Chemistry, Metabolism, and Toxicology of Cannabis: Clinical Implications

Abstract

Cannabis is one of the most widely abused substances throughout the world. The primary psychoactive constituent of cannabis, delta 9-tetrahydrocannabinol (▵9_THC), produces a myriad of pharmacological effects in animals and humans. Although it is used as a recreational drug, it can potentially lead to dependence and behavioral disturbances and its heavy use may increase the risk for psychotic disorders.
Many studies that endeavor to understand the mechanism of action of cannabis concentrate on pharmacokinetics and pharmacodynamics of cannabinoids in humans. However, there is limited research on the chronic adverse effects and retention of cannabinoids in human subjects.
Cannabis can be detected in body fluids following exposure through active/passive inhalation and exposure through breastfeeding. Cannabis detection is directly dependent on accurate analytical procedures for detection of metabolites and verification of recent use.
In this review, an attempt has been made to summarize the properties of cannabis and its derivatives, and to discuss the implications of its use with emphasis on bioavailability, limit of detection, carry over period and passive inhalation, important factors for detection and diagnosis.

Full text

Birth Order and Sibling Gender Ratio of a Clinical Sample
149
Iranian J Psychiatry 7:4, Fall 2012
Chemistry, Metabolism, and Toxicology of Cannabis:
Clinical Implications
Priyamvada Sharma
1
PhD
Pratima Murthy
1
M.M. Srinivas Bharath
2
1 Centre for Addiction Medicine,
Department of Psychiatry,
National Institute of Mental Health
& Neurosciences (NIMHANS),
Bangalore, India.
2 Department of Neurochemistry,
National Institute of Mental Health
and Neurosciences (NIMHANS),
Bangalore, India.
Corresponding author:
Dr. Priyamvada Sharma
P.B. # 2900, Hosur Road,
Bangalore-560029, Karnataka
state, India
Tel: 91-80-26995364
Fax: 91-80-26564830
Email: ps842010@gmail.com
Cannabis is one of the most widely abused substances throughout the
world. The primary psychoactive constituent of cannabis, delta 9-
tetrahydrocannabinol (Δ
9_
THC), produces a myriad of pharmacological
effects in animals and humans. Although it is used as a recreational drug,
it can potentially lead to dependence and behavioral disturbances and its
heavy use may increase the risk for psychotic disorders.
Many studies that endeavor to understand the mechanism of action of
cannabis concentrate on pharmacokinetics and pharmacodynamics of
cannabinoids in humans. However, there is limited research on the
chronic adverse effects and retention of cannabinoids in human subjects.
Cannabis can be detected in body fluids following exposure through
active/passive inhalation and exposure through breastfeeding. Cannabis
detection is directly dependent on accurate analytical procedures for
detection of metabolites and verification of recent use.
In this review, an attempt has been made to summarize the properties of
cannabis and its derivatives, and to discuss the implications of its use with
emphasis on bioavailability, limit of detection, carry over period and
passive inhalation, important factors for detection and diagnosis.
Key words: Cannabis, Cannabinoids, Mental disorders, Tetrahydrocannabinol
Cannabis has been used for both recreational and
medicinal purposes since several centuries (1-5).
Hashish, a cannabis preparation, was found in Egyptian
mummies (2). Marijuana, Hashish, Bhang and Ganja
are the most widely used illicit drugs in the world.
These psychoactive products are obtained from the
plant Cannabis sativa (Indian hemp) and some of its
subspecies. Cannabis is perceived as a recreational and
harmless drug in some countries, even in leading
medical journals and in some sections of the lay press
(3). However, in most countries, it is categorized as a
drug of abuse and its use is strictly prohibited
(3,4).Marijuana comes from leaves, stems, and dried
flower buds of the cannabis plant. Hashish is a resin
obtained from flowering buds of the hemp plant (5).
Most cannabis preparations are either smoked, or taken
orally after mixing with other substances (See table
1).The prevalence of recreational use of cannabis has
increased markedly worldwide, particularly among
young people. A survey of schoolchildren in United
Kingdom showed that more than 40% of 15-16 year
old and up to 59% of 18-year-old students admitted to
have abused cannabis at least once (6). India, which
has a population of just over a billion, has 62.5million
alcohol users, 8.75 million cannabis users, two million
who use opioids and 0.6 million who use sedatives or
hypnotics. A majority of cannabis users in India start
abusing cannabis in their adolescence and quit after
initial experimentation, while the rest develop
dependence (7,8).Cannabis abuse among younger
subjects is associated with poor academic performance
and increased school dropout. Many studies have
demonstrated that psychosis, violence, aggression,
sexual encounters, accidents, and crime are closely
associated with cannabis abuse (1-3). Cannabis use
have been associated with conduct disorders, attention-
deficit hyperactivity disorder (ADHD), and learning
disorders. Evidence suggests that cannabis dependence
in young people predicts increased risk of using other
illicit drugs, under performance in school, and
reporting of associated psychotic symptoms(7,8).
Interestingly, the biomedical benefits of cannabis have
also been recognized from millennia (5) and it has been
shown to have therapeutic potential as an appetite
stimulant, antiemetic and antispasmodic (9). Similarly,
other clinical conditions where the potential use of
cannabis has been suggested include epilepsy,
glaucoma and asthma (10).
Chemical Components of Cannabis
The cannabis plant contains more than 421 chemicals
of which 61 are cannabinoids (9,10) (Figure 1).
