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ware_8905.qxd 8/30/2005 11:01 AM Page 31 Safety issues concerning the medical use of cannabis and cannabinoids Mark A Ware MBBS MRCP MSc1,2, Vivianne L Tawfik BSc2 MA Ware, VL Tawfik. Safety issues concerning the medical Innocuité du cannabis et des cannabinoïdes use of cannabis and cannabinoids. Pain Res Manage utilisés à des fins médicales Les problèmes d'innocuité représentent un obstacle de taille à l'utilisation Safety issues are a major barrier to the use of cannabis and cannabi- du cannabis et des médicaments dérivés des cannabinoïdes à des fins cli- noid medications for clinical purposes. Information on the safety of niques. Les données d'innocuité relatives à l'utilisation de la plante peu- herbal cannabis may be derived from studies of recreational vent en effet provenir d'études sur l'utilisation du cannabis à des fins cannabis use, but cannabis exposure and effects may differ widely récréatives. Or, l'exposition au cannabis et ses effets peuvent différer con- between medical and recreational cannabis users. Standardized, sidérablement selon que les utilisateurs le consomment à des fins médi- quality-controlled cannabinoid products are available in Canada, cales ou récréatives. Au Canada, on trouve des produits dérivés des and safety profiles of approved medications are available through the cannabinoïdes standardisés et soumis à un contrôle de la qualité et les pro- Canadian formulary. In the present article, the evidence behind fils d'innocuité des médicaments approuvés peuvent être consultés par major safety issues related to cannabis use is summarized, with the l'entremise du Formulaire canadien. Dans le présent article, l'auteur offre aim of promoting informed dialogue between physicians and patients un résumé des principaux enjeux liés à l'innocuité du cannabis dans le but in whom cannabinoid therapy is being considered. Caution is advised de favoriser un dialogue éclairé entre médecins et patients chez qui on in interpreting these data, because clinical experience with cannabi- envisage un traitement par cannabinoïdes. La prudence s'impose lorsque noid use is in the early stages. There is a need for long-term safety l'on interprète les données de la recherche clinique, puisque l'expérience monitoring of patients using cannabinoids for a wide variety of con- pratique avec les cannabinoïdes en est à ses débuts. Il faudra exercer unesurveillance à long terme de l'innocuité des cannabinoïdes chez les ditions, to further guide therapeutic decisions and public policy.patients atteints de divers problèmes de santé pour mieux orienter lesdécisions thérapeutiques et les politiques en matière de réglementation.
Key Words: Adverse events; Cannabis/cannabinoid; Safety;Therapy Physicians' concerns about the use of cannabis for medical purposes, particularly in its widely used and unregulated herbal form, are often focused on safety issues. Because herbal The published literature on MEDLINE from 1966 to December cannabis has been used recreationally for many years and has 2004 was searched using the medical subject headings "marijuana been extensively studied, information on the safety concerns smoking" and "adverse effects", and with the limitations of may be obtained by extrapolating results from epidemiological human studies, studies published in English and studies available studies. Safety information about medicinal cannabinoid use with abstracts. Papers on the effects of prenatal cannabis expo- may also be obtained from preparations of single cannabinoid sure on offspring were not reviewed in detail. Abstracts were compounds, which have been approved by regulatory agencies reviewed by the lead author (MAW), and relevant papers were and have been prescribed for more than 20 years. The use of obtained and reviewed. The quality of the studies was not for- cannabis by patients with diseases such as HIV/AIDS, epilepsy, mally evaluated. Further safety information was obtained from chronic noncancer pain, glaucoma and multiple sclerosis gives safety summaries previously prepared by both authors in prepara- rise to potential safety concerns that are not addressed in tion for clinical trials, and further sources were identified from observational research on recreational users. Examples of such antecedent references. Where multiple studies were found to concerns are potential drug-drug interactions, alterations in report on the same safety concerns, the most recent or represen- the immune functions of immunocompromised patients, and tative reports were reviewed.
the risk of developing dependency disorders when cannabis is Data on the adverse events of cannabinoid drugs that are avail- used in a medical context.
able on the Canadian market were taken from the 2004 The present paper is an overview of safety issues regarding Compendium of Pharmaceuticals and Specialties (1). Data on investi- medicinal cannabis use. The aim is to promote a meaningful and gational cannabinoid drugs in development were not considered.
informed dialogue between patients and health care providers Major safety issues were categorized and explored in more regarding cannabis use.
