Health Canada info on medical marijuana

Information for Health Care Professionals
(Revised)
Marihuana (marijuana, cannabis)
dried plant for administration by ingestion or other means
Psychoactive agent
Prepared by Health Canada, July 2003
Presented in present format by CPhA, June 2004
This document has been prepared for the Drug Strategy and Controlled
Substances Programme to provide information on the use of marihuana for
medical purposes. Marihuana is not an approved therapeutic product and
the provision of this information should not be interpreted as an
endorsement of the use of this product, or marihuana generally, by Health
Canada.
Despite the similarity of format, it is not a Drug Product Monograph, which is
a document which would be required if the product were to receive a Notice of
Compliance authorizing its sale in Canada. This document is a summary of
peer reviewed literature and international reviews concerning potential
therapeutic uses and harmful effects of marihuana. It is not meant to be
comprehensive and should be used as a complement to other reliable sources
of information.
This document should not be construed as expressing conclusions from
Health Canada about the appropriate use of marihuana for medical
purposes.
Marihuana (marijuana, cannabis) is not an approved therapeutic
substance in Canada and no marihuana product has been issued a
notice of compliance by Health Canada authorizing sale in
Canada.
Health
Canada
Santé
Canada
TABLE OF CONTENTS
Page
1.0 Chemistry.................................................................................................................................1
1.1 Composition..............................................................................................................................1
1.2 Other ingredients.......................................................................................................................1
1.3 Stability and storage...................................................................................................................1
2.0 Clinical Pharmacology.............................................................................................................2
2.1 Pharmacodynamics ....................................................................................................................2
2.2 Pharmacokinetics .......................................................................................................................5
2.2.1 Absorption...................................................................................................... 5
2.2.1.1 Smoked cannabis ............................................................................ 5
2.2.1.2 Oral THC .........................................................................................6
2.2.1.3 Rectal THC ......................................................................................7
2.2.2 Distribution .....................................................................................................7
2.2.3 Metabolism .................................................................................................... 8
2.2.3.1 Inhalation ..........................................................................................8
2.2.3.2 Oral ...................................................................................................9
2.2.4 Excretion .......................................................................................................10
2.3 Pharmacokinetic-pharmacodynamic relationships ................................................................. 10
3.0 Dosing.................................................................................................................................... 11
3.1 Smoking ................................................................................................................................. 11
3.2 Oral .........................................................................................................................................12
4.0 Purported Indications and Clinical Use.............................................................................. 12
4.1 Nausea and vomiting................................................................................................................13
4.2 Wasting syndrome and loss of appetite in AIDS and cancer patients .....................................13
4.2.1 To stimulate appetite and produce weight gain in AIDS patients ................13
4.2.2 To stimulate appetite and produce weight gain in cancer patients ...............14
4.2.3 Anorexia nervosa ..........................................................................................15
4.3 Multiple sclerosis, spinal cord injury or disease......................................................................15
4.3.1 Multiple sclerosis .........................................................................................15
4.3.2 Spinal cord injury..........................................................................................15
4.4 Epilepsy...................................................................................................................................16
4.5 Pain .........................................................................................................................................16
4.5.1 Cancer pain ...................................................................................................16
4.5.2 Other pain categories ....................................................................................17
4.6 Other diseases and symptoms..................................................................................................18
4.6.1 Movement disorders......................................................................................18
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4.6.1.1 Dystonia .........................................................................................18
4.6.1.2 Huntington’s disease......................................................................18
4.6.1.3 Parkinson’s disease ........................................................................18
4.6.1.4 Tourette’s syndrome ......................................................................19
4.6.2 Glaucoma ......................................................................................................19
4.6.3 Bronchial asthma ..........................................................................................19
4.6.4 Hypertension .................................................................................................20
4.6.5 Psychiatric disorders .....................................................................................20
4.6.6 Alzheimer’s disease ..................................................................................... 21
5.0 Contraindications................................................................................................................. 21
6.0 Warnings................................................................................................................................21
7.0 Precautions ............................................................................................................................ 22
7.1 General....................................................................................................................................22
7.2 Dependence and withdrawal ....................................................................................................22
7.3 Special populations ..................................................................................................................22
7.4 Drug interactions.....................................................................................................................22
7.5 Drug screening tests.................................................................................................................23
8.0 Adverse Effects...................................................................................................................... 23
8.1 Carcinogenesis, mutagenesis and respiratory tract ..................................................................23
8.2 Immune system ........................................................................................................................24
8.3 Reproductive and endocrine systems.......................................................................................24
8.4 Cardiovascular effects..............................................................................................................25
8.5 Central nervous system............................................................................................................27
8.5.1 Cognition......................................................................................................27
8.5.2 Psychomotor performance ...........................................................................27
8.5.3 Behavioural effects ......................................................................................28
8.5.3.1 Psychiatric disorders ............................................................................28
8.5.3.2 Schizophrenia.......................................................................................29
8.5.3.3 Amotivational syndrome......................................................................29
8.5.3.4 Dependence and tolerance ...................................................................30
9.0 Overdose and toxicity ........................................................................................................... 31
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1.0 Chemistry
1.1 Composition
Marihuana (Marijuana) is the common name for Cannabis, a hemp plant that grows
throughout temperate and tropical climates in almost any soil condition. Delta-9-
tetrahydrocannabinol ( Δ9-THC, THC) is the main psychoactive ingredient of cannabis.
The flowering tops and leaves are used to produce cannabis for smoking. Marihuana is
most commonly smoked in hand-rolled cigarettes (“joints”) containing marihuana plant
material.
Although the leaves and flowering tops of Cannabis plants yield more than 60
cannabinoids, the major active components are Δ9-THC, cannabinol (CBN) and
cannabidiol (CBD) (British Medical Association, 1997, p 7).
1.2 Other ingredients
There are other components in marihuana joints which are common to tobacco and the
smoke from them is considered chemically similar to that from tobacco cigarettes
(Iverson, 2000, p 191; British Medical Association, 1997, p 14). However, some
investigators report that two potent carcinogens in tobacco smoke, benzanthracene and
benzpyrene, are present in higher amounts in marihuana smoke (Novotny, et al., 1976).
Differences in the smoking techniques used by marihuana and tobacco smokers are
reported to result in three-fold higher levels of tar and five-fold higher levels of carbon
monoxide being retained in the lungs during cannabis than during tobacco smoking (Wu,
et al., 1988). This greater retention of tar and carbon monoxide from cannabis smoke
may offset the fact that a marihuana smoker typically smokes fewer cigarettes per day
than a tobacco smoker (i.e., the exposure to tar and carbon monoxide could be similar for
both groups of smokers) (Peterson, 1979; Tashkin, et al, 1987).
1.3 Stability and storage
Most of the information on stability of marihuana does not distinguish between THC and
its carboxylic acid analogue (THCA). The latter is degraded to THC by pyrolysis during
smoking or in the inlet of gas chromatographs used in forensic analysis (Baker, et al.,
1981). Heat, light, humidity, acidity and oxidation all affect the stability of cannabis
(Garrett, et al., 1974; Mechoulam, et al., 1981). Available information suggests that THC
in recently harvested plant material stored in dry, tightly- closed, refrigerated containers
would be stable for several months. The National Institute of Drug Abuse (NIDA) reports
(Thomas, et al., 1999) that retention samples of their carefully prepared and standardized
cigarettes are stable for months, particularly when stored below 0oC. However, even at
18oC, there is a loss of only a third of the THC potency (from 2.87 to 1.8% THC) over 5
years, with some increase in the concentration of CBN.
2.0 Clinical Pharmacology
2.1 Pharmacodynamics
Most of the pharmacodynamic information on marihuana in humans refers to the effects
of the major constituent THC. CBD does not appear to be psychoactive; its principle
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action is inhibition of cytochrome P450 enzymes, which decreases the metabolism of
TCH and other drugs. CBN, while only weakly active compared to THC in the brain,
appears to have activity in isolated immune cells (National Academy of Sciences, 1999, p
2.5).
Cannabinoid receptors have been discovered in neural tissue. Two types of cannabinoid
receptors, CB1 and CB2, have been identified. Table 1, adapted from the British Medical
Association Report (British Medical Association, 1997, p 19), notes some of the effects
of cannabis. Many of the effects are biphasic, e.g., increased activity with acute or
smaller doses, decreased activity with larger doses or chronic use. Effects differ greatly
among individuals and may be greater in severely ill and elderly patients.
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Table 1: Pharmacologic actions of cannabis in man
Body System/Effect Detail of Effects
CNS
Psychological Euphoria (“high”), dysphoria, anxiety, depersonalization,
precipitation or aggravation of psychosis.
Perception Heightened sensory perception, distortion of space and time, sense,
hallucinations, misperceptions.
Sedative Generalised CNS depression, drowsiness, somnolence; additive
with other CNS depressants.
Cognition, psychomotor
performance
Fragmentation of thoughts, mental clouding, memory impairment,
global impairment of performance especially in complex
demanding tasks.
Motor function Increased motor activity followed by inertia and in coordination,
ataxia, dysarthria, tremulousness, weakness, muscle twitching.
Analgesic Currently available oral cannabinoids are similar in potency to
codeine (but from a different mechanism).
Anti-emetic, increased
appetite
With acute doses; effect reversed with larger doses or chronic use
(tolerance).
Tolerance To most behavioural and somatic effects, including the “high”.
Dependence, abstinence
syndrome
Has been produced experimentally following prolonged
intoxication: symptoms include disturbed sleep, decreased appetite,
restlessness, irritability and sweating. Information from therapeutic
use lacking.
Cardiovascular System
Heart rate Tachycardia with acute dosage, bradycardia with chronic use.
Peripheral circulation Vasodilation, conjunctival redness, postural hypotension.
Cardiac output Increased output and myocardial oxygen demand.
Cerebral blood flow Increased with acute dose, decreased with chronic use.
Respiratory system
Ventilation Small doses stimulate; larger doses depress.
Bronchodilation Coughing, but tolerance develops.
Airways obstruction From chronic smoking.
Eye Decreased intraocular pressure.
Immune system Chronic use: impaired bactericidal activity of macrophages in lung
and spleen.
Reproductive System
Males Antiandrogenic, decreased sperm count and sperm motility (chronic
use, but tolerance may develop).
Females Suppression of ovulation, complex effects on prolactin secretion;
chronic use: increased obstetric risk.
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The acute effects of smoking marihuana include almost immediate euphoria (the
marihuana “high”) as well as cardiovascular, bronchopulmonary, ocular, psychological
and psychomotor effects. Maximum euphoria occurs within 15 minutes after smoking;
the psychological effects (see Table 1) reach a plateau which can last for several hours.
However, on first dosing, some people experience dysphoria and anxiety. The effects on
the cardiovascular system (tachycardia, etc.) decline much faster as THC is distributed
out of the circulatory system. Tachycardia is the most consistent of the physiological
effects of marihuana (Beaconsfield, et al., 1972; Perez-Reyes, 1990).