Interestingly, more than 2000 compounds are produced
by pyrolysis during smoking of cannabis (10,11) and
they are represented by different classes of chemicals
including nitrogenous compounds, amino acids,
hydrocarbons, sugar, terpenes and simple fatty acids.
Original Article
Iran J Psychiatry 2012; 7:4: 149-156

Sharma, Murthy, Bharath
150
Iranian J Psychiatry 7:4, Fall 2012
These compounds altogether contribute to the unique
pharmacological and toxicological properties of
cannabis. A list of the major cannabinoids present in
cannabis is listed in table 2. Among the listed
compounds, delta
9
-tetrahydrocannabinol (Δ
9_
THC) is
considered as the most psychoactive component
contributing to the behavioral toxicity of cannabis (11).
The aim of the current review is to discuss the
properties of cannabinoids, primarily Δ
9_
THC and its
metabolites and the clinical implications thereof.
Pharmacological Actions of Cannabinoids
Δ
9_
THC has a tri-cyclic 21- carbon structure without
nitrogen and with two chiral centers in trans-
configuration (9). Δ
9_
THC is volatile viscous oil with
high lipid solubility and low aqueous solubility and a
pKa of 10.6. The metabolism of Δ
9_
THC is shown in
figure (2). Δ
9_
THC is present in cannabis as a mixture
of mono-carboxylic acids, which gets readily and
efficiently de-carboxylated upon heating (9). It
decomposes when exposed to air, heat or light (13) and
readily binds to glass and plastic. Therefore, Δ
9_
THC is
usually stored in basic or organic solvents in amber
silicate glassware to avoid loss during analytical
procedures (14).
Two hypotheses have been proposed to explain the
mechanism of in vivo action of Δ
9_
THC. According to
the first, Δ
9_
THC which is secreted as a glucuronide
acts via non-specific interactions with cellular and
organelle membranes in the brain supporting a
membrane perturbation mechanism (15,16). The
second hypothesis suggests that Δ
9_
THC interacts with
specific cannabinoid receptors (10,17,18). Delineating
a single mechanism of action is very difficult because
molecular analysis has demonstrated Δ
9_
THC to act on
several intracellular targets including opioid and
benzodiazepine receptors, prostaglandin synthetic
pathway, protein and nucleic
acid metabolism (19,20). Further, cannabinoids inhibit
macromolecular metabolism (21,22) in a dose-
Figure 1. Chemical Components of Cannabis
dependent manner and have a wide range of effects on
enzyme systems, hormone secretion and
neurotransmitters (18,21-23). The evidence of
numerous and diffuse in vivo effects support the non-
specific interaction hypothesis for THC.
Cannabinoids exert various physiological effects by
interacting with specific cannabinoid receptors (CB
receptors) present in the brain and periphery (24). CB1
receptors in the brain (25) are particularly concentrated
in anatomical regions associated with cognition,
memory, reward, anxiety, pain sensory perception,
motor co-ordination and endocrine function (26,27).
CB2 receptors are localized to the spleen and other
peripheral tissues (28). These receptors may play a role
in the immune suppressive actions of cannabinoids.
The physiological ligands for these receptors appear to
be a family of anandamides (29) which are derivatives
of arachidonic acid, related to prostaglandins. There is
an endogenous system of cannabinoid receptors and
anandamides, which normally modulate neuronal
activity by its effect on cyclic-AMP dynamics and
transport of Ca++ and K+ ions (25,30-32). Although
the physiological implications of these ligand-receptor
interactions are not completely understood, it is
suggested to be connected with opioids, GABAergic,
dopaminergic, noradrenergic, serotonergic, cholinergic,
glucocorticoid and prostaglandin systems
(26,28,30,33). The many effects of exogenous
cannabinoids derived from cannabis result from
perturbation of this complex system, but the exact
mechanism is not clear.
Behavioral and Physiological Effects of
Cannabis
Cannabis is known to have behavioral and
physiological effects (27-29).Behavioral effects include
feeling of euphoria, relaxation, altered time perception,
lack of concentration and impaired learning.
Memory and mood changes such as panic and paranoid
Figure 2. Metabolic route of Δ9-
tetrahydrocannabinol (Δ
9_
THC), its primary active
metabolite 11-hydroxy-Δ
9
-tetrahydrocannabinol (11-
OH-THC) and the primary inactive metabolite, 11-
nor-9-carboxy-Δ 9-tetrahydrocannabinol(THC-
COOH ) 12.

Chemistry,Metabolism, and Toxicology of Cannabis
151
Iranian J Psychiatry 7:4, Fall 2012
Table 1. Different Preparations of Cannabinoids (23)
Table 2. Cannabinoids and their Properties (11)
Psychoactive components
Name
Effects
Δ
9
-tetrahydrocannabinol
(Δ
9_
THC)
Main psychoactive component; causes psychological and behavioral effects
Δ
8_
tetrahydrocannabinol( Δ
8-
THC)
Less psychoactive than Δ
9
-THC.
Cannabinol(CBN)
Less powerful than Δ
9_
THC
11-hydroxy-Δ
9_
THC (11-OH-THC)
Liable for psychological effects of cannabis
Anandamide (arachidonylethanolamide)
Imitates activity of Δ
9_
THC and other cannabinoids that interact with
cannabinoid receptors.