1Montreal General Hospital; 2McGill University, Montreal, QuebecCorrespondence: Dr Mark Ware, E19.145 Montreal General Hospital, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4. Telephone 514-934-8222 ext 4386, fax 514-934-8096, e-mail [email protected] Pain Res Manage Vol 10 Suppl A Autumn 2005 2005 Pulsus Group Inc. All rights reserved ware_8905.qxd 8/30/2005 11:01 AM Page 32 Incidence of adverse events of regulated cannabinoids: Adverse events due to the use of contaminated cannabis were Probable causal relationships with incidences of greater reported only in cannabis smokers. Contamination with Aspergillus has given rise to concerns of lung infections in immunocompromised patients (5-7). Contamination with paraquat (a potent pesticide) has not been associated with adverse effects (8). Contamination with formaldehyde has been reported to impair memory (9) and may be life threaten- ing (10). Cannabis soaked in embalming fluid has been reported to cause phencyclidine-like responses (11).
Paranoid reaction The sharing of cannabis with contaminated smoking para- phernalia has been associated with small outbreaks of tubercu- losis (12) and meningococcal disease (13,14).
Safety concerns related to cannabis smoking: Respiratory Cannabis smoking poses a potential health risk. Cannabis smoke has been shown to have qualitatively the same constitu- tion as tobacco smoke but with quantitatively higher concentra- tions of polyaromatic hydrocarbons, which are known carcinogens (15). Cannabis smoke, like tobacco smoke, con- tains carbon monoxide, which preferentially binds hemoglobin at the expense of oxygen binding.
A higher prevalence of chronic bronchitis symptoms, such as cough, phlegm and wheeze, has also been noted in cannabis smokers (16-19). All symptoms were most evident in heavy, Sensation disturbance chronic users, defined as those who had smoked more than three joints per day for 25 years or more. There is a published report (20) of four cases of emphysema in adults with a history Orthostatic hypertension of cannabis smoking. However, observational surveys of heavy, chronic cannabis use have failed to find any lung damage in Data from reference 1 long-term smokers (21). Pneumomediastinum and pneumo-thorax have been reported following the prolonged Valsalvamanoeuvre that may accompany cannabis smoking (possiblythrough rupturing emphysematous bullae) (22-25).
Several case studies of young patients with carcinoma of the One hundred fifty-seven papers were identified from the liter- upper respiratory tract have been published (26). There is con- ature search for adverse effects, of which 79 were felt to be of cern that heavy cannabis smoking is a causative factor of this relevance. The product monographs for nabilone and dronabi- type of cancer, which is rare in adults under the age of 60 years, nol were obtained.
even in those who smoke tobacco and drink alcohol (27,28).
One case-control study (29) reported an increased risk of upper Cannabinoid-based drugs respiratory tract cancer due to cannabis smoking; however, two A summary of the adverse event profiles obtained from the 2004 recent case-control studies (30,31) have failed to find any Compendium of Pharmaceuticals and Specialties (1) for dronabinol increased risk of oral squamous cell cancers due to cannabis and nabilone are provided in Table 1. The most commonly smoking. No association between cannabis smoking and reported adverse events are a ‘high', drowsiness, dizziness and dry tobacco smoking-related cancers was found in a large retro- mouth. For further information, refer to the product mono- spective cohort study (32).
graphs of these drugs (2,3).
The effects of exposure to cannabis smoke in low doses in patients using cannabis therapeutically have not been deter- mined. The doses used by patients for symptom relief may be Herbal cannabis is most often smoked. Survey data suggest that low, and risks increase with heavy, chronic use of cannabis.
patients with chronic pain smoke between one and four puffsfrom a cannabis joint two to three times a day (4) (although larger doses are also known to be used by some patients). The Mood effects: Acute reactions, such as nausea, anxiety, para- exposures reported in recreational epidemiological and noia and disorientation often occur in new cannabis users but experimental studies range widely, from single exposures to are uncommon in regular cannabis users (33). Many patients over 20 years of daily heavy cannabis use.
were considered to be asymptomatic after abstinence from The major safety concerns may be divided into those about cannabis for four months (34). For patients seeking symptom the quality of the product and those about the administration relief, the psychological high associated with cannabis smoke of the drug itself. Drug administration effects are further divided inhalation may be another unwanted effect, but this mood- into effects related to the delivery system and effects directly altering effect may be an important part of the overall thera- related to the cannabinoid compounds.
peutic response. Euphoria, altered time perception and Pain Res Manage Vol 10 Suppl A Autumn 2005 ware_8905.qxd 9/8/2005 1:28 PM Page 33 Safety issues with the medical use of cannabis/cannabinoids relaxation are acute reactions that disappear within 3 h to 4 h tracking tests after three doses of 0%, 1.3% and 2.7% THC.
and are considered part of the high (35).
