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Biographical Sketches of Lead
Authors and Main Contributors
Marijuana is a green or gray mixture of dried shredded flowers and leaves
of the hemp plant Cannabis sativa. Hashish consists of resinous
secretions of the cannabis plant. Dronabinol (synthetic THC) is a light
yellow resinous oil.
Synonyms: Cannabis, marijuana, pot, reefer,
buds, grass, weed, dope, ganja, herb, boom, gangster, Mary Jane, sinsemilla,
shit, joint, hash, hash oil, blow, blunt, green, kilobricks, Thai sticks;
Source: Cannabis contains chemicals called
cannabinoids, including cannabinol, cannabidiol, cannabinolidic acids,
cannabigerol, cannabichromene, and several isomers of tetrahydrocannabinol
(THC). One of these isomers, Δ -THC, is believed to be responsible
for most of the characteristic psychoactive effects of cannabis. Marijuana
refers to the leaves and flowering tops of the cannabis plant; the buds
are often preferred because of their higher THC content. Hashish consists
of the THC-rich resinous secretions of the plant, which are collected,
dried, compressed and smoked. Hashish oil is produced by extracting the
cannabinoids from plant material with a solvent. In the U. S.,
hashish and hashish oil are Schedule I controlled substances. Dronabinol
(Marinol®) is a Schedule III controlled substance and is available
in strengths of 2.5, 5 or 10 mg in round, soft gelatin capsules.
Drug Class: Cannabis/ Marijuana:
spectrum of behavioral effects is unique, preventing classification of
the drug as a stimulant, sedative, tranquilizer, or hallucinogen. Dronabinol:
appetite stimulant, antiemetic.
Medical and Recreational Uses: Medicinal:
Indicated for the treatment of anorexia associated with weight loss in
patients with AIDS, and to treat mild to moderate nausea and vomiting
associated with cancer chemotherapy. Recreational: Marijuana
is used for its mood altering effects, euphoria, and relaxation. Marijuana
is the most commonly used illicit drug throughout the world.
Potency, Purity and Dose: THC is the major
psychoactive constituent of cannabis. Potency is dependent on THC concentration
and is usually expressed as %THC per dry weight of material. Average
THC concentration in marijuana is 1-5%, hashish 5-15%, and hashish oil ³ 20%.
The form of marijuana known as sinsemilla is derived from the
unpollinated female cannabis plant and is preferred for its high THC
content (up to 17% THC). Recreational doses are highly variable and users
often titer their own dose. A single intake of smoke from a pipe or joint
is called a hit (approximately 1/20th of a gram). The lower the potency
or THC content the more hits are needed to achieve the desired effects;
1-3 hits of high potency sinsemilla is typically enough to produce the
desired effects. In terms of its psychoactive effect, a drop or two of
hash oil on a cigarette is equal to a single “joint” of marijuana.
Medicinally, the initial starting dose of Marinol® is 2.5 mg, twice
Route of Administration: Marijuana is usually
smoked as a cigarette (‘joint’) or in a pipe or bong. Hollowed
out cigars packed with marijuana are also common and are called `. Joints
and blunts are often laced with adulterants including PCP or crack cocaine.
Joints can also be dipped in liquid PCP or in codeine cough syrup. Marijuana
is also orally ingested.
Pharmacodynamics: THC binds to cannabinoid
receptors and interferes with important endogenous cannabinoid neurotransmitter
systems. Receptor distribution correlates with brain areas involved in
physiological, psychomotor and cognitive effects. Correspondingly, THC
produces alterations in motor behavior, perception, cognition, memory,
learning, endocrine function, food intake, and regulation of body temperature.
Pharmacokinetics: Absorption is slower following
the oral route of administration with lower, more delayed peak THC levels.
Bioavailability is reduced following oral ingestion due to extensive
first pass metabolism. Smoking marijuana results in rapid absorption
with peak THC plasma concentrations occurring prior to the end of smoking.
Concentrations vary depending on the potency of marijuana and the manner
in which the drug is smoked, however, peak plasma concentrations of 100-200
ng/mL are routinely encountered. Plasma THC concentrations generally
fall below 5 ng/mL less than 3 hours after smoking. THC is highly lipid
soluble, and plasma and urinary elimination half-lives are best estimated
at 3-4 days, where the rate-limiting step is the slow redistribution
to plasma of THC sequestered in the tissues. Shorter half-lives are generally
reported due to limited collection intervals and less sensitive analytical
methods. Plasma THC concentrations in occasional users rapidly fall below
limits of quantitation within 8 to 12 h. THC is rapidly and extensively
metabolized with very little THC being excreted unchanged from the body.
