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Marijuana
14
Marijuana
values of MOE indicate that the exposure of the chemical is much lower than the NOEAL in animals. It should be noted that the MOE calculation does not take into account the differences in animal-to-human susceptibility and/or the extrapolation of dose from animals to humans.
Example of MOE
2 l day 1 divided by 70 kg (body weight), which is equal to 0.057 mg kg 1 day 1. Suppose that the NOEAL of chemical X is 150 mg kg 1 day 1, then the MOE would be more than 2600. This indicates that the exposure of chemical X is much below its NOEAL and the risk to public health is very low.
See also: Risk Assessment, Human Health.
Consider that the human exposure of a chemical X calculated via drinking water supply is 2 ppp, that is, 2 mg l 1 day 1. Suppose a 70 kg man consumes 2 l of drinking water per day then the estimated exposure dose would be 2 mg kg 1 day 1
Further Reading Klasssen CD (ed.) (2001) Casarett & Doull’s Toxicology: The Basic Science of Poisons. New York: McGraw-Hill.
Marijuana
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*
*
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Christopher P Holstege
Toxicokinetics
& 2005 Elsevier Inc. All rights reserved. This article is a revision of the previous print edition article by William A Watson, volume 2, pp. 272–273, & 1998, Elsevier Inc.
After smoking, 18–50% of the available THC is absorbed, the onset of clinical effects occurs within 10 min, and effects continue for 2–4 h. Peak plasma levels occur within 5–12 min of smoking with peak clinical effects noted at 20–30 min later, after distribution into brain and other tissues. Following ingestion, only 5–20% of THC is bioavailable, the onset of effects begins within 30–60 min, and effects persist for 4–6 h. Gastrointestinal absorption is increased by fatty foods or a lipid vehicle. Peak plasma levels occur 2–3 h after THC ingestion. THC is 97–99% protein bound with a volume of distribution of B10 l kg 1. THC undergoes substantial firstpass metabolism by the liver. THC is metabolized primarily to 11-hydroxy-delta-9-THC. The 11-hydroxy-delta-9-THC is pharmacologically active, but is further metabolized to inactive metabolites, primarily 11-nor-delta-9-THC carboxylic acid. Less than 1% of THC is excreted unchanged in the urine. The high lipid solubility results in an initial short plasma half-life, but this adipose storage produces a biologic half-life of 25–30 h. THC may be detectable in plasma for up to 15 days. With chronic high-dose use of marijuana, the presence of metabolites of THC in the urine can be detected for 6–8 weeks.
CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBER: CAS 7663-50-5 SYNONYMS: Tetrahydrocannabinol (THC); Bhang; Dronabinol; Cannabis; Ganja; Grass; Hashish; Hemp; Honey oil; Marihuana; Marinol; Mary Jane; Pot; Refeer; Weed CHEMICAL/PHARMACEUTICAL/OTHER CLASS: Psychoactive substance CHEMICAL STRUCTURE:
OH
O
C5H11
Uses Dronabinol is prescribed for its antiemetic and appetite stimulant properties. Marijuana is primarily a drug of abuse, although it is currently used by patients for the same purposes as dronabinol.
Exposure Routes and Pathways Inhalation of marijuana smoke is the most common method of use followed by ingestion. Parenteral use is uncommon. Dronabinol is an oral capsule.
Mechanism of Toxicity The mechanisms involved in THC’s central nervous system (CNS) and cardiovascular effects have not been well delineated. Specific cannabinoid receptors in the cerebral cortex may be responsible for the pharmacologic effects of THC. THC also has immunosuppressive effects and results in depression
Marijuana 15
of both B- and T-cell activity and depression of tumor necrosis factor levels by macrophages. The antiemetic effect appears to involve the CNS vomiting control center.
Acute and Short-Term Toxicity (or Exposure) Animal
The clinical effects of marijuana in animals are similar to those observed in humans. Clinical effects may be more pronounced after ingestion of marijuana than those seen with inhalation exposure.
Human
Chronic use can result in an amotivational state, paranoid behavior, worsening muscle incoordination, slurred speech, and delusions. Smoking marijuana is implicated in both chronic lung disease and the development of lung cancer. Fertility can be impaired in both males (decreased sperm count and activity) and females (decreased ovulation and abnormal menses). Prenatal marijuana use by the mother correlates with increased hyperactivity, impulsivity, and delinquency in the child. Tolerance to some CNS effects may develop with chronic use, and a withdrawal syndrome is possible after chronic high-dose use.