Inhalation of cannabis smoke had no effect on performance in Acute toxicity: Unlike opioids, cannabis does not cause cen- the divided attention task (59). Performance measures have tral respiratory depression (36). Acute hyperthermia has been shown no dose-related effects on reaction times, but a dose- reported following cannabis use and jogging on a warm day response effect on accuracy has been observed (60). Acute (37). Overdosing is extremely rare and is usually accompanied cannabis exposure has been associated with a hangover or by the use of other drugs, such as alcohol. A lethal tetrahydro- residual effect on psychomotor performance (61,62).
cannabinol (THC) dose has not been reported. From a purely Effects on driving: The literature concerning the risks of pharmacological perspective, cannabinoids appear to be very cannabis and driving is controversial, and no studies have safe. For a more detailed review of toxicity, please see the arti- been published on the effects of medicinal cannabis use on cle by Beaulieu (pages 23A-26A). Doctors at the Haight- driving. The results are often influenced by the confounding Ashbury clinic in the San Francisco Bay area who work effects of alcohol. Cannabis is known to cause mild euphoria, primarily with drug addicts have stated that it is virtually impos- altered time perception and decreased motor coordination, sible to die of a cannabis overdose (33).
which affect driving skills. Studies (63) have found that per- Anxiety and panic: Acute anxiety and panic are recognized as ceptual motor speed and accuracy are impaired after smoking possible complications of cannabis use, usually in the new user a cannabis joint. However, it has been suggested that, unlike (35,38). Patients usually respond to reassurance. Cannabis use users of alcohol, cannabis users are aware of their level of in a relaxed and supportive atmosphere may help reduce anxi- intoxication and compensate for the effects by becoming very ety. In addition, patients appreciate being made aware of likely cautious, resulting in a decrease in the speed and the fre- psychoactive effects on first doses, and gradual titration to an quency of overtaking, as well as an increase in the following effective dose may promote tolerance to adverse psychoactive distance (64). It is recognized that cannabis may have signif- effects. Some subjects may find the anxiety unpleasant enough icant effects on driving ability, with exaggerated effects in the to stop using cannabis. Feelings of paranoia have been presence of alcohol (65).
observed among recreational users with bipolar and panic dis- Seizures: Data on the risk of epileptic seizures following orders (39). The illegal status of the drug may be an important cannabis use were nonconclusive (66).
confounder in this regard.
Cardiac and other vascular effects: The cardiovascular effects Long-term effects of cannabis were recently reviewed (40). An increased relative Dependency: The risk of cannabis dependency is an important risk of nonfatal myocardial infarction in the first hour follow- consideration when contemplating its medical use. In the pres- ing cannabis smoking has been described (41). Myocardial ent supplement, this is discussed further by Gourlay (pages 38A- infarction following cannabis use and Viagra (Pfizer Canada 43A). Although dependence on cannabis has been described, it Inc) consumption has been reported (42). The increase in heart is difficult to quantify the extent of this risk. Cannabis has a rate following cannabis use may play a role by increasing lower rate of conditional dependence (the risk of developing myocardial oxygen demand, but other factors, such as plaque dependence among those who have used the drug) than alco- rupture and arrhythmias, may also have an effect (43-45).
hol, cocaine, heroin or tobacco, although the rate increases Cannabis smoking-induced tachycardia may be problematic with the amount used (67). Substance abuse rarely begins with for patients with comorbid ischemic heart disease or arrhyth- therapeutic use alone, as the experience with opioid analgesics mias. It has been found that inhalation of cannabis smoke has shown (68). Withdrawal symptoms such as cravings, irri- reduces the amount of exercise required to cause an attack of tability, anxiety, depression, reduced appetite and poor sleep angina by 50% (46). Cannabis-induced tachycardia is reduced after withdrawal from oral THC and smoked cannabis have by clonidine, an alpha-2 agonist, which suggests that THC been described (69-71), but the symptoms are limited to may play a role in sympathetic nervous system stimulation heavy, chronic users and are relatively short lived (72).
