DRUGDEX DRUG EVALUATIONS: TETRAHYDROCANNABINOLS
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BLOOD LEUKEMIA
Data collected during 1980 to 1984 by the Children's Cancer Study Group Demonstrated the association of ACUTE NONLYMPHOBLASTIC LEUKEMIA (ANLL) in children with in utero marijuana exposure. The risk of developing ANLL is increased 10-fold when mothers use marijuana during gestation (Briggs et al, 1998).
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CARDIOVASCULAR EFFECTS
1. The cardiovascular adverse side effects of dronabinol are inconsistent; however, the following side effects may occur during therapy: HYPOTENSION, HYPERTENSION, SYNCOPE, TACHYCARDIA, PALPITATIONS, VASODIALTION, AND FACIAL FLUSH (Prod Info Marinol(R), 1999; Chang et al, 1979; Ohlsson et al, 1980).
2. PAROXYSMAL ATRIAL FIBRILLATION associated with use of medical marijuana was described in a 32-year-old man and a 24-year-old woman. The first patient had PAROXYSMAL TACHYCARDIA of several months duration. He experienced marijuana intoxication once or twice a month. During a Holter monitoring period, he smoked marijuana cigarettes (without the knowledge of his doctors). The Holter electrocardiogram demonstrated numerous supraventricular episodes, including paroxysmal tachycardia and atrial fibrillation lasting for up to 2 minutes. During a 12-month period in which the patient abstained from marijuana, his sinus rhythm remained stable. The woman was admitted with paroxysmal atrial fibrillation, nausea, vomiting, consciousness disturbances, and hyporeflexia. The symptoms began a short time after she smoked a marijuana cigarette. Electrocardiography revealed atrial fibrillation of 140 beats/minute. The patient was treated with hydration, electrolytes, metoprolol, and propafenone, and discharged after 24 hours (Kosior et al, 2001).
3. The effects of cannabis on task-induced cardiovascular responses were studied in 10 male volunteers who were experienced marijuana users (Capriotti et al, 1988). The combination of task performance plus marijuana use produced increases in heart rate and mean arterial pressure greater than the changes seen with placebo plus task performance or marijuana alone; blood pressure changes were particularly significant, with increases double that seen in the placebo plus task performance group and significantly higher than those seen with marijuana alone. Prolongation of the increases in heart rate and blood pressure were also noted in the marijuana plus task performance group, suggesting that marijuana use might have significant long-term consequences for the individual. The authors concluded that this apparent increase in the risk of hypertension was supported by the difficulty in finding normotensive experienced marijuana users for participation in the study.
4. CARDIOVASCULAR EFFECTS of cannabis usage include dose-related increases in heart rate, cardiac output, and blood pressure (Perez-Reyes et al, 1982; Anderson & McGuire, 1981; Ohlsson et al, 1980; Zimmer et al, 1976; Gagnon & Elie, 1975; Malit et al, 1975; Domino et al, 1974; Clark et al, 1974; Martz et al, 1972; Weiss et al, 1972; Perez-Reyes et al, 1972; Johnson & Domino, 1971). ELECTROCARDIOGRAM (ECG) CHANGES include flattened T-waves and changes in the P-wave axis (Benowitz & Jones, 1975; Johnson & Domino, 1971) and premature ventricular contractions (Benowitz & Jones, 1975; Johnson & Domino, 1971). The initial increase in blood pressure may be followed by orthostatic hypotension (Jones, 1983; Jones, 1984).
5. Tetrahydrocannabinol (THC)-induced TACHYCARDIA is accompanied by an increase in limb blood flow, suggesting a beta-adrenergic receptor mechanism (Beaconsfield et al, 1972). Beta-blockade has been shown to reduce the acute cardiovascular effects of the drug (Jones, 1984). The tachycardia reflects alterations in both sympathetic and parasympathetic activity in the cardiac pacemaker, probably mainly due to central effects (Jones, 1983). Tachycardia induced by THC may decrease myocardial oxygen delivery and increase oxygen demand; this could induce angina in patients with ischemic heart disease (Aronow & Cassidy, 1974). The cannabis-induced increase in cardiac workload may also pose some risk to patients with hypertension or cerebrovascular disease (Jones, 1983).