Non-psychoactive components
Cannabidiol (CBD) Lacks psychoactive properties has anticonvulsant action.
Cannabichromene
Not psychoactive
(-)Δ
8-
THC-11-oic acid)
Not psychoactive has analgesic activity.
reactions have also been reported. Physiological effects
include rapid changes in heart rate and diastolic blood
pressure, conjunctival suffusion, dry mouth and throat,
increased appetite, vasodilatation and decreased
respiratory rate (31,32). Cannabis also affects the
immune and endocrine system; and its abuse is
associated with lung damage and EEG alterations
(28,30,33, 34,35).
Cannabis Dependence and Tolerance
Cannabinoids appear to affect the same reward systems
as alcohol, cocaine and opioids (34).Evidence for
cannabis dependence is now available from
epidemiological studies (6,8) of long-term users
(58,59), clinical populations (75,77) and controlled
experiments on withdrawal and tolerance
(35,36,37,38). Tolerance to cannabis can occur in
relation to mood, psychomotor performance, sleep,
arterial pressure, body temperature, and antiemetic
properties. The critical elements of cannabis
dependence include preoccupation with its use,
compulsion to use and relapse or recurrent use of the
substance (39). Over 50% of cannabis users appear to
have ‘impaired control’ over their use (40).Symptoms
such as irritability, anxiety, craving and disrupted sleep
have been reported in 61-96% of cannabis users during
abstinence (36,41,42,43).
Psychiatric Conditions Associated with Cannabis
Abuse
In addition to producing dependence, cannabis use is
associated with a wide range of psychiatric disorders
(44).While there is a clear relationship between the use
of cannabis and psychosis, different hypotheses for the
same have been propounded. One such, which
describes psychosis occurring exclusively with
cannabis use has limited evidence. There is strong
evidence that cannabis use may precipitate
schizophrenia or exacerbate its symptoms. There is
also reasonable evidence that cannabis use exacerbates
the symptoms of psychosis (37).
Heavy cannabis(30-50mg oral and 8-30 mg smoked)
use can specifically cause a mania-like psychosis and
more generally act as a precipitant for manic relapse in
bipolar patients (37,44, 45). It is possible that cannabis
exposure is a contributing factor that interacts with
other known and unknown (genetic and environmental)
factors culminating in psychiatric illness (46). It is
noticed that in many developed countries, persons with
severe mental disorders are more likely to use, abuse,
and become dependent on psychoactive substances
especially cannabis as compared to the general
population (47,48).The same phenomenon has not been
established so far in India.
Pharmacokinetics of Cannabis
Δ
9
-THC which is highly lipophilic get distributed in
adipose tissue, liver, lung and spleen (12,49,50).
Hydroxylation of Δ
9
-THC generates the psychoactive
compound 11-hydroxy Δ
9_
Tetra hydrocannabinol (11-
OH-THC) and further oxidation generates the inactive
11-nor-9-carboxy-Δ
9
-tetrahydrocannbinol
(THCCOOH). THCCOOH is the compound of interest
for diagnostic purposes. It is excreted in urine mainly
as a glucuronic acid conjugate (12). Δ
9
-THC is
rapidly absorbed through lungs after inhalation. It
quickly reaches high concentration in blood (51).
Approximately 90% of THC in blood is circulated in
plasma and rest in red blood cells. Following
inhalation, Δ
9
-THC is detectable in plasma within
seconds after the first puff and the peak plasma
concentration is attained within 3-10 minutes (51-55).
However, the bioavailability of Δ
9
-THC varies
according to the depth of inhalation, puff duration and
breath-hold. Considering that approximately 30% of
THC is assumed to be destroyed by pyrolysis, the
systemic bioavailability of THC is ~23-27 % for heavy
users (18,56) and 10-14 % for occasional users (48,49).
No.
Form
Source
Methods of abuse
1.
Marijuana/Charas/ Ganja Dried leaves, stalks, flower and seeds Smoked as joint
2.
Bhang Fresh leaves and stalk
Mixed with food items and
consumed orally
3.
Hashish oil
Leaves, seeds, stem and flowers soaked
in oil/solvent
Smoked as joint or consumed
orally

Sharma, Murthy, Bharath
152
Iranian J Psychiatry 7:4, Fall 2012
Maximum Δ
9
-THC plasma concentration was observed
approximately 8 minutes after onset of smoking, while
11-OH-THC peaked at 15 minutes and THC-COOH at
81 minutes. This Δ
9
-THC concentration rapidly
decreases to 1-4 ng/mL within 3-4 hour (57).
In comparison to smoking and inhalation, after oral
ingestion, systemic absorption is relatively slow
resulting in maximum Δ
9
-THC plasma concentration
within 1-2 hours which could be delayed by few hours
in certain cases (56, 58). In some subjects, more than
one plasma peak was observed (52, 59). Extensive liver
metabolism probably reduces the oral bioavailability of
Δ
9
-THC by 4-12% (53). After oral administration,
maximum Δ
9
-THC plasma concentration was 4.4-11
ng/mL for 20 mg (50) and 2.7-6.3 ng/mL for 15 mg
(58, 60). Much higher concentration of 11-OH THC
was produced after ingestion than inhalation (56,
58).Following assimilation via the blood, Δ
9
-THC
rapidly penetrates in to fat tissues and highly
vascularized tissues including brain and muscle
resulting in rapid decrease in plasma concentration (61,
63).This tissue distribution is followed by slow
redistribution of it from the deep fat deposits back into
the blood stream .