(47), although a reduction in parasympathetic tone has also The abuse potential of nabilone (73) and dronabinol (74) been suggested (48).
have been examined and there is no published evidence that Cannabis is known to cause postural hypotension immedi- these drugs are prone to abuse or diversion (however, see the ately after smoking (49). It also causes peripheral vasodilation, article by Gourlay). Long-term monitoring data on addictive resulting in characteristic conjunctival reddening. It is plausi- behaviours are needed.
ble that the increased heart rate and drop in blood pressure Cognitive function: The effects of long-term cannabis use on may be secondary to a drop in peripheral vascular resistance. In cognitive function remain controversial (75,76). In chronic addition, antiretroviral therapy (ie, highly active antiretroviral users (10 to 15 years), cognitive impairments, such as deficits therapy) has been shown to cause lipid abnormalities in in memory of word lists, compared with nonusers are observed, patients with HIV/AIDS. These lipid abnormalities may result but these resolve after 30 days of abstinence and may be relat- in an increased risk for ischemic heart disease, which could be ed to acute effects (77). A meta-analysis (78) of the residual exacerbated by cannabis (50).
neurocognitive effects of cannabis use reported decreases in Transient ischemic attacks (51) and cerebrovascular stroke, the performance of memory tasks. A recent study (79) suggested usually following acute cannabis use, have also been reported that patients with advanced HIV/AIDS may be at risk for aggra- in several case reports (52-56). Renal infarction following vated memory impairment due to cannabis use. The long-term cannabis smoking has also been reported (57).
effects of cannabis use on neurocognitive function may be due Cognitive function: Impaired performance has been observed to a direct effect of cannabis use or may be due to confounding using the circular lights test after subjects smoked two cannabis effects (80); further research is required to draw conclusions.
cigarettes containing 2.8% THC (58). A slight slowing of reac- Drug interactions: THC and other cannabinoids are metabo- tion was found by using digit symbol substitution and automated lized by enzymes that are also responsible for the metabolism of Pain Res Manage Vol 10 Suppl A Autumn 2005 ware_8905.qxd 8/30/2005 11:01 AM Page 34 commonly prescribed medicines. This may potentially result in Cannabis use during pregnancy has been correlated with low important drug-drug interactions. At least two cytochrome birth weight (102,103), prematurity (104) and intrauterine (CY) P450 enzyme systems, CYP2C and CYP3A, have been growth retardation (105), although contradictory findings have shown to be involved in the metabolism of cannabinoids (81).
also been reported (106). Frequent maternal cannabis use may Recently, it was found that although delta-9-THC and anti- be a weak risk factor for sudden infant death syndrome (107).
retroviral drugs are metabolized by CYP3A, administration of Risk of death: In one large retrospective cohort study of THC (smoked or orally) does not significantly reduce plasma patients with HIV/AIDS (108), current cannabis use was not concentrations of antiretroviral drugs in patients with associated with an increased risk of non-AIDS death in men HIV/AIDS (82). Potential interactions with tricyclic antide- (RR=1.72, 95% CI 0.89 to 1.39); however, it was associated pressants have been reported (83-85), but a conclusive link has with an increased risk of AIDS-related death (RR=1.90, not been established.
95% CI 1.33 to 2.73) when compared with nonusers and Immunity: It is apparent that delta-9-THC has immunomod- experimental users of cannabis. For women, current cannabis ulating effects, but the related health risks are not well defined.
use was not associated with total mortality (RR=1.09, 95% CI The dose required to obtain such effects is greater than that 0.80 to 1.49) (107). It is not clear whether the use of cannabis required for psychoactive or therapeutic effects (86). In a ran- was causally related to AIDS-related mortality or whether domized, double-blind study of the effects of smoked cannabis cannabis smoking was used to treat worsening symptoms and (3.95% THC, 1 g three times daily) and oral THC (2.5 mg was a confounder in this analysis.
three times daily) administered over 21 days in patients with Vascular effects: Peripheral arteritis, which is analogous to HIV/AIDS, neither the smoked nor the oral THC had a sig- Buerger's disease in tobacco smokers, has been reported in sev- nificant effect on CD4 cell counts or viral loads compared with eral case reports (109,110).
placebo (82).