6. TETRAHYDROCANNABINOL produces a potent effect on the heart, probably centrally mediated through the autonomic nervous system, with markedly enhanced sinus automaticity and facilitation of sinoatrial and A-V nodal conduction (Miller et al, 1977).
7. Supine blood pressure and heart rate were significantly decreased with prolonged use of delta-9-tetrahydrocannabinol (THC) (Benowitz & Jones, 1975). Twelve patients were given oral THC (2.6 to 4 milligrams/kilogram/day) for 18 to 20 days. Orthostatic hypotension with a compensatory increase in heart rate occurred upon standing in 7 of 12 patients.
8. Cardiovascular effects following single inhalations of tetrahydrocannabinol were studied in 25 volunteers (Johnson & Domino, 1971). Heart rate increased in all patients, reaching a maximum in 0.5 hour and lasting 1.5 hours. Systolic blood pressure significantly increased in those patients receiving doses of cannabis larger than 10 milligrams.
MYOCARDIAL INFARCTION
Using a case cross-over design, investigators found that the smoking of marijuana was a rare trigger of acute myocardial infarction (MI). Of 3882 patients with MIs interviewed at 64 medical centers at median 4 days after their MI, 124 (3.2%) had smoked marijuana in the preceding year. Of the 124, 37 had smoked marijuana within 24 hours of MI-symptom onset. Nine subjects reported use within 1 hour of the onset of symptoms. It was concluded that the risk of MI was increased 4.8-fold for 1 hour after smoking marijuana compared with periods of non-use (p less than 0.001). Beyond the first 60 minutes, the risk of MI appeared to decline rapidly. According to the authors, the mechanism for triggering MI may be increased myocardial oxygen demand during a time of decreased oxygen supply (Mittleman et al, 2001).
CENTRAL NERVOUS SYSTEM EFFECTS
1. Central nervous system effects are the most common adverse drug reaction (ADR) reported with dronabinol in AIDS patients during clinical trials. The following ADRs were reported in 3% to 10% of patients: DIZZINESS, EUPHORIA, PARANOID REACTION, SOMNOLENCE, and THINKING ABNORMAL. Less common CNS ADRs (ie, occurring in 0.3% to 1% of patients) include DEPRESSION, NIGHTMARES, SPEECH DIFFICULTIES, and TINNITUS (Prod Info Marinol(R), 1999).
2. A whole range of feelings described as a "high" have been associated with TETRAHYDROCANNABINOL administration. Easy laughing, elation, heightened awareness, mild aberrations of fine motor coordination, minimal distortion of activities and interactions with others have reported in a large percentage of patients receiving TETRAHYDROCANNABINOL (Prod Info Marinol(R), 1999). These effects were reported in up to 81% of the patients treated (Sallan et al, 1975). Some reports (Lucas & Laszlo, 1980; Sallan et al, 1975) indicated that therapeutic antiemetic effects were directly correlated with the achievement of a high.
3. In one study, moderate-to-severe sedation was described in approximately 60% of patients receiving oral doses of 5 to 7.5 mg/m(2) every 4 hours (Devine et al, 1987).
4. Central nervous system (CNS) adverse effects appear to be dependent on the dose and particular pharmacologic agent used (ie, synthetic DELTA-9-TETRAHYDROCANNABINOLS, crude MARIJUANA, etc), as well as the set and setting at the time of use (surroundings, preconception, previous experience, etc) Older patients (50 years of age or older) appear to be less tolerant to the CNS effects of TETRAHYDROCANNABINOL (Prod Info Marinol(R), 1999; Frytak, 1980). The intensity of central nervous system effects of TETRAHYDROCANNABINOL may also be related to the chemotherapy regimen being used. An increase in adverse CNS effects was reported in patients receiving TETRAHYDROCANNABINOL for the treatment of nausea and vomiting from MOPP (mechlorethamine, vincristine - Onconvin(R) procarbazine, and prednisone) chemotherapy (Kluin-Neleman et al, 1979).
