0.12, 95% CI -0.24 to 0.01).

In three of the trials, global impression of change scores were higher for nabiximols compared with placebo (OR 1.44, 95% CI 1.07 to 1.94).

A crossover trial of dronabinol and oral THC/cannabidiol supported these findings with consistent data, the authors wrote.

Adverse Events

With a couple of minor exceptions, Whiting’s team did not report clinically meaningful findings from trials that assessed the impact of cannabinoids on depression, anxiety, sleep disorders, glaucoma, psychosis, or Tourette syndrome.

In a crossover trial, fibromyalgia patients had improvements in insomnia with nabilone, but amitriptyline had a greater impact on sleep restfulness.

Patients with sleep apnea/hypopnea reported improvements over the placebo arm with nabilone (mean difference from baseline, -19.64, P=0.02).

In 62 of the studies, adverse events were reported, and Whiting’s team stated that they did not see much difference in adverse events based on the type of cannabinoid used or study design. Short-term adverse events reported in the trials included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination.

Limitations of the meta-analysis were the inclusion of trials that did not appropriately handle withdrawals, had selective outcome reporting, small sample sizes, and demonstrated inadequacies in their description of methods, allocation concealment, and blinding.

They concluded that future cannabinoid trial should follow the Consolidated Standards of Reporting Trials (CONSORT) and assess outcomes relevant to patients such as adverse events and quality of life.

• Reviewed by F. Perry Wilson, MD, MSCEAssistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner

LAST UPDATED 06.24.2015