Nausea and vomiting: A recent case series (87) described a cyclical vomiting syndrome associated with chronic, heavy The use of cannabis in any form poses potential health risks cannabis use (‘cannabinoid hyperemesis'), which was linked to that are well described (although some remain controversial).
an abnormal washing behaviour.
Cannabis smoking clearly poses unique risks, both from the Psychological effects: While cannabis use is associated with smoke and from potential contamination. The use of standard- depression (88) and anxiety (89), a causative link has not been ized and quality-controlled cannabis preparations with accu- established. A recent systematic review (90) did not find a rate monitoring and follow-up may identify and reduce these strong association between chronic cannabis use in young peo- risks. The use of pharmaceutical cannabis preparations has ple and psychosocial harm.
risks that are well documented on product labels, but further Long-term cognitive effects: The presence of long-term cog- research is required on the long-term effects of these products.
nitive effects following chronic, heavy use has been shown The safety of cannabinoids in children, the elderly and (75,78), particularly in the domains of memory and learning, patients with comorbid disorders (eg, diabetes, hypertension, and there is debate over whether these effects are reversible ischemic heart disease, renal and hepatic impairment, and dis- (91,92). Under medical use conditions, the relevance of these eases that damage the immune system), as well as the effects of effects has been questioned (78).
cannabinoid use on concurrent psychiatric illness (eg, depres- Psychosis and schizophrenia: An association between sion, anxiety, psychosis and drug abuse) are all subjects for fur- cannabis use and an increased risk of psychosis and schizophre- ther research.
nia has been reported (93). In a study by Zammit et al (93), Some broad clinical recommendations based on existing cannabis use was found to be a risk factor for developing schiz- safety information may be put forward, but these must be con- ophrenia (in a dose-dependent manner). Cannabis has also tinuously revised as new data are published. Patients with a his- been shown to be associated with a schizotypal personality dis- tory of a psychotic disorder such as schizophrenia should not use order (94), but the direction of this association is unclear.
cannabis. The use of cannabis during pregnancy should be Cannabis has been shown to be a risk factor in the develop- avoided. Patients with uncontrolled hypertension and active ment of psychotic symptoms in young people, particularly ischemic heart disease should avoid cannabis. Patients using among those with a predisposition for psychosis (95). Recent cannabis therapeutically should not drive or operate heavy modelling studies (96) have suggested that daily cannabis use machinery while experiencing the psychoactive effects of is causally associated with the development of psychosis.
cannabis (consistent with advice concerning the therapeutic ‘Cannabis psychosis' (97) has been shown to be clinically dis- use of other psychoactive agents such as benzodiazepines and tinct from acute schizophrenia, with a shorter duration and opioids). Patients with comorbid depression and other psychi- high rates of remission (98); however, one report (99) has atric disorders should be carefully monitored. Cannabinoids questioned the existence of cannabis psychosis disorder. A should be administered initially at low doses and titrated slowly recent retrospective study (100) and a review (101) have con- to balance the positive and negative acute effects. Patients firmed the association between cannabis use and precipitation should be advised of the nature and likelihood of acute effects, of schizophrenia in predisposed people and in people without a and close monitoring is advised during the initial dose titration.
history of schizophrenia.
Most of our current knowledge about the risks of herbal Effects on pregnancy: The effects of cannabis on the reproduc- cannabis is derived from studies of recreational users, and these tive system in humans are uncertain because the published evi- risks may or may not be relevant in a medical use paradigm.
dence is limited and inconsistent (35). Results from human The doses used may be different, the psychoactive effects at epidemiological studies are difficult to interpret because therapeutic doses may have a different impact, and the total cannabis users are more likely than nonusers to smoke tobacco, lifetime exposure may be different. A considerable cumulative drink alcohol and use other illicit drugs during pregnancy.
dose response to cannabinoids has been observed in many Pain Res Manage Vol 10 Suppl A Autumn 2005 ware_8905.qxd 8/30/2005 11:01 AM Page 35 Safety issues with the medical use of cannabis/cannabinoids areas and, therefore, some risks apply only to those who use 13. Finn R, Groves C, Coe M, Pass M, Harrison LH. Cluster of cannabis over a long period of time.
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