5. In a series of 809 patients receiving oral TETRAHYDROCANNABINOL as an antiemetic, serious toxicity was rare. In this series of patients, severe psychological disturbances were observed in 4 patients, with 2 cases of myoclonic jerking; one patient developed grand mal seizures. More frequent central nervous system symptoms were sedation (53%), elation (32%), confusion (30%), perception distortions (23%) and depression (19%) (Devine et al, 1987).
6. Cerebral atrophy has been associated with TETRAHYDROCANNABINOL use in young MARIJUANA smokers (Campbell et al, 1971). Other agents were also taken which could have caused structural abnormalities, thus minimizing the importance of these findings. However, cerebral atrophy was reported in rhesus monkeys during long-term TETRAHYDROCANNABINOL administration. No other drugs were administered (McGahan et al, 1984). Further studies are required to determine if MARIJUANA smoking can produce structural brain changes.
COGNITIVE FUNCTION
1. Cannabis use (heavy or light) was not associated with a differential decline in cognitive function over time when compared with cognitive- function decline in non-users of cannabis. This finding was based on administration of the Mini-Mental State Examination (MMSE) to 1318 persons under age 65 in the Baltimore, Maryland Epidemiological Catchment area. Scores on the MMSE in the time period 1993 to 1996 were compared with scores in 1982 on the same exam in the same cohort. There was an overall decline of 1.2 points on the MMSE over the time lapse of 12 years. There were no significant differences in cognitive function decline between heavy users, light users, and non-users of cannabis; nor were there any differences for men versus women users of cannabis (Lyketsos et al, 1999) memory loss has been shown to occur after THC exposure. Studies have been divided as to if this impairment continues after an exposure (Schwartz, 1991; Schwartz et al, 1989). Excessive smokers are most commonly affected (Chopra & Smith, 1974). Some studies have reported a degree of cognitive impairment from chronic marijuana use (Block & Ghoneim, 1993; Heishman et al, 1990; Schwartz et al, 1989) but others have not (Block & Ghoneim, 1993; Cone et al, 1988). The amount of cognitive impairment may depend on the frequency of chronic use (Block & Ghoneim, 1993). Heavy inhalational cannabis use may produce residual effects (Pope & Yurgelun-Todd, 1996; Heishman et al, 1990). Residual poor cognitive performance in heavy cannabis users may be due to cannabis-induced alterations in brain functions, drug residual in the brain, or a withdrawal effect (Block, 1996; Pope & Yurgelun-Todd, 1996)
DEPERSONALIZATION
1. Four cases of prolonged depersonalization that occurred months after MARIJUANA use were reported (Szymanski, 1981). In all 4 cases, depersonalization was reported to be identical to the "more common" depersonalization experienced by these patients during acute intoxication. Each occurrence correlated with, and may have been precipitated by, stressful life situations. Patients discussed family histories of alcoholism and/or psychiatric disorders.
2. Post-intoxicated episodes of depersonalization may have pharmacologic roots, since it may take weeks for clearance of TETRAHYDROCANNABINOLS from the body. However, when depersonalization occurs months after intoxication, pharmacologic consideration may not be a factor. Rather, depersonalization may serve as a defense mechanism (once it has been experienced) to deal with stressful life situations (Szymanski, 1981).
3. A loose association has been made with cannabis use and residual depersonalization leading to agoraphobia (Moran, 1986).
DEPRESSION/ANXIETY
In a cohort study in Australia over six years (1992 to 1998) involving students ages 14 to 15 years who were followed for 7 years, young women who used cannabis daily had a greater than fivefold (odds ratio 5.6, 95% confidence interval 2.6 to 12) increase in the likelihood of reporting depression and anxiety, after standardizing for the use of other substances. After adjustment for possible baseline confounders, teenagers who used cannabis weekly or more frequently had a predicted twofold increase in risk for anxiety and depression (Patton et al, 2002).
HALLUCINATIONS
Three of 9 patients who received TETRAHYDROCANNABINOL 15 mg/m(2) for the treatment of refractory chemotherapy-induced vomiting experienced visual hallucinations and severe distortions of time with therapy. These reactions resolved within 3 hours after tetrahydrocannabinol was discontinued (Lucas & Laszlo, 1980). VISUAL HALLUCINATIONS and distortions were also reported as adverse effects in one study (Sallan et al, 1975). Adverse effects reported in 4 case studies included illusions and auditory distortions during prolonged episodes of depersonalization (Szymanski, 1981).