It should be noted that the residual Δ
9
-THC levels are
maintained in the body for a long time following abuse.
The half- life of it for an infrequent user is 1.3 days and
for frequent users 5-13 days (64). After smoking a
cigarette containing 16-34 mg of Δ9-THC, THC-
COOH is detectable in plasma for 2-7 days (57, 65). A
clinical study carried out among 52 volunteers showed
that THC-COOH was detectable in serum from 3.5 to
74.3 hours. Initial concentration was between 14-49
ng/mL(65). This was considerably less than the THC-
COOH detection time of 25 days in a single chronic
user (66).
Metabolism and Elimination of Δ
9
-THC
Δ
9
-THC is metabolized in the liver by microsomal
hydroxylation and oxidation catalyzed by enzymes of
cytochrome P450 (CYP) complex. The average
plasma clearance rates have been reported to be 11.8±
3 L/hour for women and 14.9 ±3.7 L/hour for men
(59). Others have determined approximately 36 L/hour
for naïve cannabis users and 60 L/hour for regular
cannabis users12.
More than 65% of cannabis is excreted in the feces and
approximately 20% is excreted in urine (58).Most of
the cannabis (80-90%) is excreted within 5 days as
hydroxylated and carboxylated metabolites (67). There
are eighteen acidic metabolites of cannabis identified in
urine68 and most of these metabolites form a conjugate
with glucuronic acid, which increases its water
solubility. Among the major metabolites (Δ
9
-THC,11-
OH-THC, and THCCOOH), THCCOOH is the primary
glucuronide conjugate in urine, while 11-OH-THC is
the predominant form in feces (51,69). Since Δ
9
-THC
is extremely soluble in lipids, it results in tubular re-
absorption, leading to low renal excretion of
unchanged drug. Urinary excretion half-life of
THCCOOH was observed to be approximately 30
hours after seven days and 44-60 hours after twelve
days of monitoring (69,70). After smoking
approximately 27 mg of Δ
9
-THC in a cigarette, 11-OH-
THC peak concentration was observed in the urine
within two hours in the range of 3.2-53.3 ng/mL,
peaking at 77.0±329.7 ng/mL after 3 hours and
THCCOOH peaking at 179.4ng/mL± 146.9 after 4
hours (71, 72).
Detection and Analysis of Cannabinoids by Different
Analytical Techniques
Measurement of cannabinoids is necessary for
pharmacokinetic studies, drug treatment, workplace
drug testing and drug impaired driving investigations
(73).Because of increasing use of cannabis, developing
a whole range of efficient testing methods has become
essential. Cannabinoids can be detected in saliva,
blood, urine, hair and nail using various analytical
techniques, including immunoassays (EMIT®, Elisa,
fluorescence polarization, radioimmunoassay) (74).
Various chromatographic techniques such as Thin
Layer Chromatography (TLC) (Foltz and Sunshine,
1990), High Performance Thin layer Chromatography
(HPTLC) (72), Gas Chromatography-Mass
Spectrometry (GC-MS) (79), high performance liquid
chromatography-Mass Spectrometry (HPLC- MS) (79)
are reliable in detection and quantitation of various
cannabis metabolites .
Urine is the preferred sample because of higher
concentration and longer detection time of metabolites
in it. Moreover, urine can easily be sampled. Apart
from cut off concentration, sensitivity and specificity
of assay other factors like route of administration,
amount of cannabinoids absorbed, body fat contents
rate of metabolism and excretion, degree of dilution
and time of specimen collection also influence
delectability of Δ
9_
THC and its metabolites (12,72).
The cut off value for detection of cannabinoids
recommended by the Substance Abuse and Mental
Health Services Administration (SAMHSA)” and
European threshold of 50 ng/mL was found to be
consistent with recent or heavy cannabis abuse (51,73).
Lower concentrations of THCA can be associated with
occasional use, carry over period or probable cannabis
exposure (70). Immunoassay is adopted as a
preliminary method in the drug testing program (78).
However, false negative and false positive results occur
from structurally related drugs that are recognized by
the antibodies or occasionally artifacts such as
adulterants affecting pH, detergents and other
surfactants (73, 77). For this reason, any positive result
using immunoassay must be confirmed by
chromatographic techniques (75,78).Cannabis has a
long half-life in humans (67 days) (57). In chronic
cannabis users, it is particularly difficult to determine
whether a positive result for cannabis represents a new
episode of drug use or continued excretion of residual
drug (62). Algorithmic models have been devised to
determine whether THC levels represent new use or the

Chemistry,Metabolism, and Toxicology of Cannabis
153
Iranian J Psychiatry 7:4, Fall 2012
carry-over from previous use (62, 64). However, these
models are not very accurate in discriminating new use
and carry-over in chronic users (66).
Interactions of Cannabis with other Drugs
of Abuse
Interaction of chronic marijuana with other drugs of
abuse has not been studied in detail. It has been
demonstrated that there is no cross-tolerance between
LSD and Δ
9_
THC (80, 81).Studies are required to
understand and compare the abuse potential of
marijuana in isolation and in combination with other
drugs and its adverse effects on performance (80, 81).
