Ware et al24 conducted a crossover RCT (N = 23) to determine the efficacy of smoked MM for neuropathic pain. Participants had neuropathic pain for at least 3 months that was caused by trauma or surgery, with an average weekly pain intensity score >4 on scale of 0 to 10. Patients with pain due to cancer, nociceptive causes, unstable medical conditions, current substance abuse, history of a psychotic disorder, or suicidal ideation were excluded. Participants were assigned to a 9.4% THC group or a 0% THC group. Pain intensity was evaluated daily via telephone. Participants in the 9.4% THC group had statistically lower pain intensity compared with the 0% THC group (P = .023). Common adverse effects reported by those in the 9.4% group included headache, dry eyes, burning sensation, dizziness, numbness, and cough.
The effects of Cannabis
Marijuana is harvested from the plant Cannabis sativa and composed of 400 lipophilic chemical compounds, including phytocannabinoids, terpenoids, and flavonoids.13 The plant contains compounds termed “cannabinoids.” Two of these derivatives in particular are responsible for most of the effects of marijuana: cannabinoid delta-9- tetrahydrocannabinol (THC) and cannabidiol (CBD). THC has a comparable structure and binding mechanism to anandamide, a naturally occurring fatty acid neurotransmitter present within the human brain.14-16 The endogenous endocannabinoid system and its receptors are found throughout the entire body (brain, organs, glands, immune cells, and connective tissues).
THC binds to cannabinoid receptors CB1 and CB2. CB1 is found predominantly in the CNS. CB2 is found predominantly outside the CNS and is associated with the immune system.14-16 The effects of THC include euphoria, relaxation, appetite stimulation, improvement of nausea and vomiting, analgesia, decreased muscle spasticity, and reduced eye pressure.14,15 CBD may have anxiolytic, antipsychotic, anticonvulsive, and analgesic effects.
The rate of absorption of THC and CBD depends both on the potency of the cannabinoid as well as the mechanism of consumption. Cannabis can be administered by multiple routes, including via smoking, oral ingestion, or IV.16 When Cannabis is smoked (the route for the most rapid delivery), THC is transported from the lungs to the bloodstream and reaches peak concentrations in 3 to 10 minutes. Oral ingestion (capsules, tinctures, sprays, and edibles) has a more flexible onset of action, usually occurring in 30 to 120 minutes, with effects lasting 5 to 6 hours. IV administration has rapid effects; the onset can occur within seconds to minutes, and effects can last 2 to 3 hours. The IV form allows 90% of THC to be distributed in plasma and can rapidly penetrate highly vascularized tissues, such as the liver, heart, fat, lungs, and muscles.
Pharmaceutical manufacturers have used cannabinoid derivatives to produce Cannabis-based medications for treating medical conditions. Nabilone, a potent agonist of the CB1 receptor, became available as a Schedule II medication in 1981 and was approved for patients with chemotherapy-induced nausea and vomiting (CINV).17 In 1985, dronabinol was introduced as an antiemetic for CINV as well as an appetite stimulant for patients with conditions associated with excessive weight loss.18 Another option, nabiximols, is an oral mucosal spray that consists of THC and CBD in a 1:1 ratio.19 Nabiximols is approved in Canada for pain relief in end-stage cancer patients and pain associated with multiple sclerosis.19
In an RCT of vaporized Cannabis, 39 patients with a diagnosis of complex regional pain syndrome, thalamic pain, spinal cord injury, peripheral neuropathy, radiculopathy, or nerve injury were assigned to a medium-dose (3.53% THC), low-dose (1.29% THC), or placebo group.25 Serious mental illness, substance abuse, and medical conditions were cause for exclusion. Participants received vaporized marijuana (average 8 to 12 puffs per visit) over 3 sessions. A 30% pain reduction was achieved by 26% of those in the placebo group, 57% of those in the low-dose group, and 61% of individuals in the high-dose group; the difference between placebo and each Cannabis group was statistically significant.