The short-term psychoactive effects of marihuana smoking include euphoria, relaxation,
time-distortion, perception of enhanced sensory experiences (such as music) and loss of
inhibitions that may result in laughter (Hall, et al., 1998). This is followed by a
depressant period (Ameri, 1999). While there is some inconsistency in reports of the
acute effects on memory and motor skills (Fant, et al., 1998; Kelly, et al., 1993; Barnett,
et al., 1985), most reviews note that marihuana use is associated with impaired function
of a variety of cognitive tasks and short-term memory (Ameri, 1999; National Academy
of Sciences, 1999, p 2.27; Hollister, 1998; Miller, Ch. 15 p 227-231).
A major concern
from such an acute effect is impairment affecting driving or operation of intricate
machinery (Hansteen, et al., 1976; Smiley, et al., 1999; O’Kane, et al., 2002). There are
reports of reduced skills on flight simulators by experienced pilots 24 h after smoking one
marihuana cigarette (Leirer, et al., 1991). Plasma THC levels attained after smoking seem
to have a dose and concentration dependent effect on cognitive function (Heishman, et
al., 1990).
2.2 Pharmacokinetics
This section will be restricted to human pharmacokinetics, mainly of smoked cannabis,
but with some comparisons to oral THC, including dronabinol (Marinol®).
2.2.1 Absorption
2.2.1.1 Smoked cannabis
The estimation of dose administered by the smoking route is a major variable in
the assessment of absorption of cannabinoids (mainly THC) in humans. The
source of the plant material and the composition of the cigarette, together with the
efficiency of smoking by the subject, are additional uncontrolled factors. It might
be reasonable to consider about 10% (range 3-30%) as an average for THC
content in Canadian marihuana. It appears that habitual (heavy) marihuana
smokers can increase the amount absorbed, which is attributed to more efficient
smoking techniques (Agurell, et al., 1986).
THC absorption by inhalation is extremely rapid, with a bioavailability of 18 to
50% from the cigarette (Huestis, 1999), and is the main reason this route is
preferred by many people (Iverson, 2000, p 46-47).
Standardised cigarettes have been developed by NIDA, and the relationships
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among cannabis (THC) content, dose administered and resultant plasma levels
have been investigated. Smoking cannabis containing 1.64% THC (mean dose
13.0 mg THC) resulted in mean peak THC plasma levels of 77 ng/mL (Ohlsson,
et al., 1980).
THC levels in plasma decreased rapidly after cessation of smoking and were
below 5 ng/mL, 2 hours after smoking; mean concentrations declined by about
50%, 15 minutes after (Huestis, et al., 1992) reaching the maximum (Huestis,
1999). However, THC from a single dose can be detected in plasma for at least a
day using modern sensitive analytical techniques and for 13 days in chronic users
(Johansson, et al., 1988). The decline of THC in plasma is multiphasic and as
Harvey (Harvey, 1999) notes, the estimates of the terminal half-life of THC in
humans have increased as analytical methods have become more sensitive. There
is still no consensus. It is probably safe to say that the terminal half-life of THC
averages at least a week and could be considerably longer. The half-life in plasma
does not appear to be different between heavy and light users (Agurell, et al.,
1971).
2.2.1.2 Oral THC
Absorption from an oral dose of 20 mg THC in a chocolate cookie was described
as slow and unreliable (Agurell, et al., 1986), with a systemic availability of only
4 to 12% (Ohlsson, et al., 1980). While most subjects had peak plasma THC
concentrations between 1 to 2 hours, some of the 11 subjects only peaked at 6
hours and many had more than one peak.
Only 10-20% of synthetic THC (dronabinol, Marinol®) administered in capsules
with sesame oil enters the systemic circulation indicating extensive first-pass
metabolism (Compendium of Pharmaceuticals and Specialties, 2003). The
psychotropic effect or “high" is observed to occur more quickly by the smoking
than the oral route, which has been characterized by Iversen (Iverson, 2000, p 46-
47) as the reason “smoking is the preferred route of cannabis for many people”.
2.2.1.3 Rectal THC
Limited evidence suggests a higher bioavailability of THC by the rectal route than
by the oral route (Mattes, et al., 1993 p 745-747; Brenneisen, et al., 1996).
2.2.2 Distribution
Distribution of THC begins immediately after absorption. The plasma protein binding
of THC and its metabolites is approximately 97% (Garrett, et al., 1977; Widman, et
al., 1974). THC is mainly bound to low-density lipoproteins, with up to 10% present
in red blood cells (Walqvist, et al., 1970), while the metabolite, 11-hydroxy THC, is
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even more strongly bound with only 1% found in the free-fraction (Widman, et al.,
1973).
THC has a large apparent volume of distribution, approximately 10 L/kg, because of
its high lipid solubility. Animal studies show that it is sequestered to fatty tissues
including brain (Harvey, 1999). The highest concentrations are found in the heart and
in adipose tissue, with levels reaching 10 and 1000 times that of plasma, respectively
(Truitt Jr., 1971). THC readily crosses the blood brain barrier and the slight delay in
correlating peak plasma concentration to effects is assumed to reflect this distribution
(Agurell, et al., 1986). While immediate distribution is high in liver, spleen and body
fat are the major sites of distribution after 72 h. Spleen and body fat are the long-term
storage sites (Harvey, 1999).
There has been concern about the possible consequences of the long persistence of
THC in fatty tissues. There is no evidence that the THC residues persist in the brain.
Release from the fatty storage sites into blood is slow; levels attained are not high
enough to cause psychological effects.
2.2.3 Metabolism
Most metabolism of cannabinoids occurs in the liver and different metabolites
predominate when different routes of administration are used. The complex
metabolism of THC involves allylic oxidation, epoxidation, decarboxylation and
conjugation (Agurell, et al., 1986). Cannabinoids are good substrates for cytochrome
P450 mixed-function oxidases, mainly CYP 2C9. The major initial metabolites of
THC are 11-hydroxy THC and 11-nor-9-carboxy THC. 11-hydroxy THC is rapidly
formed by action of hepatic microsomal oxidases, and plasma levels parallel the
duration of observable drug action. 11-hydroxy THC has been found to have
psychotomimetic properties equal to THC (Christensen, et al., 1971; Perez-Reyes, et
al., 1972).
2.2.3.1 Inhalation
After smoking (1.75 and 3.55% THC cigarettes) 11-hydroxy THC (Huestis, et al.,
1992) appears rapidly and peaks shortly after THC, at about 15 minutes after the
start of smoking. It exhibited peak plasma concentrations of about 7.5 ng/mL
(about 5% of parent THC) and the AUC profile of this metabolite averaged 20%
of the parent. Similar results were obtained with intravenous administration
(Agurell, et al., 1971).
The psycho-inactive 11-nor-9-carboxy THC is the primary acid metabolite of
THC excreted in urine (Huestis, et al., 1996) and it is the cannabinoid often
screened for in forensic analysis of body fluids (Martin, et al., 1999). Peak
plasma values of this metabolite occur 1.5 to 2.5 h after smoking and are about
one third the concentration of parent THC. Following oxidation, the phase II
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metabolites of the free drug or hydroxy-THC appear to be glucuronide conjugates
(Agurell, et al., 1986).
It is known that polyaromatic hydrocarbons found in tobacco and cannabis smoke
induce the action of CYP1A2. If it is shown that the metabolism of THC also
involves this cytochrome P450 isoenzyme, then repeated exposure to cannabis
could cause the more rapid disappearance of THC via this specific enzyme
(Valjent, et al., 2002). Various other cytochrome P450, enzymes are of interest for
potential drug interactions. In human liver microsome preparations, CBD has been
shown to inhibit formation of THC metabolites catalyzed by CYP 3A, with less
effect on CYP 2C9 (Harvey, 1999). However, others suggest that CBD decreases
formation of 11-hydroxy THC by inhibition of CYP 2C9 (Bornheim, et al., 1993).
Observed and potential interactions of cannabis with other drugs are discussed
later.
2.2.3.2 Oral
After oral doses of THC, parent THC and its active metabolite, 11-OH-THC, are
present in approximately equal concentrations in plasma (Wall, et al., 1981; Cone,
et al., 1988). Concentrations of both parent drug and metabolite peak at
approximately 2 to 4 hours after oral dosing and decline over several days.
Clearance averages about 0.2 L/kg-h, but is highly variable, due to the complexity
of cannabinoid distribution (Marinol US monograph). The larger amount of 11-
hydroxy THC metabolite, from first pass metabolism by this route, which is
similar in potency to THC, complicates interpretation of potential effects. With
oral THC dosing, the absorption is slow and variable, and peak concentrations of
THC may be considered one tenth those from efficiently smoked administration
but the plasma levels of active 11-hydroxy metabolite are about 3 times higher
than observed in the plasma from smoking (Wall, et al., 1983).
2.2.4 Excretion
Following inhalation, elimination of THC and its metabolites occurs via the faeces
(65%) and the urine (20%). After five days, 80% to 90% of the total dose is excreted.
Similarly, following oral doses, THC and its biotransformation products are excreted
in both faeces and urine. Biliary excretion is the major route of elimination with
about half of a radiolabelled oral dose being recovered from the faeces within 72
hours as contrasted with 10 to 15% recovered from urine. Less than 5% of an oral
dose is recovered unchanged in the faeces. Following administration of a single oral
dose, low levels of THC metabolites have been detected for more than 5 weeks in the
urine and faeces (Harvey, 1999, p 91-103; Compendium of Pharmaceuticals and
Specialties,2003).
Traces of marihuana can be detected in urine even for weeks (Ohlsson, et al., 1980)
after dosing in forensic or employment situations when such testing may be applied.
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2.3 Pharmacokinetic-pharmacodynamic relationships
Though it is of major forensic interest, the temporal relationship between plasma
concentrations of TCH and its psychotropic, cognitive and motor effects is unclear
(Harder, et al., 1997; Cone, et al., 1993). Dose and plasma concentration vs. response for
possible therapeutic applications are ill-defined, except for some information obtained for
oral dosing with dronabinol (synthetic THC) for its limited indications (Compedium of
Pharmaceuticals and specialties, 2003). Interpretations of THC pharmacokinetics is also
complicated by the emergence of active metabolites, particularly 11-hydroxy THC (Wall,
et al., 1981; Cone, et al., 1988), which attains higher concentrations after oral than
inhalation doses. Pharmacodynamic modelling (Barnett, et al., 1982) supports a 10
ng/mL cutoff as evidence of functional impairment (McBay, 1985) which is in agreement
with the estimate of 25 – 29 ng/mL for the steady state plasma concentration at 50% of
the maximum “high” effect, or Css(50). The model was also used to simulate multiple
dosing with a 1% cigarette containing 9 mg THC (Harder, et al., 1997). The duration of
maximal “high” for this dose was estimated at about 45 minutes after dosing and declined
to 50% of this peak effect at about 100 minutes following smoking. A dosing interval of
1h with this dose would give a “continuous high” and the recovery after the last dose
would be 150 minutes. The peak plasma concentration during this dosage is estimated at
about 70 ng/mL and the Css(50) at about 30 ng/mL THC.