A unique opportunity is available in India for studying
various facts of cannabis uses since it is possible to
locate people that are abusing cannabis continuously in
one form or other over several years, both in isolation,
or in combination with other drugs. In such subjects,
the pharmacology and the interaction of cannabis with
other drugs can be studied (26, 82, 83).
Effects of Indirect Cannabis Exposure
There can be indirect exposure to cannabis through
passive smoking. It has to be noted that from
approximately 50% of Δ
9_
THC that survives pyrolysis
during the smoking, a major portion (16-53%) is
delivered to the smoker, while a lesser amount (6-53%)
is released into the air as side stream (57). A passive
inhaler in the proximity of the smoker is involuntarily
subjected to inhalation of Δ
9_
THC smoke. In a study,
five drugs-free male volunteers with a history of abuse
and two marijuana naïve subjects were inactively
exposed to the side stream of marihuana smoke81.
Analysis of Δ
9_
THC concentrations in that study
confirms that the detection time increased according to
the passive dose. The Δ
9_
THC absorbed by the passive
smoking depends on several features related to the
condition under which passive inhalation took place
(viz. environment, duration, Δ
9_
THC content, number
of smoked joints). There is now a consensus that
positive results due to passive inhalation are possible
(84) .
In an interesting study from Pakistan, major
metabolites of cannabis were found in the milk of cows
which had grazed upon naturally growing cannabis
vegetation (73). Children fed on such milk showed
metabolites of cannabis in the urine, suggesting passive
consumption through milk (83).
Δ
9_
THC is secreted into human breast milk in moderate
amounts (85, 86,87). A feeding infant would ingest
0.8% of weight adjusted maternal intake of one joint
(86-88). Another point to be considered is that cannabis
has an effect on the quality and quantity of the breast
milk (85, 86). It could inhibit lactation by inhibiting
prolactin production via direct action on the mammary
gland. However, this data has not been confirmed in
human subjects. Clinical and pharmacokinetic data
indicate that cannabis use is dangerous during breast-
feeding for the child (89). Δ
9_
THC can accumulate in
human breast milk and infants exposed to marijuana
through their mother`s milk will excreteΔ
9_
THC in
their urine during the first 2-3 weeks (88). Due to the
intake of cannabis or other drugs (psychotropic,
antiepileptic) by mothers, infant children depending on
breast-feeding might exhibit physiological effects such
as sedation or reduced muscular tone and other adverse
effects (85).
Conclusions
The recreational use of cannabis among youth has
increased worldwide over the past few decades.
Despite the demonstration of some bio-medical
applications, cannabis abuse is associated with
different disease conditions including probable risk of
developing psychiatric disorders. Hence, there have
been significant efforts to identify the toxic factors in
cannabis and establish the role of component causes
that underlie individual susceptibility to cannabinoid-
related psychotic disorders. Secondly, it has
necessitated the development of efficient methods to
identify and quantify various cannabis metabolites
from different body fluids. While immunoassay is
adopted as a preliminary test, advanced
chromatographic techniques are used for confirmation.
Research in the future should focus on the molecular
changes induced by acute and long-term exposure to
cannabis and the contribution of individual
psychoactive components.
Conflict of interest
All the authors declare that they have no conflicts of
interest.
Contributors
PS conducted the literature searches and wrote the first
draft of the manuscript. All authors contributed to and
have approved the final manuscript.
References
1. Brecher EM. The Consumers Union Report -
Licit and Illicit Drugs. Little, Brown & Co 1972.
2. Balabanova S, Parsche F,Pirsig W. First
identification of drugs in Egyptian mummies.
Naturwissenschaften 1992; 79: 358.
3. Grotenhermen F. The toxicology of cannabis
and cannabis prohibition. Chem Bio divers
2007; 4: 1744-1769.
4. Raharjo TJ, Verpoorte R. Methods for the
analysis of cannabinoids in biological
materials: a review. Phytochem Anal 2004; 15:
79-94.
5. Hazekamp A, Grotenhermen F. Review on
Clinical Studies with Cannabis and
Cannabinoids 2005-2009. Cannabinoids 2010;
5:1-21.
6. Miller PM, Plant M. Drinking, smoking, and
illicit drug use among 15 and 16 year olds in
the United Kingdom. BMJ 1996; 313: 394-397.
7. Hall WD. Cannabis use and the mental health
of young people. Aust N Z J Psychiatry 2006;
40: 105-113.

Sharma, Murthy, Bharath
154
Iranian J Psychiatry 7:4, Fall 2012
8. Malhotra A, Parthasarathy B. Cannabis Use
and Performance in Adolescents. J Indian
Assoc Child AdolescMent Health 2006; 2:59-
67.
9. Mechoulam R. Plant cannabinoids: a
neglected pharmacological treasure trove. Br J
Pharmacol 2005; 146: 913-915.
10. Appendino G, Chianese G and Taglialatela-
Scafati O. Cannabinoids: occurrence and
medicinal chemistry. Curr Med Chem 2011;
18: 1085-1099.
11. Perez-Reyes M, White WR, McDonald SA,
Hicks RE, Jeffcoat AR and Cook CE. The
pharmacologic effects of daily marijuana
smoking in humans. Pharmacol Biochem
Behav 1991; 40: 691-694.
12. Musshoff F, Madea B. Review of biologic
matrices (urine, blood, hair) as indicators of
recent or ongoing cannabis use. Ther Drug
Monit 2006; 28: 155-163.