Chemotherapy-induced nausea and vomiting. Up to 80% of patients who receive chemotherapy experience CINV, which occurs from 24 hours to 7 days after receiving such therapy.26 CINV negatively influences a patient’s QOL and may impact the decision to continue with chemotherapy. Use of MM can help to diminish vomiting by binding to central CB1 receptors and averting the proemetic effects of dopamine and serotonin.27 Two synthetically derived cannabinoids, dronabinol and nabilone, are FDA-approved for treating CINV.
In a small (N = 64) parallel-group RCT, Meiri et al27 compared dronabinol with the commonly used antiemetic ondansetron and with a combination of dronabinol and ondansetron for treating CINV in adults. The primary outcome was prevention of delayed-onset CINV. Patients were eligible for this study if they had a malignancy that did not involve bone marrow, were receiving treatment with a moderately to highly emetogenic regimen, were not pregnant, and had an estimated life expectancy of at least 6 weeks after chemotherapy. The patients were randomized to 1 of 4 treatment groups: dronabinol alone, ondansetron alone, dronabinol plus ondansetron, or placebo. Overall, 47% to 58% of the active treatment groups improved, compared with 20% of the placebo group. Combination therapy did not provide any benefit beyond any single agent alone. All active treatments reduced nausea compared with placebo; there was no difference between active treatment groups. This study was limited by low enrollment.
Tramèr et al28 conducted a systematic review of 30 randomized comparisons of MM with placebo or antiemetics. The reviewed studies were completed between 1975 to 1997 and analyzed a total of 1,366 patients. Nabilone was evaluated in 16 trials; dronabinol was utilized in 13 trials; and IM levonantradol, a synthetic cannabinoid analog of dronabinol, was used in 1 trial. These agents were found to be more effective as an antiemetic compared with prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, or alizapride. In addition, 38% to 90% of patients in these studies preferred MM over the traditional antiemetics.
A Cochrane review29 suggested that MM may be a viable option for treatment-resistant CINV; however, further studies are needed because current studies have methodological limitations.
Epilepsy. Maa and Figi30 reported a case of a 5-year-old girl who had Dravet syndrome, which resulted in 50 generalized tonic-clonic seizures daily; multiple anticonvulsants did not alleviate these seizures. Because of her recurring seizures, the patient had multiple cognitive and motor delays and needed a feeding tube. In addition to her existing antiepileptic drug regimen, she was started on adjunctive therapy with a sublingual Cannabis extract containing a high concentration of CBD. Her seizures decreased from 50 per day to 2 to 3 nocturnal convulsions per month. The treatment enabled her to stop using a feeding tube, resume walking and talking, and sleep soundly.
dos Santos et al31 reviewed studies of MM for treating epilepsy. One was a double-blind, placebo-controlled trial that included 15 patients ages 14 to 49 who had secondary generalized epilepsy with a temporal lobe focus. Eight patients received 200 to 300 mg/d of oral CBD for 8 to 18 weeks, and 7 received placebo. Seven patients had fewer seizures and 4 had no seizures. Only 1 patient in the placebo group demonstrated any improvement. Another study in this review included 19 children with treatment-resistant epilepsy: Dravet syndrome (n = 13), Doose syndrome (n = 4), Lennox-Gastaut syndrome (n = 1), or idiopathic epilepsy (n = 1). These patients experienced various types of seizures with a frequency ranging from 2 per week to 250 per day. Overall, 84% of children treated with CBD had fewer seizures: 11% were seizure-free, 42% had a >80% reduction in seizures, and 32% had a 25% to 60% reduction in seizures. Parents also noted additional benefits, including increased attention, improved mood, and improved sleep. CBD was well tolerated in most patients in both studies.
Despite these results, a Cochrane review32 found that no reliable conclusions can be drawn regarding the efficacy of MM for treating epilepsy.