Target THC plasma concentrations have been derived based on the subjective “high”
response that may or may not be related to the potential therapeutic applications.
However, it is likely that the psychoactivity that elicits this response from the central
nervous system is receptor derived and the concentrations are useful for suggesting doses
from smoking.
3.0 Dosing
3.1 Smoking
The actual dose of THC absorbed when smoked is not easily quantified (see section
2.2.1). According to the World Health Organization (World Health Organization, 1997),
a typical joint contains between 0.5 and 1.0 g of cannabis plant matter (average 750 mg)
which may vary in THC content between 7.5 and 225 mg (i.e., typically between 1 and
30%; see Table 2. The actual amount of THC delivered in the smoke has been estimated
at 20 to 70%, the remainder being lost through combustion or side stream smoke. The
bioavailability of THC (the fraction of THC in the cigarette which reaches the
bloodstream) from marihuana cigarettes in human subjects has been reported from 5 to
24%. The amount of other cannabinoids present, mainly CBN and CBD, is usually much
lower, but the amount delivered and absorbed parallels that of THC.
Table 2 shows some relationships between percentage of THC in cannabis plant material
and the amount in average joints. Bioavailability of cannabinoid depends greatly on
smoking technique (likely maximum approximately 50%).
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Table 2: Relationship of THC percent in plant material to
available dose in a joint
%THC (mg per 100 mg cannabis) mg THC per 750 mg*
(“ average joint”)
1 7.5
2.5 18.75
5 37.5
10 75
15 112.5
20 150
30 225
* WHO average weight
Assuming the desired peak plasma concentration of smoked THC is in the 50-100 ng/mL
range, (see Section 2.3) it has been shown (Huestis, et al., 1992) that this can be readily
achieved with smoke from a single 3.55 % marihuana cigarette with about 900 mg plant
material (approximately 32 mg THC).
A 750 mg joint of 5% strength (i.e., 37.5 mg THC) would yield slightly higher plasma
levels. If the current average “street” marihuana contains 10% THC, then plants yielding
joints from such a source might have an available 75 mg dose and could result in rapid
attainment of plasma concentrations above 300 ng/mL. Clearly even more potent strains
of cannabis have been reported. Patients initiating smoked marihuana therapy should
be cautioned to begin slowly and to stop smoking if tachycardia occurs.
3.2 Oral
The pharmacokinetic information described in section 2.2 reports the erratic and slow
absorption from the oral route and doses are estimated from the information for Marinol®.
4.0 Purported Indications and Clinical Use
The oral form of synthetic THC, dronabinol (2.5, 5 or 10 mg, dissolved in sesame oil) in
capsules is marketed in the US and Canada as Marinol®. It is indicated for treatment of
chemotherapy-induced emesis and for appetite stimulation in AIDS- related anorexia associated
with weight loss (Compendium of Pharmaceuticals and Specialties, 2003; Marinol US
monograph).
While there are many anecdotal reports of the therapeutic value of smoked marihuana, scientific
studies supporting the safety and efficacy of marihuana for therapeutic claims are inconclusive.
The existing scientific evidence for various symptoms is summarized in the following sections.
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4.1 Nausea and vomiting
The IOM (National Academy of Sciences, 1999, p 4.17) and other committees (Health
Department, NSW, Australia, 2000, p 41) consider that the place (if any) for smoked
marihuana would be as an adjunct to other antiemetics, when they are not fully successful
in treatment. However, there are no trials available for guidance. The BMA report
(British Medical Association, 1997, p 27) indicates the research needed to evaluate
marihuana in chemotherapy-induced emesis. This includes establishing dose ranges for
cannabinoids and clinical trials to differentiate optimum cannabinoid treatment for
specific anticancer agents and patient groups.
The IOM report suggests that, since there are now more effective antiemetic agents
available than were available in the 1980s (especially the 5-HT3 receptor antagonists),
patients are less in need of THC.
4.2 Wasting syndrome (cachexia, e.g., from tissue injury by infection or tumor) and
loss of appetite (anorexia) in AIDS and cancer patients
4.2.1 To stimulate appetite and produce weight gain in AIDS patients
The reports that marihuana is beneficial for patients with AIDS wasting syndrome
are anecdotal, although it appears to be very popular with AIDS patients
(Grinspoon et al., 1993). Studies with healthy subjects confirm an appetite
stimulating effect of smoked marihuana together with increases of food
consumption and body weight (Mattes, et al., 1994; Foltin, et al., 1988). In a
controlled, residential laboratory study in which food consumption was carefully
monitored and cannabis cigarettes were smoked with a standardized procedure,
subjects consumed significantly more calories daily compared to placebo (Foltin,
et al., 1988). There are, however no clinical trials of the smoked drug for this
indication (National Academy of Sciences, 1999, p 4.19).
Oral synthetic THC, dronabinol, administered as capsules (Marinol®) has been
approved for this indication. The Marinol product monograph summarizes a
randomized double-blind, placebo controlled-trial in 139 patients (Beal, et al.,
1995) with the 72 patients in the treatment group initially receiving 2.5 mg
dronabinol twice a day, but then having the dose reduced to 2.5 mg at bedtime
due to side effects (feeling high, dizziness, confusion and somnolence). Over the
six week treatment period dronabinol significantly increased appetite, with a trend
towards improved body-weight, and mood, and a decrease in nausea. After the six
weeks, patients were allowed to continue receiving dronabinol, during which the
appetite improvement continued.
A major concern with marihuana smoking in HIV-infected patients is that they
might be more vulnerable than other marihuana users to immunosuppressive
effects of marihuana or to the exposure of infectious organisms associated with
marihuana plant material (National Academy of Sciences, 1999, p 4.19). There
are also drug interaction concerns that are reviewed later.
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4.2.2 To stimulate appetite and produce weight gain in cancer patients
Smoked marihuana has not been studied in patients with cancer cachexia. Oral
THC (dronabinol) has been shown to improve appetite and food intake from
observations during the investigations of the anti-nausea effect (Ekert, et al., 1979;
Sallan, et al., 1980). Improved appetite and increased food intake was reported in
patients with unresectable or advanced cancer treated with open-label dronabinol
2.5 mg 2 to 3 times daily for 4 to 6 weeks, but weight gain was achieved in only a
few patients (Plasse, et al., 1991; Wadleigh, et al.,1990, p 331; Nelson, et al.,
1994). Modest weight gain was obtained with a larger dose regimen of dronabinol
(5 mg, 3 times daily), but the CNS side effects including dizziness and
somnolence were limiting (Regelson, et al., 1976). Cancer cachexia is not an
approved indication for dronabinol either in Canada or the U.S.
The immunomodulating effects of some cannabinoids could be contraindicated in
some cancer patients (both the chemotherapy and the cancer can be
immunosuppressive) (National Academy of Sciences, 1999, p 4.21).
4.2.3 Anorexia nervosa
A randomized trial of oral THC (Gross, et al., 1983) was unsuccessful for weight
gain and three of the eleven patients administered THC reported severe dysphoric
reactions. Both the British Medical Association (British Medical Association,
1997, p 46) and IOM (National Academy of Sciences, 1999, p 4.21) conclude that
marihuana is unlikely to be effective in this group of patients.
4.3 Multiple sclerosis, spinal cord injury or disease
The common symptom of these diseases is muscle spasticity. There are many anecdotal
reports that marihuana can ameliorate spasticity associated with multiple sclerosis or
spinal cord injury when other drugs fail or produce unacceptable side effects (American
Medical Association, 1997, p 10; British Medical Association, 1997, p 30; National
Academy of Sciences, 1999, p 4.23).
4.3.1 Multiple sclerosis (MS)
Published reports spanning one hundred years suggest that people with spasticity may
experience relief with cannabis (Consroe, et al., 1986). As many as 4% of MS
patients in the UK already smoke cannabis to relieve symptoms (Iverson, 2000, p
157) and in a mail survey of 233 MS patients in the UK and US, 112 (48%) reported
(Consroe, 1997) that cannabis was used to ameliorate symptoms.
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4.3.2 Spinal cord injury
Patients surviving spinal cord injuries are usually young (60% are less than 35 years
old (National Academy of Sciences, 1999, p 4.28)), and require long-term or even
life-long care. While there are no clinical trials of smoked marihuana for treatment of
muscle spasms, spinal patients reported to the IOM workshops that muscle spasms,
nausea and sleeplessness were alleviated by smoking marihuana.
4.4 Epilepsy
While some work in animals suggests that cannabinoids could have a role in treatment of
some types of epileptic seizures (Consroe, et al., 1992), (in particular CBD appeared to
have anticonvulsant without psychoactive properties (Hollister, 1986)), there are only
anecdotal and individual case reports that marihuana controls seizures in epileptics.
The potential antiepileptic activity of cannabidiol (CBD) in epileptic patients who were
poorly controlled with conventional anticonvulsants, has been investigated but is not
promising (Ames, et al., 1986, p 14; Trembly, et al., 1997, p 51; Cunha, et al., 1980).
4.5 Pain
4.5.1 Cancer pain
There are no controlled clinical trials of smoked marihuana in treatment of pain.
There are two double-blind, controlled studies of oral THC (dronabinol,
Marinol®) in cancer pain. The first (Noyes Jr., et al., 1975) was a dose ranging
study of 5, 10, 15 and 20 mg THC, given in successive days, to ten cancer
patients. Significant pain relief was found at the 15 and 20 mg dose levels, but at
these higher doses patients were heavily sedated with mental clouding common. A
second, placebo-controlled, study (Noyes, et al., 1975) compared oral 10 and 20
mg THC with 60 and 120 mg codeine in 36 patients with cancer pain. The 10 and
20 mg THC were equivalent in analgesic potency with 60 and 120 mg codeine
respectively. The 10 mg THC dose was well tolerated and, despite its sedative
effect, may have analgesic potential, but the 20 mg THC dose induced side effects
including somnolence, dizziness, ataxia, and blurred vision. Alarming extreme
anxiety was also observed at this dose. This side effect profile is supported by a
report concerning a synthetic analogue of THC also tested in controlled trials
(Staquet, et al., 1978). While it was equivalent in efficacy to codeine, it was not
considered clinically useful because of the frequency of side effects.
4.5.2 Other pain categories
Intravenous THC (0.22 mg/kg and 0.44 mg/kg) administered to patients
undergoing tooth extraction (Raft, et al., 1977) was compared to diazepam (0.157
mg/kg). High dose THC was least effective and diazepam most effective. Four
patients preferred placebo to low dose THC. A study of oral CBD, 450 mg/day in
divided doses, in 10 patients with chronic neuropathic pain (neuralgia, etc.) also
found no significant pain relief (Lindstrom, et al., 1997, p 43). Receptor studies
indicate that cannabinoids might be useful adjuncts to opioid analgesia (National
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Academy of Sciences, 1999, p 4.8). Improvement in phantom limb pain has been
documented (British Medical Association, 1997, p 43).
A meta-analysis of all cannabinoid trials for analgesia concluded that as well as
having effects on the CNS that limit their use, cannabinoids are no more effective
than codeine as analgesics (Campbell, et al., 2001).
