Risks and Contraindications
The important role of clinicians in educating their adult patients about the potential risks involved in cannabis use needs to be emphasized when making it available for therapeutic purposes. Cannabis dependence and impairment are significant public health issues, but complications from cannabis use are poorly documented. Multiple animal studies of extreme cannabinoid exposure indicate at worst mild risks from its use. In humans, three primary relative contraindications for cannabis use are pre-existing or genetic predispositions to mental health disorders, heart problems, and pregnancy.
Individuals with a variety of mental health disorders appear to gravitate to cannabis use because of a subjective perception of improved symptoms. Particularly in the naive user, higher doses (e.g., greater than 15-20 mg of THC) can induce feelings of panic and anxiety that can be problematic. Side effects of chronic cannabis intoxication, including performance declines, are more often seen in recreational consumers. Limited clinical research suggests cannabinoids may be effective in treating schizophrenia.60-61 The NASEM report notes substantial evidence of a statistical association between cannabis use and development of schizophrenia and other psychoses, and an increased rate of cannabis use is associated with a genetic predisposition to schizophrenia.62
Cannabis use consistently produces tachycardia and vascular dilation, which rarely may elevate the risk of a myocardial infarction in individuals with pre-existing heart problems.63 Those individuals with heart disease are more likely to develop chest pain after acutely consuming cannabis. While cannabis use can increase heart rate and systolic blood pressure, a decrease in peripheral vascular resistance can also result in orthostatic hypotension.64
Pregnancy contraindicates many medications, though, as with all individuals, physicians and patients should weigh the risks and benefits to arrive at clinical decisions. Lower birth weight is the most serious reported association with maternal cannabis use, but that may be explained by the prevalence of smoking as a delivery method and the concomitant CO and C02 exposure that can create hypoxia in the fetus and limit growth. A study of neonates and infants in a population of heavy cannabis users found no developmental or other problems.65-66 Ethnobotanical use of cannabis by some Caribbean cultures has traditionally treated first-trimester hyperemesis by drinking cannabis teas to remedy the nutritional risks and restore the systemic fluid needs associated with this malady.67-68 Due to the ethical challenges associated with studying women during pregnancy, any potential consequences from cannabis use on fetal stem cells causing long-term effects are poorly understood.
The antiemetic and appetite-stimulating properties of cannabis have been reported to benefit women afflicted with severe morning sickness with fewer side effects than other medications, but should women suffering from morning sickness during pregnancy use marijuana to control their nausea? In states with medical cannabis programs, health experts, regulatory officials, and most patient advocates have consistently answered “no” in the form of public service announcements and warning labels on cannabis packaging. Nevertheless, a statewide cross-sectional study in Colorado found that nearly 70% of dispensary workers endorsed using cannabis for first-trimester morning sickness, and fewer than a third spontaneously recommended consulting a healthcare professional about it.69
In contrast to morning sickness in gravid women, cannabis hyperemesis syndrome is a rare but serious adverse event associated with chronic cannabis use. This is a paradoxical condition in which an individual with consistent long-term exposure to cannabis may suddenly develop uncontrollable vomiting following cannabis use.70-72 This effect is striking given the well-documented and far more common antiemtX ic effects of cannabis use. Symptoms are reportedly often relieved by a hot shower or bath. While the etiology of the cannabis hyperemesis syndrome remains unclear, can- nabinoids are known to inhibit calcium channels, and calcium channel blocking is associated with nausea.73 Furthermore, calcium channels are temperature-sensitive, and heat increases channel firing that mitigates nausea, which may explain why afflicted patients often report that a hot shower or bath relieves their hyperemesis. The paradoxical nature of the syndrome and its rarity even among populations of heavy chronic users suggest factors other than plant constituents including that an autoimmune phenomenon may be responsible. Another explanation posited by some knowledgeable with cannabis cultivation practices is chronic exposure to azadirachtin, the active chemical compound in the biopesticide neem oil, which is commonly used in organic farming.
Contaminants and Testing
Pesticides of all types are a concern with cannabis cultivation, and inadequate regulation and testing in some U.S. state markets have resulted in cultivators using chemical insecticides and fungicides on their cannabis crops. A random testing of cannabis commercially available in California and Washington legal markets detected residual pesticide contaminants with known potential for serious health effects in a majority of analyzed samples.74 Health Canada requires testing for pesticides in the medical cannabis distributed through their program and conducts its own random testing of products. In 2018, two Canadian suppliers were required to recall their pesticide-contaminated products.75
In recent years many U.S. states have adopted regulations for what can be used safely in cannabis products intended for human consumption and require testing of products. Due to federal prohibition, universal guidelines have not been developed, and organic certification standards are unavailable for cannabis cultivation. The absence of a United States Pharmacopeia disposition on cannabis standards led the American Herbal Pharmacopeia (AHP) to issue a monograph on cannabis purity and identity standards in 2014. The American Herbal Products Association (AHPA) has similarly produced guidelines for regulators on cannabis products, including cultivation, storage, manufacturing, and dispensing. Both groups acted in collaboration with subject matter experts and patient advocates, and their standards have subsequently been widely adopted by certifying standards organizations and state agencies in the United States. Global standards organizations such as ASTM International, formerly known as the American Society for Testing and Materials, are also working to establish uniform protocols for analytic testing and other aspects of cannabis production.
Life-threatening pulmonary complications subsequent to the increased use of vaporizing devices have been recently reported. While infectious diseases do not appear to be responsible, other contaminants including tocopheryl (vitamin E) acetate remain suspect and have been investigated as a source of chemical burns progressing to reactive airway pneumonitis. Consistent state guidelines directing the enforcement of production standards have not been established while cannabis remains under federal prohibition. The Centers for Disease Control urged doctors to report suspected cases to their state health agencies, and the Food and Drug Administration is collecting information about illnesses related to e-cigarettes and vaping.76
The broad range of ECS effects requires caution in pharmacological applications. The effects of long-term chronic use of exogenous cannabinoids on the system’s function is unknown; however, limited studies of medical cannabis users enrolled for more than 30 years in the federal government’s
Investigational New Drug program have found no adverse health consequences.77 Possible down- regulation of endogenous cannabinoid receptors such as is seen in other receptor systems requires longitudinal studies to determine significance, but this may be a neuroadaptive factor of cannabis dependence. A 2012 investigation by the National Institute of Drug Abuse addressed the ECS’s receptor’s plasticity as measured by its ability to regenerate after chronic heavy exposure. Cannabis users sequestered without access to the drug had a near total recovery of their brain’s full complement of CB, receptors after only four weeks of monitored abstinence.78
Where significant patient outcome problems have been seen is with drugs that block cannabinoid receptor activity. The role of endocannabinoids in metabolism and appetite has made the ECS a target for the development of drugs to treat metabolic syndrome. Rimonabant (Acomplia® or SR141716) is one such drug that works as an inverse agonist at CB, to reduce hunger and weight gain, but at considerable cost to overall endocannabinoid tone. Although weight loss was documented with rimonabant, serious adverse side effects included nausea, seizures, depression, and suicidality, leading to withdrawal of the drug after two years on the foreign market79 In this case, drug development failed to appreciate the full extent of the CB, endocannabinoid receptor’s broad range of non-specific central effects.
