Original Author: Paul Perry, Ph.D, BCPP
Latest Reviser: Paul Perry, PhD, BCPP and William Cummings, Pharm
D
Creation Date: 1996
Last Revision Date: April 2002
Peer Review Status: Internally Peer Reviewed
Marijuana is currently the most widely used illicit drug in the nation. A nationwide survey in 1979, reported that 54% of US 12th graders used cannabis at least once in the past year, and nearly 11% of respondents reported "daily use." By the 1980s, usage began to stabilize and then decline in the US with 42% of US 12th graders used cannabis at least once in the past year, and nearly 5.5% of respondents reported "daily use." A follow-up study found that the number of "past-year" adult users between 30-49 years old increased from 15% in 1977 to 47% in 1997. Thus it appears than many users who begin their use in adolescence continue it into middle age (Brands et al 1998).
Marijuana has a variety of street names. Some of the more common ones are: Acapulco Gold, ace, bhang, Colombian, ganja, grass, hemp, herb, Indian, Jamaican, jive sticks, joint, Mexican, Panama Red, Panama Gold, pot, reefer, ragweed, tea, Thai sticks, and weed (Cox et al 1983).
Marijuana consists of a mixture of plant products, such as leaves and stems. Hashish is more potent and is comprised of dried cannabis resin and compressed flowers. Highly potent hashish oil is obtained by extracting THC from hashish, (or occasionally marijuana), with an organic solvent.
PHARMACOLOGY
Marijuana, hashish, and hashish oil are obtained from the plant Cannabis sativa, which grows in tropical and temperate climates. There are at least 20 active cannabinoids, but the main psychoactive ingredient is delta-9-tetrahydro-cannabinol (THC), which was first identified and synthesized in 1964.
THC is considered a hallucinogenic substance that is mild when compared by weight to LSD. The concentration of THC in marijuana usually ranges from traces to 8 percent, while the concentration in resin preparations is up to 20 percent for hashish and up to 70 percent for hashish oil (Cox et al 1983). A minimum delta-9-THC concentration of 1% is necessary for most people to experience the psychoactive effects of the drug (Schwartz 1984). THC is also available as an oral prescription, dronabinol (Marinol), that is utilized as either as an appetite stimulant or an antiemetics during cancer chemotherapy. It is available in 2.5, 5 and 10 mg capsules. The daily dose ranges from 2.5 to 20 mg/d.
Only about 22% of the THC contained in a cigarette may be recovered from the smoke. Smoking converts some inactive constituents such as THC-carboxylic acid and cannabidiol to THC (Mikes and Waser 1971).
Detectable levels of THC have been found in fat biopsies obtained more than 4 weeks after marijuana smoking. The redistribution of THC from tissue to blood is the rate-limiting step in its metabolism. THC is rapidly metabolized to 11-hydroxy-THC, an equipotent active metabolite, to the inactive metabolite 11-nor-9-carboxy-D9-THC or THC-acid (THC-COOH), and to numerous other cannabinoids, primarily by the cytochrome P450 oxidative enzyme system in the liver and other tissues. THC-COOH was found to be the primary cannabinoid metabolite excreted in the urine. Approximately 15-30% of a THC dose is eliminated in the urine, whereas 30-65% is excreted in the feces as 11-hydroxy-THC and THC-COOH. Most of the THC-COOH is conjugated and excreted as the water-soluble glucuronic acid (Huestis and Cone 1998). THC plasma elimination half-lives of 18-50 hours have been reported after radiolabeled THC administration and a 3- and 5-day monitoring period. A longer elimination half-life of 4.3 days (range, 2.6-7.2 days) was reported n heavy, chronic marijuana smokes after radiolabeled THC and a 10- to 15-day sample time (Huestis and Cone 1998). The elimination half-life for THC-COOH is 28.6 hours (24.9-34.5 hours) (Huestis and Cone 1998). Depending on the sensitivity of the test method used and the THC concentration, urinary metabolites may be detected by enzyme assay, radioimmunoassay, or gas chromatography/mass spectrometry for up to 3 days in casual users and up to 30 days in chronic users following the last dose of marijuana (Gorodetsky 1977).