13. Skopp G, Potsch L. An investigation of the
stability of free and glucuronidated 11-nor-
delta9-tetrahydrocannabinol-9-carboxylic acid
in authentic urine samples. J Anal Toxicol
2004; 28: 35-40.
14. Fenimore DC, Davis CM, Whitford JH,
Harrington CA. Vapor phase silylation of
laboratory glassware. Analytical Chemistry
1976;48: 2289-90.
15. Onaivi ES, Ishiguro H, Gong JP, Patel S,
Perchuk A, Meozzi PA, et al. Discovery of the
presence and functional expression of
cannabinoid CB2 receptors in brain. Ann N Y
Acad Sci 2006; 1074: 514-536.
16. Onaivi ES. Neuropsychobiological evidence for
the functional presence and expression of
cannabinoid CB2 receptors in the brain.
Neuropsychobiology 2006; 54: 231-246.
17. Chaperon F, Thiebot MH. Behavioral effects of
cannabinoid agents in animals. Crit Rev
Neurobiol 1999; 13: 243-281.
18. Pertwee RG. Pharmacological actions of
cannabinoids.Handb Exp Pharmacol 2005: 1-
51.
19. Burstein S, Hunter SA, Sedor C, Shulman S.
Prostaglandins and cannabis--IX. Stimulation
of prostaglandin E2 synthesis in human lung
fibroblasts by delta 1-
tetrahydrocannabinol.BiochemPharmacol
1982; 31: 2361-2365.
20. Grotenhermen F. Pharmacokinetics and
pharmacodynamics of cannabinoids. Clin
Pharmacokinet 2003; 42: 327-360.
21. 21-Bloom AS. Effect of delta9-
tetrahydrocannabinol on the synthesis of
dopamine and norepinephrine in mouse brain
synaptosomes.J Pharmacol ExpTher 1982;
221: 97-103.
22. Chakravarty I, Sheth AR and Ghosh JJ.Effect
of acute delta9-tetrahydrocannabinol treatment
on serum luteinizing hormone and prolactin
levels in adult female rats.FertilSteril 1975; 26:
947-948.
23. Mendelson JH, Mello NK. Effects of marijuana
on neuroendocrine hormones in human males
and females.NIDA Res Monogr 1984; 44: 97-
114.
24. Munro S, Thomas KL, Abu-Shaar M. Molecular
characterization of a peripheral receptor for
cannabinoids. Nature 1993; 365: 61-65.
25. Grotenhermen F. Cannabinoids. Curr Drug
Targets CNS NeurolDisord 2005; 4: 507-530.
26. Adams IB and Martin BR. Cannabis:
pharmacology and toxicology in animals and
humans. Addiction 1996; 91: 1585-1614.
27. Herkenham M, Lynn AB, Little MD, Johnson
MR, Melvin LS, de Costa BR, et al.
Cannabinoid receptor localization in brain.
Proc Natl Acad Sci U S A 1990; 87: 1932-
1936.
28. Gardner E, Lowinson JH. Marijuana's
interaction with brain reward systems: update
1991. Pharmacol Biochem Behav 1991; 40:
571-580.
29. Devane WA, Hanus L, Breuer A, Pertwee RG,
Stevenson LA, Griffin G, et al. Isolation and
structure of a brain constituent that binds to
the cannabinoid receptor. Science 1992; 258:
1946-1949.
30. Gardner EL, Vorel SR. Cannabinoid
transmission and reward-related events.
Neurobiol Dis 1998; 5: 502-533.
31. Matsuda LA, Lolait SJ, Brownstein MJ, Young
AC and Bonner TI. Structure of a cannabinoid
receptor and functional expression of the
cloned cDNA. Nature 1990; 346: 561-564.
32. Howlett AC, Bidaut-Russell M, Devane WA,
Melvin LS, Johnson MR, Herkenham M. The
cannabinoid receptor: biochemical, anatomical
and behavioral characterization. Trends
Neurosci 1990; 13: 420-423.
33. Musty RE, Reggio P, Consroe P. A review of
recent advances in cannabinoid research and
the 1994 International Symposium on
Cannabis and the Cannabinoids. Life Sci
1995; 56: 1933-1940.
34. Wickelgren I. Marijuana: harder than thought?
Science 1997; 276: 1967-1968.
35. Ashton CH. Pharmacolgy and effect of
cannabis:A brief review. Br J Psychiatry
2003;45:182-188.
36. Budney AJ, Hughes JR. The cannabis
withdrawal syndrome. CurrOpin Psychiatry
2006; 19: 233-238.
37. Maykut MO. Health consequences of acute
and chronic marihuana use.
ProgNeuropsychopharmacol Biol Psychiatry
1985; 9: 209-238.
38. Jones RT. Cannabis tolerance and
dependence . In. Fehr KO, Kalant H eds
.Cannabis and Health Hazards. Toronto:
Toronto Addiction Research Foundation; 1983.
39. Miller NS, Gold MS. The diagnosis of
marijuana (cannabis) dependence. J Subst
Abuse Treat 1989; 6: 183-192.
40. Jain R, Balhara YP. Neurobiology of cannabis
addiction. Indian J Physiol Pharmacol 2008;
52: 217-232.
41. Haney M. The marijuana withdrawal
syndrome: diagnosis and treatment. Curr
Psychiatry Rep 2005; 7: 360-366.