THC is primarily metabolized to 11-hydroxy-THC which has equipotent psychoactivity.
The 11-hydroxy-THC is then rapidly metabolized to the 11-nor-9-carboxy-THC
(THC-COOH) which is not psychoactive. A majority of THC is excreted via
the feces (~65%) with approximately 30% of the THC being eliminated in
the urine as conjugated glucuronic acids and free THC hydroxylated metabolites.
Molecular Interactions / Receptor Chemistry: THC
is metabolized via cytochrome P450 2C9, 2C11, and 3A isoenzymes. Potential
inhibitors of these isoenzymes could decrease the rate of THC elimination
if administered concurrently, while potential inducers
could increase the rate of elimination.
Blood to Plasma Concentration Ratio: 0.55
Interpretation of Blood Concentrations: It
is difficult to establish a relationship between a person's THC blood
or plasma concentration and performance impairing effects. Concentrations
of parent drug and metabolite are very dependent on pattern of use as
well as dose. THC concentrations typically peak during the act of smoking,
while peak 11-OH THC concentrations occur approximately 9-23 minutes
after the start of smoking. Concentrations of both analytes decline rapidly
and are often < 5 ng/mL at 3 hours. Significant THC concentrations
(7 to 18 ng/mL) are noted following even a single puff or hit of a marijuana
cigarette. Peak plasma THC concentrations ranged from 46-188 ng/mL in
6 subjects after they smoked 8.8 mg THC over 10 minutes. Chronic users
can have mean plasma levels of THC-COOH of 45 ng/mL, 12 hours after use;
corresponding THC levels are, however, less than 1 ng/mL. Following oral
administration, THC concentrations peak at 1-3 hours and are lower than
after smoking. Dronabinol and THC-COOH are present in equal concentrations
in plasma and concentrations peak at approximately 2-4 hours after dosing.
It is inadvisable to try and predict effects based on blood THC concentrations
alone, and currently impossible to predict specific effects based on
THC-COOH concentrations. It is possible for a person to be affected by
marijuana use with concentrations of THC in their blood below the limit
of detection of the method. Mathematical models have been developed to
estimate the time of marijuana exposure within a 95% confidence interval.
Knowing the elapsed time from marijuana exposure can then be used to
predict impairment in concurrent cognitive and psychomotor effects based
on data in the published literature.
Interpretation of Urine Test Results: Detection
of total THC metabolites in urine, primarily THC-COOH-glucuronide, only
indicates prior THC exposure. Detection time is well past the window
of intoxication and impairment. Published excretion data from controlled
clinical studies may provide a reference for evaluating urine cannabinoid
concentrations; however, these data are generally reflective of occasional
marijuana use rather than heavy, chronic marijuana exposure. It can take
as long as 4 hours for THC-COOH to appear in the urine at concentrations
sufficient to trigger an immunoassay (at 50ng/mL) following smoking.
Positive test results generally indicate use within 1-3 days; however,
the detection window could be significantly longer following heavy, chronic,
use. Following single doses of Marinol®, low levels of dronabinol
metabolites have been detected for more than 5 weeks in urine. Low concentrations
of THC have also been measured in over-the-counter hemp oil products – consumption
of these products may produce positive urine cannabinoid test results.
Effects: Pharmacological effects of marijuana
vary with dose, route of administration, experience of user, vulnerability
to psychoactive effects, and setting of use.
Psychological: At recreational doses, effects include relaxation,
euphoria, relaxed inhibitions, sense of well-being, disorientation, altered
time and space perception, lack of concentration, impaired learning and
memory, alterations in thought formation and expression, drowsiness,
sedation, mood changes such as panic reactions and paranoia, and a more
vivid sense of taste, sight, smell, and hearing. Stronger doses intensify
reactions and may cause fluctuating emotions, flights of fragmentary
thoughts with disturbed associations, a dulling of attention despite
an illusion of heightened insight, image distortion, and psychosis.
Physiological: The most frequent effects include increased
heart rate, reddening of the eyes, dry mouth and throat, increased appetite,
Side Effect Profile: Fatigue, paranoia, possible
psychosis, memory problems, depersonalization, mood alterations, urinary
retention, constipation, decreased motor coordination, lethargy, slurred
speech, and dizziness. Impaired health including lung damage, behavioral
changes, and reproductive, cardiovascular and immunological effects have
been associated with regular marijuana use. Regular and chronic marijuana
smokers may have many of the same respiratory problems that tobacco smokers
have (daily cough and phlegm, symptoms of chronic bronchitis), as the
amount of tar inhaled and the level of carbon monoxide absorbed by marijuana
smokers is 3 to 5 times greater than among tobacco smokers. Smoking marijuana
while shooting up cocaine has the potential to cause severe increases
in heart rate and blood pressure.