Smoking cannabis is the most common route of administration. Absorption is more efficient via smoking than ingestion. However, the "high" after oral ingestion lasts longer than the "high" obtained from smoking. In general, about 50% of the THC that is smoked will be absorbed into the blood stream compared to 5 to 10% that is absorbed with oral ingestion (Nahas 1979).
The effects of smoking marijuana begin almost immediately, usually in 2 to 3 minutes. At lower doses the peak effect is seen at 10 to 20 minutes and the duration of effect is 90 minutes to 2 hours. At higher doses, the duration of action may last up to 3 to 4 hours (Thomas and Chesher 1973).
The oral dose of marijuana must be three to five times greater than the smoked dose to produce equivalent effects. The onset of action is 30 minutes to 1 hour after ingestion and the symptoms persist from 3 to 4 hours for low doses, 6 to 8 hours for larger doses and up to 24 hours for very large doses (Thomas and Chesher 1973).
Tolerance develops to the desired psychoactive effects of marijuana with prolonged use. Tolerance towards the sedative effects seems to develop before tolerance to the stimulatory effects. The development of tolerance is complex and appears to follow a J-shaped time curve. The initial dip in the curve represents reverse tolerance, whereas the upward sweep represents tolerance. The phenomenon of reverse tolerance, where the novice consumes more drug than the experienced user to get "high," has been explained by the novice's inability to appreciate the subtle effects of marijuana intoxication and their inefficiency at smoking (Thomas and Chesher 1973). If high-dose regular smokers wish to maintain the desired intensity of psychoactive effects, they must either increase their daily dose or cease smoking for several days to restore the baseline effect (Brands et al 1998). There is no evidence that cross-tolerance develops between cannabis and other hallucinogens (Cox et al 1983).
With regular use, marijuana abusers can also develop psychological and mild physical dependence. At doses currently used in the United States, most marijuana users can stop suddenly without fear of severe withdrawal symptoms. A mild withdrawal syndrome involving restlessness, insomnia, nausea, irritability, anorexia, diaphoresis, nervousness, anxiety, and sweating. More rarely chills, fever, and tremors are reported. The withdrawal reaction lasts for less than a week, although the sleep disturbance may persist longer (Johnston et al 1980, Brands et al 1998).
EFFECTS OF SHORT TERM USE
The signs and symptoms associated with the marijuana "high" vary according to dosage. Thus, three categories will be considered: low, moderate and high doses. (See table 1) (Thomas and Chesher 1973).
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TABLE 1: Average Dose Range of D-9-THC for a 70 kg Subjecta |
||
|
Dose Category |
THC bioavailable (mg) |
Cigarette Equivalentsb |
|
Low |
0.4-0.8 |
1/8-1/4 |
|
Moderate |
2.5-5.0 |
1-2 |
|
High |
15-30 |
6-12 |
Low to Moderate Doses. At low to moderate doses, 5 mg of THC or less, the user may experience CNS and behavioral effects such as disinhibition, garrulousness, relaxation, drowsiness, feeling of well-being, euphoria, distortions of the perception of time, body image, and distance, increased auditory and visual acuity, enhanced tactile, olfactory, kinesthetic, and gustatory senses, spontaneous laughter, impairment of recent memory, mild confusion, decreased concentration, decreased muscle strength and balance, impaired ability to perform complex motor tasks, fearfulness, anxiety, and panic or even mild paranoia (Cox et al 1983).
Cardiovascular signs include increased heart rate, increased peripheral blood flow; slight drop in body temperature, mild orthostatic hypotension, conjunctival injection. Respiratory signs include bronchodilation and irritation of mucosal membranes lining the respiratory tract. Increased appetite and dryness of the mouth and throat are the gastrointestinal effects (Cox et al 1983).
High Doses. At high doses, 10-30 mg THC or more, intensification of the low-dose effects may occur as well as any of the following: synesthesias, pseudo-hallucinations, impaired judgment, slowed reaction time, confusion, impaired performance of simple motor tasks, depersonalization, pronounced paranoia, agitation, extreme panic, and even true hallucinations (Cox et al 1983).