42. Vandrey R, Budney AJ, Kamon JL, Stanger C.
Cannabis withdrawal in adolescent treatment

Chemistry,Metabolism, and Toxicology of Cannabis
155
Iranian J Psychiatry 7:4, Fall 2012
seekers. Drug Alcohol Depend 2005; 78: 205-
210.
43. Hall W, Degenhardt L, Teesson M. Cannabis
use and psychotic disorders: an update. Drug
Alcohol Rev 2004; 23: 433-443.
44. Hall W, Degenhardt L, Teesson M. Cannabis
use and psychotic disorders: an update. Drug
Alcohol Rev 2004; 23: 433-443.
45. Kulhalli V, Isaac M and Murthy P. Cannabis-
related psychosis: Presentation and effect of
abstinence. Indian J Psychiatry 2007; 49: 256-
261.
46. Leweke FM, Koethe D. Cannabbis and
Psychiatric disoreder: it is not only addiction
.Addiction Biol 2008;13:264-275.
47. Sewell RA, Skosnik PD, Garcia-Sosa I,
Ranganathan M, D'Souza DC. [Behavioral,
cognitive and psychophysiological effects of
cannabinoids: relevance to psychosis and
schizophrenia]. Rev Bras Psiquiatr 2010; 32
Suppl 1: S15-30.
48. Castle D, Murray R. Marijuana and madness,
First edition. United Kingdom: Cambridge
university press;2004.
49. McBurney LJ, Bobbie BA, Sepp LA. GC/MS
and EMIT analyses for delta 9-
tetrahydrocannabinol metabolites in plasma
and urine of human subjects. J Anal Toxicol
1986; 10: 56-64.
50. Chiarotti M, Costamagna L. Analysis of 11-nor-
9-carboxy-delta(9)-tetrahydrocannabinol in
biological samples by gas chromatography
tandem mass spectrometry (GC/MS-MS).
Forensic SciInt 2000; 114: 1-6.
51. Vandevenne M, Vandenbussche H, Verstraete
A. Detection time of drugs of abuse in urine.
ActaClinBelg 2000; 55: 323-333.
52. Law B, Mason PA, Moffat AC, Gleadle RI, King
LJ. Forensic aspects of the metabolism and
excretion of cannabinoids following oral
ingestion of cannabis resin. J Pharm
Pharmacol 1984; 36: 289-294.
53. Owens SM, McBay AJ, Reisner HM, Perez-
Reyes M. 125I radioimmunoassay of delta-9-
tetrahydrocannabinol in blood and plasma with
a solid-phase second-antibody separation
method. Clin Chem 1981; 27: 619-624.
54. Wahlqvist M, Nilsson IM, Sandberg F, Agurell
S. Binding of delta-1-tetrahydrocannabinol to
human plasma proteins. Bio chem Pharmacol
1970; 19: 2579-2584.
55. Widman M, Agurell S, Ehrnebo M, Jones G.
Binding of (+)- and (minus)-delta-1-
tetrahydrocannabinols and (minus)-7-hydroxy-
delta-1-tetrahydrocannabinol to blood cells and
plasma proteins in man. J Pharm Pharmacol
1974; 26: 914-916.
56. Hollister LE, Gillespie HK, Ohlsson A, Lindgren
JE, Wahlen A, Agurell S. Do plasma
concentrations of delta 9-tetrahydrocannabinol
reflect the degree of intoxication? J Clin
Pharmacol 1981; 21: 171S-177S.
57. Huestis MA, Henningfield JE, Cone EJ. Blood
cannabinoids. I. Absorption of THC and
formation of 11-OH-THC and THCCOOH
during and after smoking marijuana. J Anal
Toxicol 1992; 16:276-82.
58. Lemberger L, Axelrod J, Kopin IJ. Metabolism
and disposition of delta-9-tetrahydrocannabinol
in man. Pharmacol Rev 1971; 23: 371-380.
59. Karschner EL, Schwilke EW, Lowe RH, Darwin
WD, Herning RI, Cadet JL, et al. Implications
of plasma Delta9-tetrahydrocannabinol, 11-
hydroxy-THC, and 11-nor-9-carboxy-THC
concentrations in chronic cannabis smokers. J
Anal Toxicol 2009; 33: 469-477.
60. Kogan NM, Mechoulam R. Cannabinoids in
health and disease. Dialogues Clin Neurosci
2007; 9: 413-430.
61. Haggerty GC, Deskin R, Kurtz PJ, Fentiman
AF, Leighty EG. The pharmacological activity
of the fatty acid conjugate 11-palmitoyloxy-
delta 9-tetrahydrocannabinol. Toxicol Appl
Pharmacol 1986; 84: 599-606.
62. Musshoff F, Madea B. Review of biologic
matrices (urine, blood, hair) as indicators of
recent or ongoing cannabis use. Ther Drug
Monit 2006; 28: 155-163.
63. Huestis MA. Pharmacokinetics and
metabolism of the plant cannabinoids, delta9-
tetrahydrocannabinol, cannabidiol and
cannabinol. Handb Exp Pharmacol 2005: 657-
690.
64. Smith-Kielland A, Skuterud B, Morland J.
Urinary excretion of 11-nor-9-carboxy-delta9-
tetrahydrocannabinol and cannabinoids in
frequent and infrequent drug users. J Anal
Toxicol 1999; 23: 323-332.