PSYCHOSIS
1. Cannabis use is an independent risk factor for the development of psychosis in psychosis-free persons and an even greater risk factor in persons with an established vulnerability to psychotic disorder. In a prospective, longitudinal, population-based study in the Netherlands, where personal use of cannabis is legal, subjects were followed for 3 years. Among the 4,045 subjects who, at baseline, had a lifetime absence for all individual items of the CIDI (Composite International Diagnostic Interview) psychosis section, cannabis use at any time prior to baseline was associated with a high risk of psychosis at the 3-year interview: odds ratio=24 (adjusted for age, sex, single marital status, level of education, experience with discrimination). The effect of cannabis use prior to baseline was stronger than the effect of cannabis use during the study. Cannabis use was associated with a greater risk of a pathology-level psychosis among individuals with a history of psychosis at baseline than among those with a lifetime absence of psychosis at baseline (p=0.0014). If the relation between cannabis use and psychosis is causal, the incidence of pathology-level psychosis could have been reduced by 67% if the cannabis exposure had been eliminated from the population (van Os et al, 2002).
2. No convincing support for a separate clinical diagnosis of "cannabis psychosis" was found in a review of the literature (Thornicroft, 1990). Cannabis can, however, produce brief acute organic reactions and, in moderate to heavy doses, psychotic episodes in clear consciousness. He further states that ingestion of MARIJUANA in naive users or increasingly heavy use in habitual users can precipitate a schizophreniform episode. Heavy users may also have an increased risk of developing schizophrenia in the subsequent 15 years.
3. The propensity of MARIJUANA to produce psychosis was demonstrated when psychiatric symptoms in 20 psychotic males with confirmed high urinary cannabinoid levels were compared with 20 matched cannabis-free controls (Rottanburg et al, 1982). Patients with high cannabis levels exhibit significantly more hypomania and agitation than controls and significantly less affective flattering, auditory hallucinations, incoherence of speech and hysteria than the control group. Marked improvement was observed in the cannabis group after one week following admission. These data suggest that heavy use of MARIJUANA can result in a psychotic illness characterized by HYPOMANIC FEATURES which can be indistinguishable from true hypomania or schizophrenic-like illness.
SCHIZOPHRENIA
1. In a 1969 to 1970 Swedish study of 50,087 male conscripts (18 to 20 years), cannabis increased the risk of developing schizophrenia in a dose dependent fashion by 30%, both in subjects who had ever used cannabis and for subjects who had only used cannabis and no other substances. A larger risk was demonstrated in subjects who used cannabis on more than 50 occasions (Zammit et al, 2002).
2. Cannabis use in adolescence increases the possibility of having schizophrenia symptoms as adults. In a 1972 to 1973 New Zealand multidisciplinary health and development study that involved a general population cohort (n=1037) and the analysis of data from a representative group (n=759) of living study members, subjects were divided into 3 groups based upon cannabis use at ages 15 and 18 years. Symptoms of depression and schizophrenia and diagnoses of schizophreniform disorder and depression were the psychiatric outcomes at age 26. Study findings concluded that cannabis use is related to an increased risk of having schizophrenia symptoms, even after psychotic symptoms that preceded the onset of cannabis use was controlled. A greater risk for schizophrenia outcomes is present if cannabis use occurs early (by age 15) rather than later (by age 18). Risk was cannabis-specific and not related to other drug use. Later depression was not predicted by early cannabis use. The authors suggest that in psychologically susceptible adolescents, cannabis use should be discouraged (Arseneault et al, 2002).
3. Cannabis use (or abuse) may exacerbate existing schizophrenia (Allebeck et al, 1993; Thomas, 1993; Andreasson et al, 1987).
SEIZURES
Tetrahydrocannabinol (THC) has been implicated in producing convulsions in high doses (Craigmill, 1979; Feeney, 1979; Consroe et al, 1977). In dogs nabilone (a synthetic cannabinoid) produced grand mal seizures after an intravenous dose of 0.4 milligram/kilogram (Gilbert, 1981).