Human
Toxicity primarily involves the CNS and cardiovascular system. Euphoria, increased apparent visual and auditory sensory perception, and altered perceptions of time and space are common with mild intoxication. Larger doses can impair memory, decrease attention and cognition, and result in lethargy. Impaired sensory interpretation and performance of complicated mental tasks increases the risk of trauma with activities such as operating a motor vehicle. Decreased balance, ataxia, and muscle incoordination can occur. Anxiety, panic attacks, paranoia, depression, confusion, and hallucinations can occur with high doses; these effects are more common in less experienced, younger users. Cardiovascular effects include increased heart rate and cardiac output and decreased exercise tolerance. Bronchodilation and, less frequently, bronchoconstriction may be seen. The pupils will constrict slightly and the conjunctiva will become red secondary to congestion of the blood vessels. A dry mouth is common. The intravenous administration of marijuana has been associated with severe multiple organ system failure, including renal failure, rhabdomyolysis, increased hepatic enzymes, shortness of breath, headaches, and hypotension.
Chronic Toxicity (or Exposure) Animal
Nonhuman primates have displayed behavioral signs of withdrawal after chronic administration of THC. Chronic administration of THC via gavage over 2 years found no evidence of carcinogenic effect in rats and equivocal findings in mice at higher doses. Chronic use of THC has been shown to induce tumor regression in rodents.
In Vitro Toxicity Data The active moieties of marijuana have been studied for medicinal purposes in a variety of models. Some canabinoids have displayed effects on neuronal transmission and alterations of calcium homeostasis. Other cannabinoids have been shown to stimulate cell death (apoptosis), which may help explain observed antitumor effects in some animal models.
Clinical Management Clinical management is primarily supportive. Reassurance is generally effective in treating alterations in thought process, although benzodiazepines may be necessary in uncommon, severe toxicity. If large amounts of marijuana are ingested, activated charcoal administration may be considered for recent exposures.
See also: Drugs of Abuse.
Further Reading Johnson BA (1990) Psychopharmacological effects of cannabis. British Journal of Hospital Pharmacy 43: 114–122. Macnab A, Anderson E, and Susak L (1989) Ingestion of cannabis: A cause of coma in children. Pediatric Emergency Care 5: 238–239. Onaivi ES (ed.) (2002) Biology of marijuana: From Gene to Behavior. London: Taylor and Francis. Schwartz RH (2002) Marijuana: a decade and a half later, still a crude drug with underappreciated toxicity. Pediatrics 109(2): 284–289. Selden BS, Clark RF, and Curry SC (1990) Marijuana. Emergency Medicine Clinics of North America 8: 527–539.
Marijuana
values of MOE indicate that the exposure of the chemical is much lower than the NOEAL in animals. It should be noted that the MOE calculation does not take into account the differences in animal-to-human susceptibility and/or the extrapolation of dose from animals to humans.
Example of MOE
2 l day 1 divided by 70 kg (body weight), which is equal to 0.057 mg kg 1 day 1. Suppose that the NOEAL of chemical X is 150 mg kg 1 day 1, then the MOE would be more than 2600. This indicates that the exposure of chemical X is much below its NOEAL and the risk to public health is very low.
See also: Risk Assessment, Human Health.
Consider that the human exposure of a chemical X calculated via drinking water supply is 2 ppp, that is, 2 mg l 1 day 1. Suppose a 70 kg man consumes 2 l of drinking water per day then the estimated exposure dose would be 2 mg kg 1 day 1
Further Reading Klasssen CD (ed.) (2001) Casarett & Doull’s Toxicology: The Basic Science of Poisons. New York: McGraw-Hill.
Marijuana
*
*
*
*
Christopher P Holstege
Toxicokinetics
& 2005 Elsevier Inc. All rights reserved. This article is a revision of the previous print edition article by William A Watson, volume 2, pp. 272–273, & 1998, Elsevier Inc.
After smoking, 18–50% of the available THC is absorbed, the onset of clinical effects occurs within 10 min, and effects continue for 2–4 h. Peak plasma levels occur within 5–12 min of smoking with peak clinical effects noted at 20–30 min later, after distribution into brain and other tissues. Following ingestion, only 5–20% of THC is bioavailable, the onset of effects begins within 30–60 min, and effects persist for 4–6 h. Gastrointestinal absorption is increased by fatty foods or a lipid vehicle. Peak plasma levels occur 2–3 h after THC ingestion. THC is 97–99% protein bound with a volume of distribution of B10 l kg 1. THC undergoes substantial firstpass metabolism by the liver. THC is metabolized primarily to 11-hydroxy-delta-9-THC. The 11-hydroxy-delta-9-THC is pharmacologically active, but is further metabolized to inactive metabolites, primarily 11-nor-delta-9-THC carboxylic acid. Less than 1% of THC is excreted unchanged in the urine. The high lipid solubility results in an initial short plasma half-life, but this adipose storage produces a biologic half-life of 25–30 h. THC may be detectable in plasma for up to 15 days. With chronic high-dose use of marijuana, the presence of metabolites of THC in the urine can be detected for 6–8 weeks.
CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBER: CAS 7663-50-5 SYNONYMS: Tetrahydrocannabinol (THC); Bhang; Dronabinol; Cannabis; Ganja; Grass; Hashish; Hemp; Honey oil; Marihuana; Marinol; Mary Jane; Pot; Refeer; Weed CHEMICAL/PHARMACEUTICAL/OTHER CLASS: Psychoactive substance CHEMICAL STRUCTURE:
OH
O
C5H11
Uses Dronabinol is prescribed for its antiemetic and appetite stimulant properties. Marijuana is primarily a drug of abuse, although it is currently used by patients for the same purposes as dronabinol.
Exposure Routes and Pathways Inhalation of marijuana smoke is the most common method of use followed by ingestion. Parenteral use is uncommon. Dronabinol is an oral capsule.
Mechanism of Toxicity The mechanisms involved in THC’s central nervous system (CNS) and cardiovascular effects have not been well delineated. Specific cannabinoid receptors in the cerebral cortex may be responsible for the pharmacologic effects of THC. THC also has immunosuppressive effects and results in depression
Marijuana 15
of both B- and T-cell activity and depression of tumor necrosis factor levels by macrophages. The antiemetic effect appears to involve the CNS vomiting control center.
Acute and Short-Term Toxicity (or Exposure) Animal
The clinical effects of marijuana in animals are similar to those observed in humans. Clinical effects may be more pronounced after ingestion of marijuana than those seen with inhalation exposure.
Human
Chronic use can result in an amotivational state, paranoid behavior, worsening muscle incoordination, slurred speech, and delusions. Smoking marijuana is implicated in both chronic lung disease and the development of lung cancer. Fertility can be impaired in both males (decreased sperm count and activity) and females (decreased ovulation and abnormal menses). Prenatal marijuana use by the mother correlates with increased hyperactivity, impulsivity, and delinquency in the child. Tolerance to some CNS effects may develop with chronic use, and a withdrawal syndrome is possible after chronic high-dose use.
Human
Toxicity primarily involves the CNS and cardiovascular system. Euphoria, increased apparent visual and auditory sensory perception, and altered perceptions of time and space are common with mild intoxication. Larger doses can impair memory, decrease attention and cognition, and result in lethargy. Impaired sensory interpretation and performance of complicated mental tasks increases the risk of trauma with activities such as operating a motor vehicle. Decreased balance, ataxia, and muscle incoordination can occur. Anxiety, panic attacks, paranoia, depression, confusion, and hallucinations can occur with high doses; these effects are more common in less experienced, younger users. Cardiovascular effects include increased heart rate and cardiac output and decreased exercise tolerance. Bronchodilation and, less frequently, bronchoconstriction may be seen. The pupils will constrict slightly and the conjunctiva will become red secondary to congestion of the blood vessels. A dry mouth is common. The intravenous administration of marijuana has been associated with severe multiple organ system failure, including renal failure, rhabdomyolysis, increased hepatic enzymes, shortness of breath, headaches, and hypotension.
Chronic Toxicity (or Exposure) Animal
Nonhuman primates have displayed behavioral signs of withdrawal after chronic administration of THC. Chronic administration of THC via gavage over 2 years found no evidence of carcinogenic effect in rats and equivocal findings in mice at higher doses. Chronic use of THC has been shown to induce tumor regression in rodents.
In Vitro Toxicity Data The active moieties of marijuana have been studied for medicinal purposes in a variety of models. Some canabinoids have displayed effects on neuronal transmission and alterations of calcium homeostasis. Other cannabinoids have been shown to stimulate cell death (apoptosis), which may help explain observed antitumor effects in some animal models.
Clinical Management Clinical management is primarily supportive. Reassurance is generally effective in treating alterations in thought process, although benzodiazepines may be necessary in uncommon, severe toxicity. If large amounts of marijuana are ingested, activated charcoal administration may be considered for recent exposures.
See also: Drugs of Abuse.
Further Reading Johnson BA (1990) Psychopharmacological effects of cannabis. British Journal of Hospital Pharmacy 43: 114–122. Macnab A, Anderson E, and Susak L (1989) Ingestion of cannabis: A cause of coma in children. Pediatric Emergency Care 5: 238–239. Onaivi ES (ed.) (2002) Biology of marijuana: From Gene to Behavior. London: Taylor and Francis. Schwartz RH (2002) Marijuana: a decade and a half later, still a crude drug with underappreciated toxicity. Pediatrics 109(2): 284–289. Selden BS, Clark RF, and Curry SC (1990) Marijuana. Emergency Medicine Clinics of North America 8: 527–539.