65. Reiter A, Hake J, Meissner C, Rohwer J,
Friedrich HJ, Oehmichen M. Time of drug
elimination in chronic drug abusers. Case
study of 52 patients in a "low-step"
detoxification ward. Forensic SciInt 2001; 119:
248-253.
66. Lowe RH, Abraham TT, Darwin WD, Herning
R, Cadet JL, Huestis MA. Extended urinary
Delta9-tetrahydrocannabinol excretion in
chronic cannabis users precludes use as a
biomarker of new drug exposure. Drug Alcohol
Depend 2009; 105: 24-32.
67. Goulle JP, Saussereau E, Lacroix C. [Delta-9-
tetrahydrocannabinol pharmacokinetics]. Ann
Pharm Fr 2008; 66: 232-244.
68. Halldin MM, Andersson LK, Widman M,
Hollister LE. Further urinary metabolites of
delta 1-tetrahydrocannabinol in
man.Arzneimittelforschung 1982; 32: 1135-
1138.
69. Huestis MA, Cone EJ. Urinary excretion half-
life of 11-nor-9-carboxy-delta9-
tetrahydrocannabinol in humans.Ther Drug
Monit 1998; 20: 570-576.
70. Kelly P, Jones RT. Metabolism of
tetrahydrocannabinol in frequent and
infrequent marijuana users. J Anal Toxicol
1992; 16: 228-235.
71. Johansson EK, Hollister LE, Halldin MM.
Urinary elimination half-life of delta-1-
tetrahydrocannabinol-7-oic acid in heavy
marijuana users after smoking.NIDA Res
Monogr 1989; 95: 457-458.
72. Manno JE, Manno BR, Kemp PM, Alford DD,
Abukhalaf IK, McWilliams ME, et al. Temporal
indication of marijuana use can be estimated

Sharma, Murthy, Bharath
156
Iranian J Psychiatry 7:4, Fall 2012
from plasma and urine concentrations of
delta9-tetrahydrocannabinol, 11-hydroxy-
delta9-tetrahydrocannabinol, and 11-nor-
delta9-tetrahydrocannabinol-9-carboxylic acid.
J Anal Toxicol 2001; 25: 538-549.
73. Altunkaya D, Clatworthy AJ, Smith RN, Start
IJ. Urinary cannabinoid analysis: comparison
of four immunoassays with gas
chromatography-mass spectrometry. Forensic
Sci Int 1991; 50: 15-22.
74. Fraser AD, Worth D. Monitoring urinary
excretion of cannabinoids by fluorescence-
polarization immunoassay: a cannabinoid-to-
creatinine ratio study. Ther Drug Monit 2002;
24: 746-750.
75. Kerrigan S, Phillips Jr WH, Jr. Comparison of
ELISAs for opiates, methamphetamine,
cocaine metabolite, benzodiazepines,
phencyclidine, and cannabinoids in whole
blood and urine. Clin Chem 2001; 47: 540-547.
76. Fraser AD, Worth D. Urinary excretion profiles
of 11-nor-9-carboxy-delta9-
tetrahydrocannabinol and 11-hydroxy-delta9-
THC: cannabinoid metabolites to creatinine
ratio study IV. Forensic SciInt 2004; 143: 147-
152.
77. Sharma P, Bharath MM and Murthy P.
Qualitative high performance thin layer
chromatography (HPTLC) analysis of
cannabinoids in urine samples of Cannabis
abusers. Indian J Med Res 2010; 132: 201-
208.
78. Huestis MA, Mitchell JM and Cone EJ.
Detection times of marijuana metabolites in
urine by immunoassay and GC-MS. J Anal
Toxicol 1995; 19: 443-449.
79. Hidvegi E, Somogyi GP. Detection of
cannabigerol and its presumptive metabolite in
human urine after Cannabis
consumption.Pharmazie 2010; 65: 408-411.
80. Hollister LE. Interactions of cannabis with
other drugs in man.NIDA Res Monogr 1986;
68: 110-116.
81. Ramsay M,Percy A.Drug misuse declared:
results of the 1994 British Crime Survey.
London:Home office; 1996.
82. Huestis MA.Human cannabinoid
pharmacokinetics. ChemBiodivers 2007; 4:
1770-1804.
83. Kalant OJ. Report of the Indian Hemp Drugs
Commission, 1893-94: a critical review. Int J
Addict 1972; 7: 77-96.
84. Niedbala RS, Kardos KW, Fritch DF, Kunsman
KP, Blum KA, Newland GA, et al. Passive
cannabis smoke exposure and oral fluid
testing. II. Two studies of extreme cannabis
smoke exposure in a motor vehicle. J Anal
Toxicol 2005; 29: 607-615.
85. Garry A, Rigourd V, Amirouche A, Fauroux V,
Aubry S, Serreau R. Cannabis and
breastfeeding. J Toxicol 2009; 2009: 1-5.
86. Perez-Reyes M, Wall ME .Presence of delta9-
tetrahydrocannabinol in human milk. N Engl J
Med 1982; 307: 819-820.
87. Fernandez-Ruiz J, Gomez M, Hernandez M,
de Miguel R, Ramos JA. Cannabinoids and
gene expression during brain development.
Neurotox Res 2004; 6: 389-401.
88. Liston J. Breastfeeding and the use of
recreational drugs--alcohol, caffeine, nicotine
and marijuana. Breastfeed Rev 1998; 6: 27-30.