TOXICITY
It is noteworthy that the dose where a subject experiences an acute toxic psychosis and hallucinations is at least five times that required for a "mild to moderate doses." By comparison, a dose of alcohol five times greater than that required for a "social high" frequently results in coma or death (Thomas and Chesher 1973). As of yet, there have been no reports of deaths directly attributable to cannabis overdose. However, due to the drug's negative effect on perceptual and motor coordination, a number of deaths have been indirectly caused due to fatal mishaps, such as motor vehicle accidents.
The diagnosis of cannabis toxicity is defined operationally in the DSM-IV. The criteria for cannabis intoxication are as follows:
A. Recent use of cannabisB. Clinically significant maladaptive behavioral or psychological changes (e.g., impaired motor coordination, euphoria, anxiety, sensation of slowed time, impaired judgment, social withdrawal) that developed during, or shortly after cannabis use.
C. Two or more of the following psychological symptoms within 2 hours of use:
1. conjunctival injection2. increased appetite
3. dry mouth
4. tachycardia
D. The symptoms are not due to a general medical condition and are not better accounted for by another mental disorder.
Associated with the diagnosis cannabis intoxication are additional descriptors and/or specifiers that include cannabis intoxication delirium, cannabis-induced psychotic disorder with delusions, cannabis-induced psychotic disorder with hallucinations, cannabis-induced psychotic disorder with delusions, cannabis-induced anxiety disorder, and cannabis related disorder not otherwise specified. Cannabis-induced delusional disorders are rare in the United States, but are reported frequently in countries such as India and Egypt where high dose cannabis preparations are used extensively. Occasionally, the delusional disorder may not resolve within a few hours and the subject requires psychiatric hospitalization. A diagnostic problem then arises when trying to determine whether a psychotic individual abused marijuana, or whether the abuse of cannabis directly caused the psychosis. By evaluating the patient's premorbid and post-morbid state, one can attempt to solve this problem by determining the course of the disorder (Johnston et al 1980).
The diagnosis of cannabis dependence is defined operationally in the DSM-IV. The DSM-IV criteria for the diagnosis of cannabis dependence are as follows (DSM-IV 1994):
A. Cannabis abuse: A destructive pattern of cannabis use, leading to significant social, occupational, or medical impairment.B. Must have three (or more) of the following, occurring when the cannabis use was at its worst:
1. Cannabis tolerance: Either need for markedly increased amounts of cannabis to achieve intoxication, or markedly diminished effect with continued use of the same amount of cannabis.2. Greater use of cannabis than intended: Cannabis was often taken in larger amounts or over a longer period than was intended
3. Unsuccessful efforts to cut down or control cannabis use: Persistent desire or unsuccessful efforts to cut down or control cannabis use
4. Great deal of time spent in using cannabis, or recovering from hangovers
5. Cannabis caused reduction in social, occupational or recreational activities: Important social, occupational, or recreational activities given up or reduced because of cannabis use.
6. Continued using cannabis despite knowing it caused significant problems: Continued cannabis use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been worsened by cannabis
C. Associated features:
1. Learning Problem2. Psychotic
3. Euphoric Mood
4. Depressed Mood
5. Somatic or Sexual Dysfunction
6. Addiction
7. Odd or Eccentric or Suspicious Personality
D. Differential Diagnosis: Some disorders display similar or sometimes even the same symptom. The clinician, therefore, in his diagnostic attempt has to differentiate against the following disorders which one needs to be ruled out to establish a precise diagnosis.