4.6 Other diseases and symptoms
4.6.1 Movement disorders
The endogenous cannabinoid system appears to be intricately involved in normal
physiology, specifically in the control of movement, formation of memories and
appetite control and may be involved in the pathology of several neurological
diseases. The contribution of cannabinoids to Huntington’s disease, Parkinson’s
disease and tremor has been reviewed (Glass, 2001).
4.6.1.1 Dystonia
No controlled study of smoked marihuana in dystonic patients has been
published. However, there was a preliminary open trial (Consroe, et al., 1986,
30: 277-282) of an oral cannabinoid. CBD, administered in five dystonic
patients (100 mg/day rising to 600 mg/day over 6 weeks), showed modest
dose-related improvements in all five, but worsening of tremor and hypokinesia
in 2 patients with co-existing Parkinson’s disease. Results of a double-blind
randomized, placebo- controlled study of a synthetic cannabinoid (nabilone)
showed no significant reduction in dystonia (Fox, et al., 2002).
4.6.1.2 Huntington’s disease
A double-blind, placebo-controlled trial (Consroe, et al., 1991) of oral CBD, 10
mg/kg/day in 15 patients with Huntington’s disease found no beneficial effects of
treatment .
4.6.1.3 Parkinson's disease
There are theoretical reasons from research on brain transmission pathways that
support a role for cannabinoids in the treatment of Parkinsonism. However, the
one published clinical trial of smoked marihuana (1 g cigarettes containing 2.9%
THC) involving five cases of idiopathic Parkinson’s disease (Frankel, et al., 1990,
53: 436) found no improvement in tremor after the patients smoked marihuana,
whereas all subjects benefited from the administration of levodopa and
apomorphine. A small randomized clinical trial of the synthetic cannabinoid,
nabilone, in seven patients with Parkinson’s disease found that the treatment
reduced levodopa-induced dyskinesia (Sieradzan, et al., 2001).
4.6.1.4 Tourette's syndrome
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Four case histories suggest that smoked marihuana use can reduce tics in
Tourette’s patients (National Academy of Sciences, 1999, p 4.32). In one report of
3 patients, it is hypothesized that beneficial effects of marihuana might have been
due to anxiety-reducing properties of marihuana rather than to a specific anti-tic
effect (Sandyk, et al., 1988, p 444-445). A randomized, double-blind, placebo
controlled trial of single oral doses of THC (5, 7.5 or 10 mg) in 12 patients with
Tourette’s syndrome showed plasma concentration-related improvements in
control of tics and obsessive-compulsive behaviour, with no serious side effects;
although transient, mild side effects were noted in five patients (Muller-Vahl, et
al., 2002). A related study showed that in contrast to healthy marihuana users,
single does of THC (5-10 mg) caused no cognitive impairment measured by
objective tests in 12 patients with Tourette’s syndrome (Muller-Vahl, et al.,
2001).
4.6.2 Glaucoma
The high intraocular pressure (IOP) of glaucoma can be reduced by marihuana (oral
or smoked) and there are a few reports from treatment of glaucoma patients (British
Medical Association, 1997, p 55). One reviewer remarks (Green, 1998) that
“smoking of marijuana plant material for the reduction of elevated IOP in glaucoma
is ill-advised, given its toxicological profile.” Research with cannabinoids, including
the discovery of ocular cannabinoid receptors, could lead to improved agents for
glaucoma treatment (Jarvinen, et al., 2002).
4.6.3 Bronchial asthma
While cannabinoids are bronchodilators, there have been very few studies of the
bronchodilator effect in asthmatic patients. A double-blind, placebo-controlled study
of smoked marihuana (2% THC), oral THC (15 mg) and isoprenaline (0.5%) in 14
asthmatic subjects showed reversal of experimental bronchospasm by
bronchodilation which was almost equivalent (Tashkin, et al., 1976). However,
tolerance to this effect developed after several weeks (Tashkin, et al., 1976).
Another single-blind investigation of smoked marihuana (0.9 and 1.9% THC) found
that it caused significant and prolonged bronchodilation, but tachycardia occurred
with the higher dose (Vachon, et al., 1976). It is clear that smoked marihuana is not
suitable for chronic use in asthma because of bronchial irritation from various
components of smoke (British Medical Association, 1997, p 60).
4.6.4 Hypertension
Cannabinoids cause postural hypotension, but tolerance to the cardiovascular effects
develops rapidly and together with adverse effects would preclude their consideration
as a treatment for long-term use in hypertension (British Medical Association, 1997,
p 64).
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4.6.5 Psychiatric disorders
Cannabis has been advocated as a treatment for anxiety, depression, sleep disorders
and alcohol and opiate withdrawal symptoms (Iverson, 2000, p 172). Use is
anecdotal and occurred before modern psychotherapeutic agents became available.
One anecdote concerns relief of depression by smoking marihuana, with much faster
mood alteration than from amitriptyline, a conventional antidepressant that usually
takes some weeks to take effect (Grinspoon, et al., 1993). Trials for treatment of
chemotherapy-induced nausea with cannabinoids have mentioned some
antidepressant effect (Regelson, et al., 1976). However, these are offset by the
potential for severe psychological side effects.
Anecdotal information and some animal studies suggest that cannabinoids may be
useful in treatment of opiate withdrawal, but there are no clinical studies to support
this indication (British Medical Association, 1997, p 64).
4.6.6 Alzheimer’s disease
Two possible indications for cannabinoid treatment in Alzheimer’s are to stimulate
appetite (i.e., to combat food refusal) and improve behaviour. Although oral THC
(dronabinol, Marinol®) has been investigated in 11 patients and showed efficacy
(Volicer, et al., 1997), there are concerns about the known THC effects on memory
of healthy adults in this condition in which memory is already diminishing. There
are also obvious concerns about the fire hazards of smoking marihuana in cognitively
impaired patients.
5.0 Contraindications
Marihuana is contraindicated in any patient who has a history of hypersensitivity to any
cannabinoid or to smoking. Marihuana should not be used in patients with a history of psychotic
disorders, particularly schizophrenia.
6.0 Warnings
The dose of marihuana is difficult to estimate and is affected by source of plant material, its
processing and by different smoking techniques. These include depth of inhalation and breathholding
and the number and frequency of puffs as well as how much of the cigarette is smoked.
Smoking should be gradual and should cease if the patient begins to feel disoriented or agitated.
Experienced smokers are able to “titrate” their dose, but naïve smokers should take great care
and be supervised.
Marihuana can produce physical and psychological dependence and has the potential for abuse.
The drug has complex effects in the CNS. These can result in cognitive and memory impairment,
mood changes, altered perception and decreased impulse control. Patients should be supervised
when administration s initiated.
Any patient experiencing a psychotic reaction to marihuana should stop taking the drug
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immediately and be kept under observation until the normal mental state is regained.
Occupational hazards: Patients using marihuana should be warned not to drive or perform
hazardous tasks such as operating heavy machinery because impairment of mental alertness and
physical coordination may decrease their ability to perform such tasks. Such impairment can last
for over 24 hours after using due to the long half-life of THC.
Pregnancy: Use of marihuana during pregnancy should be avoided as there is evidence of long
term development problems in children exposed to marihuana in utero.
Lactation: Cannabinoids are excreted in human milk and may be absorbed by the nursing baby.
Because of potential risks to the child, nursing mothers should not use marihuana.
7.0 Precautions
7.1 General
The risk/benefit ratio of marihuana should be carefully evaluated in patients with the
following medical conditions, because of individual variation in response and tolerance to
its effects as well as the difficulty in dosing noted in section 3.0:
• Marihuana should be used with caution in patients with cardiac disorders because
of occasional hypotension, possible hypertension, syncope, or tachycardia.
• Smoked marihuana is not recommended in patients with respiratory insufficiency
such as asthma or chronic obstructive pulmonary disease.
• Marihuana should be used with caution in patients with a history of substance
abuse, including alcohol abuse or dependence, because they may be more prone to
abuse marihuana, which itself, is a frequently abused substance.
• Patients with mania, depression, or schizophrenia should be under careful
psychiatric monitoring if marihuana is taken, because it may exacerbate these
illnesses.
• Marihuana should be used with caution in patients receiving concomitant therapy
with sedatives, hypnotics or other psychoactive drugs because of the potential for
additive or synergistic CNS effects.
• Patients should be advised of the negative effects on memory and to report any
mental or behavioural changes that occur after using marihuana.
7.2 Dependence and withdrawal
Tolerance, psychological and physical dependence may occur with prolonged use of
marihuana. Tolerance to cardiovascular effects occurs quickly, but the dependence is
slower to develop and appears more likely with higher, more frequent dosing.
7.3 Special populations
Marihuana should be used with caution in pregnant, pediatric and elderly patients,
because there is insufficient knowledge about its use in these patient populations and the
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potential for harm is likely to outweigh benefits (see Warnings, Pregnancy and
Lactation).
7.4 Drug interactions
THC and CBD are metabolized by the cytochrome P450 system and in vitro human
microsomal studies have suggested a potential for interaction with other drugs. CBD has
been shown to inhibit formation of THC metabolites catalyzed by CYP 3A with less
effect on CYP 2C9. For this reason there is concern that in patients undergoing multiple
drug therapy, such as treatment of AIDS or cancer, clinically significant drug interactions
might occur. However, both with dronabinol and smoked marihuana clinically
significant interactions have not been detected. Protein binding is another possible source
of interaction and patients exposed to marihuana should be monitored for a change in
dosing requirements if they are taking other drugs that are highly protein-bound.
7.5 Drug screening tests
Because of the long half-life of elimination of cannabinoids and their metabolites, drug
screening tests can be positive long after using marihuana (weeks with some tests).
8.0 Adverse Effects
This section includes known cannabis-related effects (e.g., cardiac) as well as effects related to
smoking (e.g., respiratory).
8.1 Carcinogenesis, mutagenesis and respiratory tract
The only epidemiological study in relatively young health maintenance organization
(HMO) clients found an increased number of men with prostate cancer in smokers of
cannabis and other non-tobacco materials. In this study, limited by the demographics of
the HMO clientele and the low marihuana exposures, there were no other associations
found between marihuana use and other cancers (Sidney, et al., 1997). A case control
study (Zhang, et al., 1999) suggested that marihuana use may increase the risk of head
and neck cancer with a strong dose-response pattern. The risk was increased 36-fold in
those using both marihuana and tobacco compared to non-smoking controls. There has
also been a rise in the number of cancers of the respiratory and digestive systems that are
rare in young patients and are attributed to marihuana smoking (Hyman, 1999; Hall, et
al., 1998). In addition there are many cellular and molecular studies that provide strong
evidence that smoked marihuana is carcinogenic (National Academy of Sciences, 1999, p
3.41).
