Medical Marijuana and Other Cannabinoids _____________________________________________________
DATA FROM MEDICINAL CANNABIS TRIALS Results from RCTs of smoked cannabis found that side effects were generally dose-related, mild-to-moderate in severity, time- limited, and less common in experienced cannabis users. Most frequent were dizziness or lightheadedness (30% to 60% of subjects), dry mouth (10% to 25%), fatigue (5% to 40%), muscle weakness (10% to 25%), myalgia (25%), and palpita- tions (20%). Cough and throat irritation occurred initially in a few participants. Euphoria was reported in some but not all subjects, with the low incidence attributed to plasma THC concentrations less than 25% of the levels generally found with recreational cannabis use. Infrequently, tachycardia and pos- tural hypotension were noted, a potential concern in patients with cardiovascular disease. Tachycardia was a frequent acute physiologic effect, with it and other acute cardiovascular effects rapidly resolving due to the brief period of THC occupancy and then distribution out of the circulatory system [14]. A dose-effect relationship was found, with higher rates of seda- tion, ataxia, and loss of balance following higher dose levels [133; 134]. Tolerance to cardiovascular, autonomic, and other subjective and cognitive side effects developed rapidly over the initial 2 to 12 days of therapy [88]. As with other therapeutics, large inter-individual differences in side effects were observed, and severely ill patients, elderly persons, and patients taking multiple concurrent medications may be especially prone [14]. Anxiety or psychotic symptoms were uncommon, dose-related, occurred primarily during acute administration of high doses, and in most cases could be avoided by dose titration [60]. Suc- cessful resolution or management of cannabis side effects has been described with several agents ( Table 2 ) [135].
absorbed into the plant at high concentrations. Organophos- phate pesticides are found less often in cannabis grown out- doors versus indoor cultivation [137]. Concerns over inorganic and biologic contaminant ingestion prompted Health Canada and the OMC to carefully control all aspects of cultivation, test the product for the presence of mold spores and 28 different metals including heavy metals, and pre-emptively irradiate all cannabis products before distribution to medical or research users [14; 27]. This is not currently done to most cannabis available in the United States. Pulmonary Function Physician and patient concerns over pulmonary harm from cannabis smoking have been based on the known hazards from smoking tobacco, findings of carcinogenic compounds in can- nabis smoke, and earlier epidemiologic studies associating long- term cannabis use with respiratory dysfunction [138]. This has contributed to reluctance over medical smoked cannabis use. Although many carcinogens and tumor promoters are com- mon to tobacco and cannabis smoke, differences in the active constituents result in different biologic outcomes. Molecules in tobacco smoke enhance carcinogenic pathways through several mechanisms, including circumvention of normal cel- lular checkpoint protective mechanisms; activation of respi- ratory epithelial cell nicotine receptors; promotion of tumor angiogenesis; stimulation of enzymes that convert polycyclic aromatic hydrocarbons found in smoke into carcinogens; and prevention of apoptotic cascades (cell death) in cells accumu- lating sufficient genetic damage. In contrast, molecules in cannabis smoke inhibit carcinogenic pathways through down- regulation of immunologically generated free radical produc- tion (the innate response to inhaled smoke and particulate); THC blockade of enzymatic conversion of smoke constituents into carcinogens; the absence of cannabinoid receptors in respiratory epithelial cells (which maintains DNA damage checkpoint mechanism integrity with prolonged cannabis smoke exposure); and the anti-angiogenic, tumor-retardant, and anti-inflammatory activity of many cannabinoid smoke constituents [139; 140; 141].
AREAS OF SAFETY CONCERN Contaminants in the Cannabis Plant
Cannabis may be contaminated by a variety of organisms, such as Aspergillus fungus and bacteria, that can result in fulminant pneumonia, especially in immunocompromised persons. Nonbiologic contaminants can include heavy metals such as aluminum and cadmium from the soil, with cadmium readily
PHARMACOLOGIC MANAGEMENT OF CANNABIS SIDE EFFECTS
Symptom
Therapeutic Agent
Palpitations and tachycardia Arrhythmia, atrial fibrillation
Propranolol
Flecainide, propafenone, digoxin
Acute psychotic state Acute intoxication
Olanzapine, haloperidol
Propranolol Cannabidiol
Acute anxious psychotic symptoms from very high-dose THC
Acute panic anxiety state
Lorazepam, alprazolam
Acute manic and depressive syndromes during intoxication
Benzodiazepines, antipsychotics
COX-2 inhibitors a
Cognitive impairment with repeated use a Based on preclinical studies of primates. Source: [135; 136]
Table 2
132
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