1. Nonpathologic cannabis use for recreational or medical purposes2. Repeated episodes of Cannabis Intoxication.
MENTAL DISTURBANCES WITH NEGATIVE PSYCHIATRIC HISTORY
Toxic Psychosis
Hall (1994) of the National (Australian) Drug and Alcohol Research Center suggests there is good reason to believe that cannabis use may be a contributory cause of major psychological disorders such as psychotic disorders (i.e. illnesses in which symptoms of hallucinations, delusions and impaired reality testing are predominant features). This opinion is based on numerous observations related to cannabis use. First, THC is a psychoactive substance, which produces some of the symptoms found in psychotic disorders including euphoria, distorted time-perception, cognitive dysfunction and memory impairment. Second, under controlled laboratory conditions with normal volunteers, THC at high doses produces psychotic symptoms including visual and auditory hallucinations, delusional ideas, thought disorder, and symptoms of hypomania. Third, a putative "cannabis psychosis" has been identified by clinical observers in regions of the world with a long history of chronic, heavy cannabis use such as India, Egypt, and the Caribbean. There are a number of ways in which cannabis use could be associated with psychotic disorders without being a contributory cause of such disorders. One possibility is that the psychosis is a contributory cause of cannabis use, and that cannabis is used to self-medicate depression, anxiety, negative psychotic symptoms, or the side effects of antipsychotic drugs. Another possibility is that drug use among schizophrenic individuals is consequence of pre-existing personality characteristics which predispose them to use illicit drugs and to develop schizophrenia. A third possibility is that heavy cannabis use may be a marker of the use of stimulants such as amphetamines and cocaine, which there cause acute paranoid psychoses initially indistinguishable from schizophrenia (Hall et al 1994).
The possibility of an acute "cannabis psychosis" is based on case reports that associate a history of cannabis use with a psychotic presentation. The cases have been described as either a "toxic psychosis" or a functional psychosis. The toxic psychoses presents as a patients with psychotic symptoms and confusion. The patient is described as a cannabis naïve individual with a negative psychiatric history who smoked a large quantity of cannabis. Recovery is usually rapid after discontinued usage (Bernhardson and Gunne 1972). A functional psychosis occurs without confusion (exacerbation of schizophrenia, and schizophreniform psychoses). Various authors describe a heterogeneous clinical picture, often with manic features (Thacore et al 1976).
A one-year prospective study in Sweden evaluated 11 patients with a genuine cannabis-induced psychosis who were admitted to two mental hospitals (Palsson et al 1982). Patients with any history of pre-existing psychosis or multiple substance abuse were excluded. The features of the disorder were similar in all 11 patients, with a mixture of affective and schizophrenic-like symptoms, such as depression, anxiety, auditory hallucinations, delusions, confusion and frequently marked aggressiveness. The symptoms were similar, but the duration of the psychosis varied. Of the 11 patients, the duration of the psychosis was less than 2 months in four cases, in 6 cases a more prolonged transitory course of psychosis developed, and in one patient after four years his symptoms had not fully resolved. These groups corresponded well to what Granville-Grossman (1978) calls acute, subacute and chronic cannabis psychosis. The authors noted that diagnostically the cases resembled cycloid psychosis. However, they differed in the following respects 1) cannabis psychosis had less explicit bipolarity of symptoms than cycloid psychosis; 2) more confusion than mood change was seen with cannabis psychosis; 3) there was a less pronounced family history with the cannabis group (1/11); and 4) more aggressiveness and destruction was observed with cannabis. The 11 reported cases in the Swedish study have a symptomatology closely consistent with that reported elsewhere in the literature (Bernhardson and Gunne 1972). In all 11 cases, there was an intensification of the abuse during weeks or months preceding the psychosis. The patients with subacute, recurrent symptoms had without exception precipitated their symptoms by relapse into cannabis abuse. The course of the illness was self-limiting as long as the patient does not sustain injury as a result of being disorientated. No medication was usually indicated in toxic psychosis. However, some physicians used antipsychotics, antidepressants and ECTs depending on the severity and duration of the psychosis.
Rottanburg et al (1982) compared the mental state of 20 psychotic men with high urinary cannabinoid levels with that of 20 matched cannabis-free controls. All patients in both groups were psychotic, with the predominant diagnosis in the control group being schizophrenia. A blinded observer recorded the patients' mental status. All patients underwent toxicological analysis to exclude the presence of alcohol and other exogenous agents. The cannabis group showed a significantly higher occurrence of hypomanic symptoms and agitation than the controls and a lower occurrence of auditory hallucinations, affective flattening and incoherent speech. The cannabis subjects had an excellent short-term outcome. After 1 week the cannabis group showed marked improvement, especially with regard to the psychotic features, whereas the controls remained virtually unchanged.
Depressive Reactions
In novice marijuana users, rarely in regular users, marijuana may precipitate reactive or neurotic depressions. The majority of depressive reactions are of short duration and end spontaneously, as noted in studies by Weil (1970) and Kemp (1970).