Epidemiological studies have found mild pulmonary function changes in heavy cannabis
smokers, including reduction of forced expiratory volume in 1 second (FEV1), increase in
airway resistance and decrease in airway conductance (Bloom, et al., 1987; Roth et al.,
1998; Tashkin, et al., 1987). Heavy chronic smokers presented with symptoms of
bronchitis, including wheezing, production of phlegm and chronic cough and it may be a
risk factor for chronic obstructive pulmonary disease in later life (Hall, et al., 1998;
Taylor, et al., 2002). All changes were most evident in heavy chronic users, defined as
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those who smoked more than 3 joints per day for 25 years (Sidney et al., 1997; Tashkin,
1999). The effects on the respiratory tract defence system may increase the risk of
infection in chronic users (Denning, 1991). Thus although additional epidemiological
studies are required to determine the potential causal relationship between marihuana use
and the development of respiratory infection and/or cancer, evidence is mounting that
habitual smoking of marihuana has a number of adverse effects on the respiratory and
immune systems (see below) that may be clinically relevant (Tashkin, et al., 2002).
8.2 Immune system
The effects of marihuana smoking on the immune system are inconclusive. Among
patients suffering from AIDS, the increased mortality and reports of opportunistic
bacterial and fungal infections associated with marihuana use cause concern. Reviews
suggest (Cabral, 2001; Klein, 2001) that such patients may be exposed to more pathogens
or that the immune system is suppressed by marihuana (National Academy of Sciences,
1999, p 3.39).
8.3 Reproductive and endocrine systems
Results of human epidemiological studies have been conflicting; some report reduced
birth weight (Zuckerman, et al., 1989) and others no effect on birth weight (Shiono, et al.,
1995) among women who smoked cannabis during pregnancy. There appears to be some
long-term effects on development of children born to mothers who used marihuana
during pregnancy. Two longitudinal investigations over 20 years (Fried, 2002),
confirmed by a third (Richardson, et al., 2002), suggest that such in utero exposure
impacts negatively on attentional behaviour and visual analysis/hypothesis testing but not
on standardized derived IQ scores. In later years these behavioural effects have a negative
influence on aspects of executive function. Also, frequent maternal cannabis use may be
a weak risk factor for sudden infant death syndrome (SIDS) (Scragg, et al., 2001).
There is little information concerning transfer of cannabinoids and their metabolites in
human milk (Chao, et al., 1976; Perez-Reyes, et al., 1982). However, in habitual maternal
users of marihuana the above influences in development and behaviour would also be
relevant. In a case-control study (Astley, et al., 1990), exposure to marihuana from the
mother’s milk, during the first month postpartum, appeared to be associated with a
decrease in infant motor development at one year of age.
8.4 Cardiovascular effects
The most consistent acute physiological effect of smoking marihuana is dose-related
tachycardia (Trouve, et al., 1999). While cardiovascular changes have not usually been a
problem for healthy young users, the tachycardia induced by cannabis smoking may be
problematic to those already suffering from cardiac disorders or angina (National
Academy of Sciences 1999 p 3.44). It was found that inhalation of cannabis smoke
reduces the amount of exercise required to cause an attack by 50% (Aronow, et al.,
1974). Recently, marihuana has been associated with an increased relative risk of
nonfatal myocardial infarction in the first hour following smoking (Mittleman, et al.,
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2001). This may be due to increasing myocardial oxygen demand from the increase in
heart rate following cannabis use. However, other drug use could confound reports
(Hollister, 1998).
Cannabis is known to cause postural hypotension immediately after smoking (Merritt, et
al., 1982). It also causes peripheral vasodilatation, which can impact on body
temperature perception and is involved in characteristic conjunctival reddening. The
mechanisms for those effects on the autonomic nervous system are not understood
(National Academy of Sciences, 1999p 3.44).
Chronic marihuana smoking appears to induce tolerance to the cardiac accelerating
effect. In fact, after about 8 days of constant dosing with equivalent of 10 mg of THC per
day (equivalent to 100 mg of marihuana containing 10% THC), bradycardia with
hypotension (decrease in supine blood pressure) was observed (Chesher, et al., 1999).
THC and smoked marihuana poses health risks to people with cardiovascular disease
because of the resulting increased cardiac work, increased catecholamine levels,
carboxyhemoglobin and postural hypotension (Trouve, et al., 1999; Jones, 2002; Sidney,
2002).
AIDS patients may be at risk of cardiovascular effects from interactions of their antiviral
drugs, such as ritonavir, which has been shown to cause plasma lipid abnormalities that
increase risk of cardiovascular events (Purnell, et al., 2000). As this patient population
may use cannabis for weight gain or other amelioration of symptoms, the additional
cardiovascular effects from the marihuana should be considered in risk assessment.
8.5 Central nervous system
According to the Marinol® (oral THC) product monograph, the most commonly
encountered CNS events in controlled clinical trials were drowsiness, dizziness and
transient impairment of sensory and perceptual functions (Compendium of
Pharmaceuticals and Specialties, 2003). Psychotropic effects were observed in most
patients; these included the “high” (easy laughing, elation, heightened awareness) in 24%
of the THC group. Five percent of patients in the THC group and none in the placebo
group experienced weakness or sluggishness, hallucinations, memory lapse and ataxia.
Other events reported were dry mouth, paresthesias, visual distortions (all at 3%),
paranoia, depersonalization (each 2%) and disorientation with confusion (1%).
8.5.1 Cognition
Marihuana impairs cognition involving short-term memory, attention and
concentration. The digit span task has been used to estimate the effects of
cannabis on recent memory, but results have been inconsistent. Differences may
be due to the dosage used (% THC), the smoking procedure or whether the digit
span task assesses forward or backward recall (Heishman, et al., 1989).
Methodological issues have contributed to difficulties in assessing the effects of
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chronic use (Pope Jr, et al., 1995). However, overall, studies suggest that chronic
users of marihuana suffer varying degrees of cognitive impairment that can be
long lasting (Hollister, 1998). Cannabis intoxication significantly impairs the
ability to learn and recall word lists or short stories. Recent studies comparing 51
long-term marihuana smokers (mean age 24 years) with nonsmoking and shortterm
user controls have confirmed that deficits in attention and memory occur
with heavy cannabis use, and that these continue beyond the period of intoxication
and are cumulative with longer periods of use (Solowij, et al., 2002).
8.5.2 Psychomotor performance
Cannabis exposure impairs psychomotor performance and patients must be
warned not to drive after smoking marihuana. The period of time to abstain from
operating complex machinery depends on the dose, the disease being treated and
the patient’s age and gender. Individuals are affected differently by prolonged
exposure to marihuana and there is some evidence of greater effects on
adolescents. Discrimination of marihuana’s effects from the normal effects of
aging on cognition and performance has not been fully researched (Solowij, et al.,
1999). Performance impairment appears to be less among people who are heavy
users of cannabis compared to occasional users (National Academy of Sciences,
1999, p 3.8). It has been suggested that, unlike alcohol, cannabis users are aware
of their level of intoxication and compensate to become hyper-cautious, resulting
in decrease of speed, decreased frequency of overtaking as well as an increase in
following distance (Gieringer, 1988). Others disagree with this assertion
(Moskowitz, 1985).
8.5.3 Behavioural effects
8.5.3.1 Psychiatric disorders
It is noted in the Marinol® (dronabinol, oral THC) product monograph
(Compendium of Pharmaceutical and Specialties, 2003) that this drug should
be used with caution and careful psychiatric monitoring in patients with mania,
depression or schizophrenia because Marinol® may exacerbate these illnesses.
This reflects the IOM report (National Academy of Sciences, 1999, p 3.23,
3.29) and also the knowledge that psychiatric disorders are associated with
substance dependence and are risk factors for drug abuse.
Acute toxic reactions such as nausea, anxiety, paranoia and disorientation often
occur in naïve marihuana smokers but are uncommon in regular users (Noyes
Jr, et al., 1975). The triggering of psychosis by marihuana has not been
definitively established, but it appears that cannabis is frequently used by
psychotic patients (Hollister, 1998). Heavy cannabis smoking, and even lighter
use in susceptible individuals, can produce an acute psychosis including
anxiety, agitation, amnesia, delusions, hallucinations and hypomanic symptoms
(Australian Commonwealth Government, Department of Health and Ageing,
1994).
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8.5.3.2 Schizophrenia
Self-reported use of cannabis in childhood has been associated with an
increased risk of developing schizophrenia and this risk was related to
frequency of marihuana exposure (Zammit, et al, 2002). A cohort study of
over 1000 children, followed to age 26 from birth, showed a three-fold
increased risk of psychotic disorders in cannabis users and suggested that
cannabis exposure among psychologically vulnerable adolescents should be
strongly discouraged (Arseneault, 2002, p 1212-1213). Heavy marihuana use
can aggravate symptoms and cause more relapses (Alleback, 1999; National
Academy of Sciences, 1999, p 3.29). Follow-up studies confirm the increased
risk of poor prognosis in psychosis for those using marihuana (Caspari, 1999;
van Os, et al., 2002). Individuals with schizophrenia or with a family history of
this disorder are likely to be at greater risk of suffering adverse psychiatric
effects from marihuana (Johns, 2001).
8.5.3.3 Amotivational syndrome
This syndrome is used to describe young people who show little interest in
school, work or other goal-oriented activity as well as withdrawing from social
activities. While it is an ill-defined condition, this is a common feature of
chronic intoxication with many different psychoactive drugs and when the
chronic intoxication is treated or “cured” the behaviour improves. There is no
convincing evidence to show a casual relationship between marihuana smoking
and such behavioural characteristics (National Academy of Sciences, 1999, p
3.31).
8.5.3.4 Dependence and tolerance
Tolerance to most of the effects of marihuana can develop after a few doses
and it also disappears rapidly (National Academy of Sciences, 1999, p 3.8). In
normal subjects tolerance develops to mood, intraocular pressure, EEG
changes, psychomotor performance, antiemetic effects (Jones, et al., 1976) as
well as to cardiovascular effects (Compton, et al., 1990). The dynamics of
tolerance differs for different effects (Pertwee, 1991). Tolerance to some of the
cannabis effects develops both when THC is administered orally (30 mg four
times a day) and when a roughly equivalent dose was given by smoking
(Haney, et al., 1999) (3.1% cigarette, 5 x 10 second puffs). Both groups
became tolerant to the “high”, but there was no diminution of the appetite
stimulating effect from either route of administration.
There is evidence that cannabis dependence occurs with chronic heavy
recreational use. Some individuals report problems in controlling such use
despite resulting personal difficulties (Australian Commonwealth Government,
Department of Health and Ageing, 1994; Stephens, et al., 1993). Dependence is
unlikely to be problematic when cannabis is used therapeutically although
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withdrawal effects may be uncomfortable (British Medical Association, 1997,
p 67). These include restlessness, anxiety, mild agitation, irritability, tremor,
insomnia and EEG/ sleep disturbance, nausea, diarrhea and cramping.
Withdrawal has been studied in subjects, including adolescents who smoked
marihuana recreationally (Crowley, et al., 1998). These effects are considered
mild compared to the physical “syndromes” experienced with alcohol or opiate
withdrawal (Jones, et al., 1976) and the pattern of withdrawal is less clear than
for these drugs (Smith, 2002).