Duration of Effects: Effects from smoking
cannabis products are felt within minutes and reach their peak in 10-30
minutes. Typical marijuana smokers experience a high that lasts approximately
2 hours. Most behavioral and physiological effects return to baseline
levels within 3-5 hours after drug use, although some investigators have
demonstrated residual effects in specific behaviors up to 24 hours, such
as complex divided attention tasks. Psychomotor impairment can persist
after the perceived high has dissipated. In long term users, even after
periods of abstinence, selective attention (ability to filter out irrelevant
information) has been shown to be adversely affected with increasing
duration of use, and speed of information processing has been shown to
be impaired with increasing frequency of use. Dronabinol has an onset
of 30-60 minutes, peak effects occur at 2-4 hours, and it can stimulate
the appetite for up to 24 hours.
Tolerance, Dependence and Withdrawal Effect: Tolerance
may develop to some pharmacological effects of dronabinol. Tolerance
to many of the effects of marijuana may develop rapidly after only a
few doses, but also disappears rapidly. Marijuana is addicting as it
causes compulsive drug craving, seeking, and use, even in the face of
negative health and social consequences. Additionally, animal studies
suggests marijuana causes physical dependence. A withdrawal syndrome
is commonly seen in chronic marijuana users following abrupt discontinuation.
Symptoms include restlessness, irritability, mild agitation, hyperactivity,
insomnia, nausea, cramping, decreased appetite, sweating, and increased
Drug Interactions: Cocaine and amphetamines
may lead to increased hypertension, tachycardia and possible cardiotoxicity.
Benzodiazepines, barbiturates, ethanol, opioids, antihistamines, muscle
relaxants and other CNS depressants increase drowsiness and CNS depression.
When taken concurrently with alcohol, marijuana is more likely to be
a traffic safety risk factor than when consumed alone.
Performance Effects: The short term effects
of marijuana use include problems with memory and learning, distorted
perception, difficultly in thinking and problem-solving, and loss of
coordination. Heavy users may have increased difficulty sustaining attention,
shifting attention to meet the demands of changes in the environment,
and in registering, processing and using information. In general, laboratory
performance studies indicate that sensory functions are not highly impaired,
but perceptual functions are significantly affected. The ability to concentrate
and maintain attention are decreased during marijuana use, and impairment
of hand-eye coordination is dose-related over a wide range of dosages.Impairment
in retention time and tracking, subjective sleepiness, distortion of
time and distance, vigilance, and loss of coordination in divided attention
tasks have been reported. Note however, that subjects can often “pull
themselves together” to concentrate on simple tasks for brief periods
of time. Significant performance impairments are usually observed for
at least 1-2 hours following marijuana use, and residual effects have
been reported up to 24 hours.
Effects on Driving: The drug manufacturer
suggests that patients receiving treatment with Marinol® should be
specifically warned not to drive until it is established that they are
able to tolerate the drug and perform such tasks safely. Epidemiology
data from road traffic arrests and fatalities indicate that after alcohol,
marijuana is the most frequently detected psychoactive substance among
driving populations. Marijuana has been shown to impair performance on
driving simulator tasks and on open and closed driving courses for up
to approximately 3 hours. Decreased car handling performance, increased
reaction times, impaired time and distance estimation, inability to maintain
headway, lateral travel, subjective sleepiness, motor incoordination,
and impaired sustained vigilance have all been reported. Some drivers
may actually be able to improve performance for brief periods by overcompensating
for self-perceived impairment. The greater the demands placed on the
driver, however, the more critical the likely impairment. Marijuana may
particularly impair monotonous and prolonged driving. Decision times
to evaluate situations and determine appropriate responses increase.
Mixing alcohol and marijuana may dramatically produce effects greater
than either drug on its own.
DEC Category: Cannabis
DEC Profile: Horizontal gaze nystagmus not
present; vertical gaze nystagmus not present; lack of convergence present;
pupil size normal to dilated; reaction to light normal to slow; pulse
rate elevated; blood pressure elevated; body temperature normal to elevated.
Other characteristic indicators may include odor of marijuana in car
or on subject’s breath, marijuana debris in mouth, green coating
of tongue, bloodshot eyes, body and eyelid tremors, relaxed inhibitions,
incomplete thought process, and poor performance on field sobriety tests.