Panic Reactions
The majority of all adverse responses to marijuana are panic reactions in which people begin to fear that they are dying or losing their minds. Panic reactions, or "bad trips", may become so severe as to be incapacitating and may stimulate an acute psychotic state. These reactions appear to vary in frequency depending on the environment or setting that the individual becomes intoxicated in (Weil 1970). Smith (1981) reports that roughly 50% of marijuana smokers in the United States have on some occasion experienced this adverse reaction. Treatment of these panic reactions is simple patient observation in a non-stimulatory environment (Weil 1970).
"Flashbacks"
Marijuana smokers who try hallucinogens occasionally find that the "high" experienced with marijuana use changes after using other hallucinogens. The cannabis user may have a repeat experience of a previous hallucination. For example, a person who experiences a hallucination on LSD or mescaline might see the exact same hallucination days later while high on marijuana alone (Weil 1970).
MENTAL DISTURBANCES WITH POSITIVE PSYCHIATRIC HISTORY
Toxic Psychosis
Evidence suggests that marijuana is a greater risk to patients who have suffered psychotic illness and to those who have had major affective illnesses prior to use. In addition, depressed individuals who are heavy marijuana users may be less responsive to conventional antidepressant drug treatment. Marijuana use in these individuals should be avoided. It should be kept in mind that even though a toxic psychosis due to marijuana abuse has a relatively good prognosis, the psychosis mobilized or aggravated by cannabis in schizophrenic patients does not simply because of the poor prognosis associated with schizophrenia (Weil 1970, Kemp 1970).
Cannabis use could conceivably precipitate a latent psychosis, i.e. bring forward an episode of schizophrenia or manic-depressive psychosis in a vulnerable or predisposed individual. This could occur either as a result of a specific pharmacological effect of THC (or other constituents of cannabis preparations), or as the result of stressful experiences while intoxicated, such as a panic attack or a paranoid reaction to the acute effects of cannabis (Edwards, 1976). Schizophrenia is the disorder about which concern has been most often expressed in the case of cannabis use. A related hypothesis suggests that cannabis use exacerbates the symptoms of a functional psychosis such as schizophrenia or manic-depressive psychosis. This could occur if cannabis use precipitated a relapse in the same way that it has been hypothesized to precipitate the onset of a latent psychosis. Alternatively, the pharmacological effects of cannabis might impair the effectiveness of the antipsychotic drugs used to treat major psychoses (Hall et al 1994).
Ablon and Goodwin administered oral THC doses of 5 mg/d to 20 mg bid to under double blind conditions to 8 unipolar and 5 bipolar patients. Dysphoric reactions were noted in 75% of the unipolar patients but in only 20% of the bipolar patients (p<0.10). This compared to a 33% dysphoria rate in normal volunteers. The authors hypothesized that the THC acted as a "mood intensifier" and best ought to be avoided in patients with unipolar affective illness (Ablon and Goodwin 1974).
Knudsen and Vilmar (1984) described their experience with ten schizophrenic patients with a history of cannabis abuse. All of the patients had been receiving depot antipsychotics for at least 6 months prior to their most recent exacerbation of their illness. The cannabis produced an initial beneficial effect for the patients in that the anergia, anhedonia, and low imaginative capacity caused by the antipsychotic were reversed. However, later a recurrence of the unpleasant positive schizophrenic symptoms led to the patients being rehospitalized.
It is often asked if cannabis can precipitate chronic psychosis, particularly schizophrenia. Andreasson et al (1987) studied a cohort of male Swedish enrollees, followed up through a national psychiatric case register. They discovered that using cannabis between one and 10 times at enrolment increased the relative risk of schizophrenia to 1.3 while the risk rose to 6.0 for patients who used cannabis on 50 or more occasions. The relative risk was recalculated after adjusting for 11 factors, which independently contributed to schizophrenia risk and still the relative risk ranged from 2.9 to 6.1 depending on the confounding variable. Other possible issues with this study include; the time gap between self-reported cannabis use at enrolment and later schizophrenia, the use of other substances (especially amphetamines), the adequacy of psychological assessment at enrolment, and the reliability of self-reported drug use at enrolment. Although high consumers of cannabis did increase the risk of schizophrenia, it accounted for only a 21 of the 274 cases while only 49 of the cases admitted to ever using cannabis.