9.0 Overdose/Toxicity
The LD50 is estimated to be 20,000 to 40,000 times the amount in one marihuana cigarette
(approximately 1500 lb) smoked in a period of 15 minutes (Annas, 1997). Marihuana is not a
completely benign agent and it has a variety of physiological effects, but aside from the hazards
consequent to smoking, the adverse effects are within the range tolerated for other medications
(National Academy of Sciences, 1999, p3.49). Cannabis often produces unwanted effects,
typically dizziness, sedation, intoxication, clumsiness, dry mouth, lowered blood pressure or
increased heart rate (Robson, 2001). The rare acute complications (such as panic attacks,
psychosis, convulsions, etc.) that present to the Emergency Department can be managed with
conservative measures (Seldon, et al., 1990). As is stated for overdose with Marinol®
(Compendium of Pharmaceuticals and Specialties, 2003), signs and symptoms with smoked
marihuana are an extension of the psychotomimetic and physiologic effects of THC. If disturbing
psychiatric symptoms occur at the prescribed dosage, the patient should be closely observed in a
quiet environment and supportive measures, including reassurance, should be used.
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Bibliography
1. Agurell, S., Halldin, M., Lindgren, J.E., Ohlsson, A., Widman, M., Gillespie, H.,
Hollister, L. Pharmacokinetics and metabolism of )1-tetrahydrocannabinol and other
cannabinoids with emphasis on man. Pharmacol Rev, 1986; 38: 21-43
2. Agurell, S., Leander, K. Stability, transfer and absorption of cannabinoid constituents of
cannabis (Hashish) during smoking. Acta Pharm Suecica, 1971; 8: 391-402
3. Allebeck, P. Cannabis and psychiatric syndrome. In Marihuana and Medicine. Eds. GG
Nahas, KM Sutin, D Harvey, S Agurell, Humana Press, Totowa, N.J., 1999; p 665-669
4. Ameri, A. The effects of cannabinoids on the brain. Progress in neurobiology, 1999; 58:
315-348
5. American Medical Association, Council of Scientific Affairs 1997. Medical Marijuana,
Chicago, IL http://www.ama-assn.org/ama/pub/article/2036-
6124.html#major_proposed_medical_uses p 10
6. Ames, F.R., Cridland, S. Anticonvulsant effect of cannabidiol. S Afr Med J. 1986; 69:14
7. Annas, G.J. Reefer madness-The Federal response to California’s Medical-Marijuana
Law. New Eng J Med, 1997; 337: 435-439
8. Aronow, W.S., Cassidy, J. Effect of marihuana and placebo-marihuana smoking on
angina pectoris. N.Engl.J.Med. 1974; 291: 65-67
9. Arseneault, L., Cannon, M., Poulton, R., Murray, R., Caspi, A., Moffitt, T.E. Cannabis
use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ.
2002; 325: 1212-1213
10. Astley, S.J., Little, R.E. Maternal marijuana use during lactation and infant development
at one year. Neurotoxicol Teratol 1990; 12: 161-168
11. Australian Commonwealth government, Department of Health and Ageing, National
Drug Strategy, Monograph Series No.44 The health and psychological effects of cannabis
use. National Drug and Alcohol Research Centre, University of New South Wales.
Wayne Hall, Louisa Degenhardt, Michael Lynskey. 1994
12. Baker, P.B., Taylor, B.J., Gough, T.A. The tetrahydrocannabinol and
tetrahydrocannabinolic acid content of cannabis products. J Pharm Pharmacol, 1981; p 33
13. Barnett, G., Chiang, C.W., Perez-Reyes, M., Owens, S.M. Kinetic study of smoking
marijuana. J Pharmacokinet Biopharm. 1982; 10: 495-506
14. Barnett, G., Licko, V., Thompson, T. Behavioral pharmacokinetics of marijuana.
Psychopharmacology (Berl). 1985; 85: 51-56
15. Beaconsfield, P., Ginsburg, J., Rainsbury, R. Marihuana smoking. Cardiovascular effects
in man and possible mechanisms. N Engl J Med. 1972; 287: 209-212
16. Beal, J.A., Olson, R., Laubenstein, L., Morales, J.O., Bellman, P., Yangco, B., Lefkowitz,
L., Plasse, T.F., Shepard, K.V. Dronabinol as a treatment for anorexia associated with
weight loss in patients with AIDS. J Pain Symptom Management, 1995; 10: 89-97
17. Bloom, J.W., Kaltenborn, W.T., Paoletti, P., Camilli, A., Lebowitz, M.D. Respiratory
effects of non-tobacco cigarettes. Br. Med. J 1987; 295: 1516-1518
18. Bornheim, L.M., Everhart, E.T., Li, J., Correia, M.A. Characterization of cannabidiolmediated
cytochrome P450 inactivation. Biochem Pharmacol. 1993; 45: 1323-1331
-24-
19. Brenneisen, R., Egli, A., Elsohly, M.A., Henn, V., Spiess, Y. The effect of orally and
rectally administered delta 9-tetrahydrocannabinol on spasticity: a pilot study with 2
patients. International Journal Clin Pharmacol Ther. 1996; 34: 446-52
20. British Medical Association. Therapeutic uses of cannabis. Harwood Academic
Publishers, Amsterdam, 1997
21. Cabral, G. Marijuana and cannabinoids: effects on infections, immunity, and AIDS. J.
Cannabis Ther, 2001; 1: 61-85
22. Campbell, F.A., Tramer, M.R., Carroll, D., Reynolds, D.J., Moore, R.A., McQuay, H.J.
Are cannabinoids an effective and safe treatment option in the management of pain? A
qualitative systematic review. BMJ. 2001; 323: 13-16
23. Caspari, D. Cannabis and schizophrenia: results of a follow-up study. Eur Arch
Psychiatry Clin Neurosci 1999; 249:45-49
24. Chao, F.C., Green, D.E., Forrest, I.S., Kaplan, J.N., Winship-Ball, A., Braude, M. The
passage of 14C-delta-9-tetrahydrocannabinol into the milk of lactating squirrel monkeys.
Res Commun Chem Pathol Pharmacol 1976; 15: 303-317
25. Chesher, G., Hall, W. Effects of cannabis on the cardiovascular and gastrointestinal
systems. The health effects of cannabis, eds H Kalant, W Corrigall, W. Hall. R Smart,
Centre for Addiction and Mental Health, Toronto, 1999; p 437-458
26. Christensen, H.D., Freudenthal, R.I., Gidley, J.T., Rosenfeld, R., Boegli, G., Testino, L.,
Brine, D.R., Pitt, C.G., Wall, M.E. Activity of delta-8- and delta-9-tetrahydrocannabinol
and related compounds in the mouse. Science. 1971; 172: 165-167
27. Compendium of Pharmaceuticals and Specialties (CPS), Canadian Pharmacists
Association, Ottawa, 2003; p 949
28. Compton, D.R., Dewey, W.L., Martin, B.R. Cannabis dependence and tolerance
production. Adv Alcohol Substance Abuse. 1990; 9(1-2): 129-147
29. Cone, E.J., Huestis, M.A. Relating blood concentrations of tetrahydrocannabinol and
metabolites to pharmacologic effects and time of marijuana usage. Ther Drug Monit.
1993; 15: 527-532.
30. Cone, E.J., Johnson, R.E., Paul, B.D., Mell, L.D., Mitchell, J. Marijuana-laced brownies:
behavioral effects, physiologic effects, and urinalysis in humans following ingestion.
Journal of Analytical Toxicology. 1988; 12: 169-75
31. Consroe, P., Laguna, J., Allender, J., Snider, S., Stern, L., Sandyk, R., Kennedy, K.,
Schram, K. Controlled clinical trial of cannabidiol in Huntington’s disease. Pharmacol
Biochem Behav. 1991; 40: 701-708
32. Consroe, P., Musty, R., Rein, J., Tillery, W., Pertwee, R. The perceived effects of smoked
cannabis on patients with multiple sclerosis. Eur Neurol 1997; 38(1): 44-48
33. Consroe, P., Sandyk, R. Potential role of cannbinoids for therapy of neurological
disorders. In Marijuana/Cannabinoids: Neurobiology and Neurophysiology, eds. A
Bartke and L Murphy, CRC Press, Boca Raton, FL, 1992 pp 459-524
34. Consroe, P., Sandyk, R., Snider, S.R. Open label evaluation of cannabidiol in dystonic
movement disorders. Int J Neurosci. 1986; 30: 277-82
35. Consroe, P., Snider, S.R. Therapeutic potential of cannabinoids in neurological disorders,
in: R Mechoulam (ed.) Marijuana/Cannabinoids as therapeutic agents. CRC Press, Boca
Raton, FL, 1986; 21-49
-25-
36. Crowley, T.J., Macdonald, M.J., Whitmore, E.A., Mikulich, S.K. Cannabis dependence,
withdrawal, and reinforcing effects among adolescents with conduct symptoms and
substance use disorders. Drug Alcohol Depend. 1998; 50: 27-37
37. Cunha, J.M., Carlini, E.A., Pereira, A.E., Ramos, O.L., Pimentel, C., Gagliardi, R.,
Sanvito, W.L., Lander, N., Mechoulam, R. Chronic administration of cannabidiol to
healthy volunteers and epileptic patients. Pharmacology. 1980; 2: 175-85
38. Denning, D.W., Follansbee, S.E., Scolaro, M., Norris, S., Edelstein, H., Stevens, D.A.
Pulmonary aspergillosis in the acquired immunodeficiency syndrome. N Engl J Med.