ENDOCRINE/METABOLIC
ENDOCRINE EFFECTS
The use of MARIJUANA can cause lowered levels of testosterone (Mendelson et al, 1974). Some reports associate the use of MARIJUANA in the inhaled form and TETRAHYDROCANNABINOL in the oral form with lowering levels of luteinizing hormone, growth hormone and follicle-stimulating hormone. Lowered hormone levels were still within the normal range and no physical correlations were found (Anderson & McGuire, 1981).
HYPOGLYCEMIA
TETRAHYDROCANNABINOL has been shown to have no significant effect on blood glucose (Anderson & McGuire, 1981).
GASTROINTESTINAL
GASTROINTESTINAL EFFECTS
1. In clinical trials using dronabinol, the following digestive adverse drug reactions were reported in 3% to 10% of patients: ABDOMINAL PAIN, NAUSEA, and VOMITING (Prod Info Marinol(R), 1999).
2. DRY MOUTH has been noted with tetrahydrocannabinol (THC) ingestion. In some studies, dry mouth can be the most frequent side effect occurring during THC therapy for emesis. Moderate-to-severe dryness of the mouth has occurred in 38% and 50% of patients receiving 5 or 7.5 mg/m(2) every 4 hours, respectively (Devine et al, 1987; Lucas & Laszlo, 1980; Anderson & McGuire, 1981).
KIDNEY/GENITOURINARY
SEXUAL DYSFUNCTION
1. Kolodny et al (1974) reported that plasma testosterone declined from normal values in nonusers to significantly lower levels in men who reported smoking 5 to 9 joints/week. There seemed to be a correlation between extent of use and degree of testosterone level reduction. The subjects of this study were brought into the hospital on 2 separate days for blood sample collections. No attempt to verify the subject's drug history was reported. In a related study, the acute effects of marijuana smoking on testosterone levels in 13 healthy male users were examined. Measurements of plasma testosterone were made at 15, 30, 60, 120, and 180 minutes after subjects smoked 1 or 3 marijuana cigarettes. Significant reductions in testosterone levels were seen at 120 and 180 minutes. In contrast, Cone et al (1986) did not detect any acute changes in serum testosterone levels in 4 patients who randomly smoked either placebo cigarettes or 1 or 2 marijuana cigarettes (each containing 2.8% THC) on 3 separate days.
2. Mendelson et al (1972) reported the results of a study of 27 male marijuana users. They were housed on an inpatient hospital ward under close observation and underwent 5 days of abstinence from marijuana smoke to obtain baseline values. This was followed by 21 days of smoking known amounts of marijuana, then 5 more days of abstinence. Plasma testosterone levels were assessed daily. In this study, no consistent or significant effect of marijuana use on testosterone levels was found. In 1978, Mendelson repeated his study using the same inpatient protocol but a more sensitive technique for detecting plasma testosterone level fluctuations. This method involved hourly plasma sampling and daily averaging of the hourly levels on days 5, 26, and 29 of the protocol. Although major episodic fluctuations in testosterone levels were noted, the changes could not be correlated to marijuana use; no systematic relationship between marijuana smoking and increases or decreases in plasma testosterone could be found. Other reports of human use support the Mendelson data (Cushman, 1975; Coggins et al, 1976; Mendelson et al, 1978).
LIVER
HEPATOTOXICITY
Liver concentrations of radioactive cannabinoids ((14)C DELTA-8-TETRAHYDROCANNABINOLS and/or metabolites) increased (accumulated) in rats after chronic administration of (14)C DELTA-8-TETRAHYDROCANNABINOLS (Nahas et al, 1981).
OCULAR
OCULAR EFFECTS
1. Ingestion or inhalation of TETRAHYDROCANNABINOL causes a characteristic reddening of the conjunctiva (Ohlsson et al, 1980; Hollister et al, 1981). This sign appears to be the most reliable index of the TETRAHYDROCANNABINOL "high".
2. Although the mechanism is unknown, TETRAHYDROCANNABINOL has been shown to cause a DECREASE IN INTRAOCULAR PRESSURE.
3. VISION DIFFICULTIES have been reported as an infrequent adverse effect of DRONABINOL therapy (Prod Info Marinol(R), 1999).
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