The association between cannabis use and schizophrenia is strengthened by studies demonstrating the use of cannabis among schizophrenic patients. A Newcastle study examined substance use in all outpatients with schizophrenia. It was found that 29.9% of patients had used cannabis at some time in their life, with 7.7% and 28.3% having lifetime diagnosis of cannabis abuse and dependence, respectively (Fowler et al 1998). In this study alcohol was used more commonly than cannabis, while amphetamines were the third most commonly used substance.
Various hypotheses have been suggested to explain the prevalence of cannabis use in schizophrenia. Besides the causation/precipitation role, it has been proposed that cannabis may be used as self-medication for psychotic or dysphoric symptoms, or to relieve the side effects of antipsychotic drugs. However, the relationship may also be due to a convergence of the common peak ages of onset for schizophrenia and cannabis use, or demographic differences.
Linszen et al (1994) studied 93 patients with schizophrenia prospectively over a year and found a higher rate of relapse in the cannabis-users than in the non-users, with a differential risk of relapse according to level of cannabis use. This was still seen after adjusting for age, sex, age at first hospital admission, and alcohol use. However, this study was limited by failure to consider poly-substance use, reliance on self-report alone, and the gross measure of compliance used.
A CNS endogenous cannabinoid system was identified in 1990. The cannabinoid one receptor (CB1) was found in the hippocampus, associated cortical areas, cerebellum and basal ganglia (Herkenham et al 1990). Cannabis administration also increases the activity of tyrosine hydroxylase, an enzyme linked to dopamine metabolism (Hernandez et al 1997). These findings suggest that cannabis could lead to psychosis by modulating dopaminergic transmission. The discovery of these receptors has also led to the finding of endogenous cannabinoids, such as anandamide.
A second study found higher concentrations of two endogenous cannabinoids in the cerebrospinal fluid of 10 patients with schizophrenia compared with 11 non-psychotic control patients (Leweke et al 1999). It was hypothesized that the hypercannabinergic state in the schizophrenic patients was a function of the patients' dopamine hyperactive state. However, only a small number of subjects were studied and confounding factors such as substance use may have biased the findings.
Affective Disorder
It is often difficult to diagnose certain psychiatric disorders in the presence of substance abusers, especially bipolar disorder. The difficulty is ascertaining whether the cannabis use is exacerbating the patient's symptoms or the patient is using the cannabis as a form of self-medication to either benefit the illness or counteract medication adverse effects. In any case, cannabis is often a poor choice in any psychiatric disorder or at least not helpful in that one more drug simply confuses the clinical picture.
The use of cannabis as a mood-stabilizer in bipolar disorder has been suggested by case reports and marijuana usage in bipolar patients. Grinspoon and Bakalar (1998) found that many patients reported that cannabis was useful in the treatment of their bipolar disorder. Some patients used it to treat mania and/or depression. The patients suggested that it was more effective than conventional drugs or helped to relieve the side effects of those drugs. One patient claimed that cannabis curbed her manic rages. Others described the use of cannabis as a supplement to lithium (allowing reduced consumption) or for relief of lithium's side effects. It is problematic to conduct a controlled cannabis treatment trial in bipolar disorder due to legal issues. Therefore, much of the information available comes from case studies where the amount of THC ingested and its effect on bipolar disorder entirely subjectively derived from patient reports.
Geller et al. (1998) performed a randomized, double-blind, placebo-controlled study of lithium (0.9-1.3 mEq/L) in adolescents with bipolar disorder with secondary substance dependency disorder (SDD). The subjects were 16.3 + 1.2 years old and were assessed during a 6-week outpatient protocol that included random weekly urine collection for drug assays and random and weekly serum collection for lithium levels. Using both intent-to-treat (N=25) and completer (N=21) analyses, there were significant differences on continuous and categorical measures between the active and placebo groups for both psychopathology measures and weekly random urine drug assays. The mean scheduled weekly serum lithium level of active responders was 0.9 mEq/L. Addiction to both alcohol and marijuana was the most frequent category of SDD. Mean age at onset of bipolar disorder was 9.6 + 3.9 years and of SDD was 15.3 + 1.3 years. There were multigenerational mood disorders and SDD in 96% and 56% of families, respectfully. Lithium was an effective treatment for bipolar disorder with secondary SDD. The mean 6-year interval between the onset of bipolar disorder and onset of SDD strongly argues for earlier recognition of bipolar disorder to help prevent later SDD.