1991; 324: 654-662
39. Ekert, H., Waters, K.D., Jurk, I.H., Mobilla, J., Loughnan, F. Amelioration of cancer
chemotherapy-induced nausea and vomiting by delta-9-tetrahydrocannabinol. Med J
Aust. 1979; 2:657-659
40. Fant, R.V., Heishman, S.J., Bunker, E.B., Pickworth, W.B. Acute and residual effects of
marijuana in humans. Pharmacol Biochem Behav. 1998; 60: 777-784
41. Foltin, R.W., Fischman, M.W., Byrne, M.F. Effects of smoked marijuana on food intake
and body weight of humans living in a residential laboratory. Appetite. 1988; 11: 1-14
42. Fox, S.H., Kellett, M., Moore, A.P., Crossman, A.R., Brotchie, J.M. Randomised,
double-blind, placebo-controlled trial to assess the potential of cannabinoid receptor
stimulation in the treatment of dystonia. Mov Disord. 2002; 17: 145-149
43. Frankel, J.P., Hughes, A., Lees, A.J., Stern, G.M. Marijuana for parkinsonian tremor. J
Neurol Neurosurg Psychiatry. 1990; 53: 436
44. Fried, P.A.Conceptual issues in behavioral teratology and their application in determining
long-term sequelae of prenatal marihuana exposure. J Child Psychol Psychiatry. 2002;
43: 81-102
45. Garrett, E.R., Hunt, C.A. Physicochemical properties, solubility and protein binding of
delta-9- THC. Journal Pharm Science, 1974; 63
46. Garrett, R., Hunt, C.A. Pharmacokinetics of delta-9-tetrahydrocannabinol in dogs.
Journal Pharm Science. 1977; 66: 395-407
47. Gieringer, D.H. Marijuana, driving, and accident safety. J Psychoactive Drugs. 1988; 20:
93-101
48. Glass, M. The role of cannabinoids in neurodegenerative diseases. Prog
Neuropsychopharmacol Biol Psychiatry 2001; 25: 743-65
49. Grinspoon, L., Bakalar, J.B. Marijuana the forbidden medicine, Yale University Press,
Newhaven, 1993
50. Green, K. Marijuana smoking vs cannabinoids for glaucoma therapy. Arch Ophthalmol
1998; 111: 1433-1437
51. Gross, H., Egbert, M.H., Faden, V.B., Godberg, S.C., Kaye, W.H., Caine, E.D., Hawks,
R., Zinberg, N.E. A double-blind trial of delta-9-THC in primary anorexia nervosa. J Clin
Psychopharmacology, 1983; 3: 165-171
52. Hall, W., Solowij, N. Adverse effects of cannabis. Lancet. 1998; 352: 1611-1616
53. Haney, M., Ward, A.S., Comer, S.D., Foltin, R.W., Fischman, M.W. Abstinence
symptoms following smoked marijuana in humans. Psychopharmacology (Berl). 1999;
141: 395-404
-26-
54. Hansteen, R.W., Miller, R.D., Lonero, L., Reid, L.D., Jones, B. “Effects of cannabis and
alcohol on automobile driving and psychomotor tracking.” Annals of the New York
Academy of Science, 1976; 282: 240-256
55. Harder, S., Rietbrock, S. Concentration –effect relationship of delta-9-
tetrahydrocannabinol and prediction of psychotropic effects after smoking marihuana.
International Journal of Clin Pharmacol Ther. 1997; 35: 155-159
56. Harvey, D.J. “Absorption, distribution and biotransformation of the cannabinoids” in
Marihuana and Medicine. Eds GG Nahas, KM Sutin, D Harvey, S Agurell, 1999; 91-103
57. Heishman S.J., Huestis M.A., Henningfield J.E., Cone E.J. Acute and residual effects of
marijuana: profiles of plasma THC levels, physiological, subjective, and performance
measures. Pharmacol Biochem Behav. 1990; Nov; 37(3): 561-565
58. Heishman, S.J., Stitzer, M.L., Yingling, J.E. Effects of tetrahydrocannabinol content on
marijuana smoking behavior, subjective reports, and performance. Pharmacol. Biochem.
Behav. 1989; 34: 173-179
59. Hollister, L.E. Health aspects of cannabis. Pharmacol Rev. 1986; 38: 1-20
60. Hollister, L.E. Health aspects of cannabis: revisited. International Journal of
Neuropsychopharmacology. 1998; 1: 71-80
61. Huestis, M. “Pharmacokinetics of THC in inhaled and oral preparations” in Marihuana
and Medicine. Eds GG Nahas, KM Sutin, D Harvey, S Agurell, Humana Press, 1999; p
105-116
62. Huestis, M.A., Henningfield, J.E., Cone, E.J. Blood cannabinoids I. Absorption of THC
and formation of 11-OH-THC and THCCOOH during and after smoking marijuana.
Journal of Analytical Toxicology, 1992; 16: 276-282
63. Huestis, M.A., Mitchell, J.M., Cone, E.J. Urinary excretion profiles of 11-nor-9-carboxydelta
9-tetrahydrocannabinol in humans after single smoked doses of marijuana. Journal
of Analytical Toxicology. 1996; 20: 441-452
64. Huestis, M.A., Sampson, A.H., Holicky, B.J., Henningfield, J.E., Cone, E.J.
Characterization of the absorption phase of marijuana smoking. Clin Pharmacol Ther.
1992; 52: 31-41
65. Hyman, G. Marihuana smoking, a possible carcinogen or co-carcinogen. In Marihuana
and Medicine. Eds. GG Nahas, KM Sutin, D Harvey, S Agurell, Humana Press, Totowa,
N.J., 1999; p 289-290
66. Iversen, L.L. The science of marijuana. Oxford University Press, Oxford New York,
2000; p 46-157
67. Jarvinen, T., Pate, D.W., Laine, K. Cannabinoids in the treatment of glaucoma.
Pharmacol Ther 2002; 95: 203-220
68. Johansson, E., Agurell, S., Hollister, L.E., Halldin, M.M. Prolonged apparent half-life of
delta 1-tetrahydrocannabinol in plasma of chronic marijuana users. J Pharm Pharmacol.
1988; 40: 374-375
69. Johns, A. Psychiatric effects of cannabis. Br J Psychiatry. 2001; 178: 116-122
70. Jones, R.T. Cardiovascular system effects of marijuana. J Clin Pharmacol 2002; 2 (11
Suppl): 58S-63S
71. Jones, R.T., Benowitz, N., Bachman, J. Clinical studies of cannabis tolerance and
dependence. Ann N Y Acad Sci. 1976; 282: 221-239
-27-
72. Kelly, T.H., Foltin, R.W., Fischman, M.W. Effects of smoked marijuana on heart rate,
drug ratings and task performance by humans. Behav Pharmacol.1993; 4: 167-178
73. Klein, T. Cannabinoids and the immune system. Pain Res Management, 2001; 6: 95-101
74. Leirer, V.O., Yesavage, J.A., Morrow, D.G. Marijuana carry-over effects on aircraft pilot
performance. Aviat Space Environ Med. 1991; 62: 221-227
75. Lindstrom, P., Lindblom, U., Boreus, L. Lack of effect of cannabidiol in sustained
neuropathia. , presented at Marihuana International Conference, Melbourne, 1987, cited
from British Medical Association. Therapeutic uses of cannabis. Harwood Academic
Publishers, Amsterdam, 1997; p 43
76. Marinol® U.S monograph Unimed Pharmaceuticals Inc.
http://www.marinol.com/pdf/Marinol.pdf
77. Martin, B.R., Cone, E.J. Chemistry and pharmacology of cannabis. In The health effects
of cannabis”, eds H Kalant, W Corrigall, W. Hall. R Smart, Centre for Addiction and
Mental Health, Toronto, 1999; p 21-68
78. Mattes, R.D., Engelman, K., Shaw, L.M., Elsohly, M.A. Cannabinoids and appetite
stimulation. Pharmacol Biochem Behav. 1994; 49: 187-195
79. Mattes, R.D., Shaw, L.M., Edling-Owens, J., Engelman, K., Elsohly, M.A. Bypassing the
first-pass effect for the therapeutic use of cannabinoids. Pharmacol Biochem Behav 1993;
44: 745-747
80. McBay, A.J. Cannabinoid testing: Forensic and analytical aspects. Lab management,
1985; 23: 36-41
81. Mechoulam, R. Chemistry of cannabis. Handbook Exp Pharmacol, 1981; 55
82. Merritt, J.C., Cook, C.E., Davis, K.H. Orthostatic hypotension after delta 9-
tetrahydrocannabinol marihuana inhalation. Ophthalmic Res. 1982; 14: 124-128
83. Miller, L.L. “Acute effects on human memory”, in Marihuana and Medicine. Eds GG
Nahas, KM Sutin, D Harvey, S Agurell, Ch 15. pp 227-231
84. Mittleman, M.A., Lewis, R.A., Maclure, M., Sherwood, J.B., Muller, J.E. Triggering
myocardial infarction by marijuana. Circulation. 2001; 103: 2805-2809
85. Moskowitz, H. Marihuana and driving. Accid Anal Prev. 1985; 17: 323-345
86. Muller-Vahl, K.R., Koblenz, A., Jobges, M., Kolbe, H., Emrich, H.M., Schneider, U.
Influence of treatment of Tourette’s syndrome with delta-9-THC on neuropsychological
performance. Pharmacopsychiatry. 2001; 34: 19-24
87. Muller-Vahl, K.R., Schneider, U., Koblenz, A., Jobges, M., Kolbe, H., Daldrup, T.,
Emrich, H.M. Treatment of Tourette’s syndrome with Delta 9-THC: a randomized
crossover trial. Pharmacopsychiatry. 2002; 35: 57-61
88. National Academy of Sciences, Institute of Medicine (IOM) Marihuana and medicine:
Assessing the science base. National Academy Press, Washington, D.C., 1999 2.5 - 4.32
89. Nelson, K., Walsh, D., Deeter, P., Sheehan, F. A phase II study of delta-9-
tetrahydrocannabinol for appetite stimulation in cancer-associated anorexia. J Palliative
Care. 1994; 10: 14-18
90. Novotny, M., Lee, M.L., Bartle, K.D., A possible chemical basis for the higher
mutagenicity of marijuana smoke as compared to tobacco smoke. Experientia 1976; Mar
15;32
-28-
91. Noyes Jr, R., Brunk, S.F., Avery, D.A., Canter, A.C. The analgesic properties of delta-9-
tetrahydrocannabinol and codeine. Clin Pharmacol Ther. 1975; 18: 84-89
92. Noyes Jr, R., Brunk, S.F., Baram, D.A., Canter, A. Analgesic effect of delta-9-
tetrahydrocannabinol. J Clin Pharmacol. 1975; 15: 139-143
93. Ohlsson, A., Lindgren, J.E., Wahlen, A., Agurell, S., Hollister, L.E., Gillespie, H.K.
Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and
intravenous administration and smoking. Clin Pharmacol Ther. 1980; 28: 409-416
94. O’Kane, C.J., Tutt, D.C., Bauer, L.A. Cannabis and driving: a new perspective.Emerg
Med (Fremantle) 2002; 14: 296-303
95. Plasse, T.F., Gorter, R.W., Krasnow, S.H., Lane, M., Shepard, K.V., Wadleigh, R.G.
Recent clinical experience with dronabinol. Pharmacol Biochem Behav. 1991; 40: 695-
700
96. Perez-Reyes, M. Marijuana smoking: factors that influence the bioavailability of
tetrahydrocannabinol. NIDA Res Monogr. 1990; 99: 42-62
97. Perez-Reyes, M., Wall, M.E. Presence of delta-9-tetrahydrocannabinol in human milk. N
Engl J Med 1982; 307: 819-820
98. Perez-Reyes, M., Timmons, M.C., Lipton, M.A., Davis, K.H., Wall, M.E. Intravenous
injection in man of 9 -tetrahydrocannabinol and 11-OH- 9 -tetrahydrocannabinol..