Panel’s Assessment of Driving Risks: Low
doses of THC moderately impair cognitive and psychomotor tasks associated
with driving, while severe driving impairment is observed with high doses,
chronic use and in combination with low doses of alcohol The more difficult
and unpredictable the task, the more likely marijuana will impair performance.
References and Recommended Reading:
Aceto MD, Scates SM, Lowe JA, Martin BR. Cannabinoid precipitated withdrawal
by the selective cannabinoid receptor antagonist, SR 141716A. Eur
J Pharmacol 1995;282(1-3): R1-2.
Adams IB, Martin BR. Cannabis: pharmacology and toxicology in animals
and humans. Addiction 1996;91(11):1585-614.
Barnett G, Chiang CW, Perez-Reyes M, Owens SM. Kinetic study of smoking
marijuana. J Pharmacokinet Biopharm 1982;10(5):495-506.
Baselt RC. Drug effects on psychomotor performance. Biomedical
Publications, Foster City, CA; pp 403-415;2001.
Hansteen RW, Miller RD, Lonero L, Reid LD, Jones B. Effects of cannabis
and alcohol on automobile driving and psychomotor tracking. Ann NY
Acad Sci 1976;282:240-56.
Heishman SJ. Effects of abused drugs on human performance: Laboratory
assessment. In: Drug Abuse
Handbook. Karch SB, ed. New York, NY: CRC Press, 1998, p219.
Huestis MA. Cannabis (Marijuana) - Effects on Human Performance and
Behavior. Forens Sci Rev 2002;14(1/2):15-60.
Huestis MA, Sampson AH, Holicky BJ, Henningfield JE, Cone EJ. Characterization
of the absorption phase of marijuana smoking. Clin Pharmacol Ther 1992;52(1):31-41.
Huestis MA, Henningfield JE, Cone EJ. Blood cannabinoids: I. Absorption
of THC and formation of 11-OH-THC and THC-COOH during and after marijuana
smoking. J Anal Toxicol 1992;16(5):276-82.
Huestis MA, Henningfield JE, Cone EJ. Blood cannabinoids II: Models
for the prediction of time of marijuana exposure from plasma concentrations
of ∆-9-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-∆-9-tetrahydrocannabinol
(THC-COOH). J Anal Toxicol 1992;16(5):283-90.
Hunt CA, Jones RT. Tolerance and disposition of tetrahydrocannabinol
in man. J Pharmacol Exp Ther 1980;215(1):35-44.
Klonoff H. Marijuana and driving in real-life situations. Science 1974;186(4161);317-24.
Leirer VO, Yesavage JA, Morrow DG. Marijuana carry-over effects on
aircraft pilot performance. Aviat Space Environ Med 1991;62(3):221-7.
Mason AP, McBay AJ. Cannabis: pharmacology and interpretation of effects. J
Forensic Sci 1985;30(3):615-31.
Physicians’ Desk Reference,
Medical Economics Company,
Montvale, NJ, 2002.
Plasse TF, Gorter RW, Krasnow SH, Lane M, Shepard KV, Wadleigh RG.
Recent clinical experience with Dronabinol. Pharmacol Biochem Behav 1991;40(3):695-700.
Pope HG Jr, Yurgelun-Todd D. The residual cognitive effects of heavy
marijuana use in college students. JAMA 1996;275(7):521-7.
Ramaekers JG, Robbe HW, O’Hanlon JF. Marijuana, alcohol and actual
driving performance. Hum Psychopharmacol 2000;15(7):551-8.
Robbe HW, O'Hanlon JF. Marijuana and actual driving performance. US
Department of Transportation/National Highway Traffic Safety Administration November:
1-133 (1993). DOT HS 808 078.
Smiley A, Moskowitz HM, Ziedman K. Effects of drugs on driving: Driving
simulator tests of secobarbital, diazepam, marijuana, and alcohol. In Clinical
and Behavioral Pharmacology Research Report. J.M. Walsh, Ed. U.S.
Department of Health and Human Services, Rockville, 1985, pp 1-21.
Solowij N, Michie PT, Fox AM. Differential impairment of selective
attention due to frequency and duration of cannabis use. Biol Psychiatry 1995;37(10):731-9.
Thornicroft G. Cannabis and psychosis. Is there epidemiological evidence
for an association? Br J Psychiatry 1990;157:25-33.
Varma VK, Malhotra AK, Dang R, Das K, Nehra R. Cannabis and cognitive
functions: a prospective study. Drug Alcohol Depend 1988;21(2):147-52.
WHO Division of Mental Health and Prevention of Substance Abuse: Cannabis:
a health perspective and research agenda. World Health Organization 1997.