Preliminary data suggest that cannabidiol (160 mg) (Marinol) may be an effective hypnotic, and that THC (0.1 mg/kg) may have antidepressant properties in cancer patients and others (Grinspoon and Bakalar 1993). There is considerable debate as to whether cannabis may actually benefit depression. Although there is preliminary evidence that cannabis may have antidepressant effects, it is argued that there are significant drawbacks to its usage. Marijuana usage is associated with "amotivational syndrome", in which chronic high-dose cannabis users become apathetic, socially withdrawn, and perform at a level of everyday functioning well below their capabilities prior to the start of cannabis usage. Although depressed patients may experience some symptom relief, the response may be illusionary if they experience a loss of motivation and productivity. Cannabis affects the users' mood and affect such that chronic heavy use could adversely affect self-medicating patients whose adjustment prior to their cannabis use was poor (Hall et al 1994).
Anxiety
Nabilone (a synthetic cannabinoid) (1 mg TID) produced "dramatic improvements" on the Hamilton Anxiety Scale in 20 anxious patients in comparison to placebo (P<0.001), which were mirrored by other measures (Fabre and McLendon 1981). Seven days into the study, nabilone treatment group's anxiety scores were halved with the change persisted improvement persisting for the remainder of the study. Side effects included dry mouth, dry eyes, and drowsiness. There were more dropouts from the placebo group (P<0.03). The authors concluded that nabilone was a "very effective anxiolytic deserving of further study". A second study compared nabilone (1-2.5 mg BID) to placebo in 11 anxious patients (Ilaria et al 1981). Significant improvements in anxiety scores were found on the Hamilton Anxiety Scale and Global Improvement Scale. The only clinically significant adverse effect was postural hypotension associated with dizziness, lightheadedness, or weakness. This was dose-related, experienced by most patients, and tended to be tolerated over time. The problem with both studies is that a diagnosis of neurotic anxiety is not specific enough by today's diagnostic DSM-IV standards to determine what anxiety symptoms were being benefited by the drug.
Adolescents
In this group of patients there seems to be an increase in substance use disorders occurring in the presence of untreated psychiatric disorders. These disorders include: ADHD (Kaminer 1992, Wilens et al 1996), anxiety disorders, conduct disorders, and mood disorders (Deykin et al 1986; Kashani et al 1985). Marijuana has been found to be the most commonly abused drug among ADHD children, adolescents, and adults (Biederman et al 1995; Wilens et al 1994). Therefore, patients being treated for psychiatric disorders, such as ADHD, are at an increased risk of using marijuana.
ADVERSE REACTIONS TO CHRONIC MARIJUANA USE (Johnston et al 1980)
Adverse reactions reported to be associated with prolonged cannabis abuse may include the following:
Depression: Chronic exposure produces lethargy, sedation and depression in many species, and/or aggressive irritability in monkeys. Kandel and Davies (1992) reported on the characteristic problems reported by near daily cannabis users (aged 28-29 years) who were identified in a prospective study of the consequences of adolescent drug use. The major adverse consequences associated with use were: subjectively experienced cognitive deficits, reduced energy, depression, and problems with spouse. Kolansky and Moore (1971, 1972) reported cases of psychiatric disorder in adolescents and young adults (38 cases) and among adults (13 cases) who had used marijuana at least twice per week. The clinical picture was one of "very poor social judgment, poor attention span, poor concentration, confusion, anxiety, depression, apathy, passivity, indifference and often slowed and slurred speech" (Kolansky and Moore, 1971).
Cognition: Acute usage of cannabis is often associated with reports of transient cognitive changes. However, there has been insufficient research on the impact of long-term cannabis use on cognitive functioning in adolescents and young adults, or on the effects of chronic use on the cognitive decline that occurs with normal aging. Gender differences have not been examined to date and may be important, given that such differences have become apparent in differential responses to alcohol. There is clinical and experimental evidence, which suggests that long-term use of cannabis produces subtle cognitive impairments in specific aspects of memory, attention and the organization and integration of complex information. While these impairments may be subtle, they could potentially affect functioning in daily life. The evidence suggests that increasing duration of use leads to progressively greater impairment. It is not known to what extent such impairment may recover with prolonged abstinence (Hall et al 1994).