Science. 1972; 177: 633-635
99. Pertwee, R.G. Tolerance to and dependence on psychotropic cannabinoids. In The
biological bases of drug tolerance and dependence. Ed JA Pratt, Academic Press.,
London, 1991
100. Peterson, RC. Importance of inhalation patterns in determining the effects of marijuana
use. Lancet, 1979 (I)
101. Pope Jr, H.G., Gruber, A.J., Yurgelun-Todd, D. The residual neuropsychological effects
of cannabis: the current status of research. Drug Alcohol Depend. 1995; 8: 25-34
102. Purnell, J.Q., Zambon, A., Knopp, R.H., Pizzuti, D.J., Achari, R., Leonard, J.M., Locke,
C., Brunzell, J.D. Effect of ritonavir on lipids and post-heparin lipase activities in normal
subjects. AIDS 2000; 14: 51-57
103. Raft, D., Gregg, J., Ghia, J., Harris, L. Effects of intravenous tetrahydrocannabinol on
experimental and surgical pain. Psychological correlates of the analgesic response. Clin
Pharmacol Ther. 1977; 21: 26-33
104. Regelson, W., Butler, J.R., Schulz, J., et al. Delta-9-tetrahydrocannabinol as an effective
antidepressant and appetite-stimulating agent in advanced cancer patients. In: Braude
MC, Szara S, eds. The Pharmacology of Marihuana: A Monograph of the National
Institute on Drug Abuse. New York: Raven Press; 1976; p 763-776
105. Richardson, G.A., Ryan, C., Willford, J., Day, N.L., Goldschmidt, L. Prenatal alcohol
and marijuana exposure: effects on neuropsychological outcomes at 10 years.
Neurotoxicol Teratol 2002; 24: 309-320
106. Robson, P. Therapeutic aspects of cannabis and cannabinoids. Br J Psychiatry. 2001; 178:
107-115
107. Roth, M.D., Arora, A., Barsky, S.H., Kleerup, E.C., Simmons, M., Tashkin, D.P. Airway
inflammation in young marijuana and tobacco smokers. Am.J.Respir.Crit Care Med,
1998; 157(3 Pt 1): 928-937
-29-
108. Sallan, S.E., Cronin, C., Zelen, M., Zinberg, N.E. Antiemetics in patients receiving
chemotherapy for cancer: a randomized comparison of delta-9-tetrahydrocannabinol and
prochlorperazine. New England Journal Medicine. 1980; 302: 135-138
109. Sandyk, R., Awerbuch, G. Marijuana and Tourette’s syndrome. J Clin Psychopharmacol.
1988; 8: 444-445
110. Scragg, R.K., Mitchell, E.A., Ford, R.P., Thompson, J.M., Taylor, B.J., Stewart, A.W.
Maternal cannabis use in the sudden death syndrome. Acta Paediatr 2001; 90: 57-60
111. Selden, B.S., Clark, R.F., Curry. S.C. Marijuana. Emerg Med Clin North Am. 1990; 8:
527-539
112. Shiono, P.H., Klebanoff, M.A., Nugent, R.P., Cotch, M.F., Wilkins, D.G., Rollins, D.E.,
Carey, J.C., Behrman, R.E. The impact of cocaine and marijuana use on low birth weight
and preterm birth: a multicenter study. Am J Obstet Gynecol. 1995; 172(1 Pt 1): 19-27
113. Sidney, S. Cardiovascular consequences of marijuana use. J Clin Pharmacol 2002; Nov;
42 (11 Suppl): 64S-70S
114. Sidney, S., Quesenberry Jr, C.P., Friedman, G.D., Tekawa, I.S. Marijuana use and cancer
incidence (California, United States). Cancer Causes Control. 1997; 8: 722-728
115. Sieradzan, K.A., Fox, S.H., Hill, M., Dick, J.P., Crossman, A.R., Brotchie, J.M.
Cannabinoids reduce levodopa-induced dyskinesia in Parkinson’s disease: a pilot study.
Neurology. 2001; 57: 2108-11
116. Smiley, A. Marijuana: On-road and driving-simulator studies, in “Health effects of
cannabis”, H Kalant, W Corrigall, W hall, R Smart (eds), Centre for Addiction and
mental Health, Toronto, 1999; p173-179
117. Smith, N.T. A review of the published literature into cannabis withdrawal symptoms in
human users. Addiction. 2002; 97: 621-632
118. Solowij, N. Long-term effects of cannabis on the central nervous system. In “the Health
effects of cannabis”, 1999; p 195-265
119. Solowij, N., Stephens, R., Roffman, R.A., Babor, T. Does marijuana use cause long-term
cognitive deficits? JAMA. 2002; 287: 2653-2654
120. Staquet, M., Gantt, C., Machin, D. Effect of a nitrogen analog of tetrahydrocannabinol on
cancer pain. Clin Pharmacol Ther. 1978; 23: 397-401
121. Stephens, R.S., Roffman, R.A., Simpson, E.E. Adult marijuana users seeking treatment. J
Consult Clin Psychol. 1993; 61: 1100-1104
122. Tashkin, D.P. Marihuana and the lung. In Marihuana and Medicine. Eds. GG Nahas, KM
Sutin, D Harvey, S Agurell, Humana Press, Totowa, N.J., 1999; p 279-287
123. Tashkin, D.R., Baldwin, G.C., Sarafian, T., Dubinett, S., Roth, M.D. Respiratory and
immunologic consequences of marijuana smoking. J Clin Pharmacol 2002; 42 (11
Suppl): 71S-81S
124. Tashkin, D.P., Coulson, A.H., Clark, V.A., Simmons, M., Bourque, L.B., Duann, S.,
Spivey, G.H., Gong H. Respiratory symptoms and lung function in habitual heavy
smokers of marijuana alone, smokers of marijuana and tobacco, smokers of tobacco
alone, and nonsmokers. Am Rev Respir Dis, 1987; 135: 209-216
125. Tashkin, D.P., Shapiro, B.N.J., Frank, I.M. Acute effects of marihuana on airway
dynamics in spontaneous and experimentally produced bronchial asthma. In The
pharmacology of marihuana. eds. MC Braude, S Szara, Raven Press , New York, 1976
-30-
126. Tashkin, D.P., Shapiro, B.J., Lee, E.Y., Harper, C.E. Subacute effects of heavy
marihuana smoking on pulmonary function in healthy men. New Eng J Med, 1976; 294:
125-129
127. Taylor, D.R., Fergusson, D.M., Milne, B.J., Horwood, L.J., Moffitt, T.E., Sears, M.R.,
Poulton, R. A longitudinal study of the effects of tobacco and cannabis exposure on lung
function in young adults. Addiction 2002; 97: 1055-1061
128. Thomas, B.F., Parker, V.L., Caddell, L.W., Jones, L.V., Sabharwal, S.K., McDaniel, A.I.,
Keimowitz, A.R., Scheffler, N.M., Hart, E.D., Mitchell, J.M., Davis, K.H. Composition
of a standard marihuana cigarette. Chapter 6 In Marihuana and medicine, eds, Nahas,
G.G., Sutin, K.M., Harvey, D., Agurell, S. 1999
129. Trembly, B., Sherman, M. Double-blind clinical study of cannabidiol as a secondary
anticonvulsant. Presented at Conference on cannabis and cannabinoids, Kolympari, 1990,
cited in British Medical Association. Therapeutic uses of cannabis. Harwood Academic
Publishers, Amsterdam, 1997; p51
130. Trouve, R., Nahas, G. Cardiovascular effects of marihuana and cannabinoids. In
Marihuana and Medicine, Assessing the science base. Eds. GG Nahas, KM Sutin, D
Harvey, S Agurell, Humana Press, Totowa, N.J., 1999; p 291-304
131. Truitt Jr, E.B. Biological disposition of tetrahydrocannabinols. Pharmacol.Rev. 1971; 23:
273-278
132. Vachon, L., Mikus, P., Morrisey, W., Fitzgerald, M., Gaenser, E. Bronchial effects of
marihuana smoke in asthma. In The pharmacology of marihuana. eds. MC Braude, S
Szara, Raven Press , New York, 1976
133. Valjent, E., Mitchell, J.M., Besson, M.J., Caboche, J., Maldonado, R. Behavioural and
biochemical evidence for interactions between Delta 9-tetrahydrocannabinol and
nicotine. Br J Pharmacol. 2002; 135: 564-578
134. van Os, J., Bak, M., Hanssen, M., Bijl, R.V., de Graaf, R., Verdoux, H. Cannabis use and
psychosis: a longitudinal population-based study. Am J Epidemiol 2002; 156: 319-327
135. Volicer, L., Stelly, M., Morris, J., McLaughlin, J., Volicer, B.J. Effects of dronabinol on
anorexia and disturbed behavior in patients with Alzheimer’s disease. Int J Geriatr
Psychiatry. 1997; 12: 913-919
136. Wadleigh, R., Spaulding, G.M., Lumbersky, B. et al. Dronabinol enhancement of
appetite in cancer patients. Proc Am Soc Oncol. 1990; 9: 331
137. Wahlqvist, M., Nilsson, I.M., Sandberg, F., Agurell, S. Binding of delta-1-
tetrahydrocannabinol to human plasma proteins. Biochem Pharmacol. 1970; Sep;19(9):
2579-84
138. Wall, M.E., Perez-Reyes, M. The metabolism of delta 9-tetrahydrocannabinol and related
cannabinoids in man. J Clin Pharmacol. 1981; 21(8-9 Suppl): 178S-189S
139. Wall, M.E., Sadler, B.M., Brine, D., Taylor, H., Perez-Reyes, M. Metabolism,
disposition, and kinetics of delta-9-tetrahydrocannabinol in men and women. Clin
Pharmacol Ther. 1983; 34: 352-63
140. 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. Journal Pharm Pharmacol. 1974; 26: 914-916
-31-
141. Widman, M., Nilsson, I.M., Agurell, S., Borg, H., Granstrand, B. Plasma protein binding
of 7-hydroxy- 1-tetrahydrocannabinol: an active 1-tetrahydrocannabinol metabolite. J
Pharm Pharmacol. 1973; Jun;25(6):453-457
142. Working Party on the Use of Cannabis for Medical Purposes, Health Department of New
South Wales, Australia, 2000; Vol II, p 41.
http://www.druginfo.nsw.gov.au/druginfo/reports/canrep2.pdf
143. World Health Organization. Cannabis: a health perspective and research agenda, 1997;
http://www.who.int/substance_abuse/docs/cannabis.pdf
144. Wu, T.-C., Tashkin, D.P., Djahed, B., Rose, J.E. Pulmonary hazards of smoking
marihuana as compared to tobacco. New England Journal of Medicine, 1988; 318
145. Zammit, S., Allebeck, P., Andreasson, S., Lundberg, I., Lewis, G. Self reported cannabis
use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort
study. BMJ 2002; 325: 1199-1201
146. Zhang, Z.F., Morgenstern, H., Spitz, M.R., Tashkin, D.P., Yu, G.P., Marshall, J.R., Hsu,
T.C., Schantz, S.P. Marijuana use and increased risk of squamous cell carcinoma of the
head and neck. Cancer Epidemiol Biomarkers Prev 1999; 8: 1071-1078
147. Zuckerman, B., Frank, D.A., Hingson, R., Amaro, H., Levenson, S.M., Kayne, H.,
Parker, S., Vinci, R., Aboagye, K., Fried, L.E. Effects of maternal marijuana and cocaine
use on fetal growth. N Engl J Med. 1989; 320: 762-768