Pulmonary: bronchitis, sinusitis, pharyngitis, chronic cough, large airway obstruction, emphysema. A known carcinogen, benzpyrene, is present in cannabis smoke in concentrations 5 to 15 times higher than nicotine smoke. Concurrent use of nicotine and cannabis is more than additive in producing precancerous changes in lung cells (Tennant 1971).
Cardiovascular: tachycardia and reduced exercise tolerance in persons with heart disease.
Reproductive Function: decreased levels of sex hormones such as testosterone, decreased sperm count and sperm mobility, menstrual cycles may be anovulatory. Animal data suggests possible teratogenic effects.
Immune System: impaired function of lymphocytes, DNA, RNA, and protein uptake may be impaired (Johnston et al 1980). (The clinical significance of this has yet to be established.)
DRUG INTERACTIONS
Tricyclic Antidepressants: A case study of four male adolescents aged 15-18 years being treated with a tricyclic antidepressant (nortriptyline, desipramine) for ADHD found transient cognitive changes, delirium, and tachycardia after smoking marijuana (Wilens et al 1997).
A 16-year-old male with ADHD and oppositional defiant disorder, was receiving 75 mg/day (1.3 mg/kg) nortriptyline, with levels of 105 ng/ml (normal, 50 to150 ng/ml) and a normal ECG (heart rate=86). He had no medical condition and had been compliant with his medication. Thirty minutes after smoking one marijuana cigarette, he experienced lightheadedness, "a racing heart," and confusion. Emergency room evaluation revealed a heart rate of 130 beats per minute and normal blood pressures. Mental status examination was significant for delirium with orientation deficits in place and time, confusion, and short-term memory loss. Laboratory studies indicated an ECG with sinus tachycardia and a serum and subsequent urine toxicological screen positive for marijuana and nortriptyline (level 100 ng/ml) only. His delirium and tachycardia completely resolved spontaneously 24 hours after his marijuana use.
An 18-year old college student with depression and ADHD, was treated with desipramine at 200 mg/day (2.5 mg/kg/day). He reported experiencing severe confusion, lightheadedness, "spaciness," and "feeling ill" after smoking marijuana. He reported no similar experiences after smoking marijuana (the same "batch") prior to desipramine therapy. Examination 12 hours later revealed complaints of edginess, severe dry mouth and lightheadedness, and a mental status examination significant for confusion and short-term memory impairment. He was normotensive, with a heart rate of 110 beats per minute (previously 84 while taking desipramine). His laboratory studies were remarkable for a urine toxicology screen revealing only desipramine (level 85 ng/ml) and marijuana metabolites. He reported symptoms abating 48 hours after his initial marijuana use.
A 15-year-old male with ADHD and depression, was treated with 150 mg of desipramine daily (level 75 ng/ml) and 50 mg of sertraline. A severe "confusional state" developed after he smoked two marijuana cigarettes. He experienced labile mood, irritability, and "a racing heart". He did not seek medical attention and noted that these symptoms abated after 16 hours.
A 16-year-old male with ADHD and conduct disorder was treated with desipramine and clonidine. During routine psychopharmacological follow-up, he reported using marijuana on weekends for the preceding 4 weekends. He described a change in his "high" since receiving desipramine. In particular he noted hallucinations, depersonalization, and confusion. On further questioning, he noted mild shortness of breath and elevated heart rate. Subsequently, he also reported intermittent alcohol use and noted further that while on desipramine he would become more rapidly and severely intoxicated.
Although marijuana users often experience these side effects, the majority of toxic reactions occur at relatively higher doses (Thomas 1993). Therefore, the presence of delirium and tachycardia at relatively low doses is suggestive of a drug interaction. THC is metabolized by cytochrome P450 hepatic enzyme as are the tricyclic antidepressants (Gilman et al 1990). The presentation of these four cases suggest an anticholingeric toxicity secondary to elevated blood levels of the tricyclic antidepressants.
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