29/8/2017 Cannabis use and disorder: Pathogenesis and pharmacology - UpToDate

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Cannabis use and disorder: Pathogenesis and pharmacology

Author: David A Gorelick, MD, PhD

Section Editor: Andrew J Saxon, MD
Deputy Editor: Richard Hermann, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2017. | This topic last updated: Oct 28, 2016.

INTRODUCTION — Cannabis (also called marijuana) is the most commonly used illegal psychoactive substance
worldwide [1]. Its psychoactive properties are primarily due to one cannabinoid: delta-9-tetrahydrocannabinol
(THC); THC concentration is commonly used as a measure of cannabis potency [2].

The legal status of cannabis use, for medical as well as recreational purposes, varies internationally as well as
across the United States. The potency of cannabis has increased significantly around the world in recent
decades, which may have contributed to increased rates of cannabis-related adverse effects. Cannabis use
disorder develops in approximately 10 percent of regular cannabis users, and may be associated with cognitive
impairment, poor school or work performance and psychiatric comorbidity such as mood disorders and
psychosis.

The pathogenesis and pharmacology of cannabis use and cannabis use disorder in adults are reviewed here, as
are synthetic cannabinoids. The medico-legal context, epidemiology, comorbidity, and health consequences of
cannabis use and cannabis use disorder in adults are discussed separately as are the clinical manifestations,
course, assessment, diagnosis, and treatment of cannabis use disorder. Acute cannabis intoxication is also
reviewed separately. (See "Cannabis use and disorder: Epidemiology, comorbidity, health consequences, and
medico-legal status" and "Cannabis use and disorder: Clinical manifestations, course, assessment, and
diagnosis" and "Treatment of cannabis use disorder" and "Cannabis (marijuana): Acute intoxication".)

STREET TERMS — Slang terms used for cannabis include Aunt Mary, BC bud, blunt (cannabis within tobacco),
boom, chronic, dope, gangster, ganja, grass, hash, herb, hydro, indo, joint (cannabis cigarette), kif, Mary Jane,
mota, pot, reefer, roach, sinsemilla, skunk, smoke, weed, and yerba [3]. Synthetic cannabinoids have street or
“brand” names that include synthetic weed, legal high, spice, K2, Blaze, RedX Dawn, Paradise, Demon, Black
Magic, Spike, Mr. Nice Guy, Ninja, Zohai, Dream, Genie, Sence, Smoke, Skunk, Serenity, Yucatan, Fire, and
Crazy Clown [3].

PATHOGENESIS — The cannabis plant contains more than 100 unique terpenophenolic compounds known as
(phyto)cannabinoids, most of which have not been fully characterized scientifically [4]. Its psychoactive
properties are primarily due to one cannabinoid: delta-9-tetrahydrocannabinol (THC); THC concentration is
commonly used as a measure of cannabis potency [2].

The THC content of cannabis seized by law enforcement has increased significantly around the world since the
late 1960s, from approximately 1 to 5 percent to as much as 15 percent, along with a decrease in cannabidiol
(CBD, a phytocannabinoid without psychoactive effects, so little or no abuse liability) content [2,5]. This increase
in THC concentration and THC:CBD ratio may contribute to increased rates of cannabis-related adverse effects.

Delta-9-tetrahydrocannabinol (THC) binds to and is a partial agonist at two types of endogenous G-protein-
coupled cannabinoid receptors: CB1 and CB2. CB1 receptors are distributed throughout the brain and elsewhere

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in the body, including vascular endothelium, liver, and adipose tissue. CB2 receptors are present on immune
cells throughout the body (including brain microglia) and on some neurons [6].

THC activates CB1 receptors in the dopaminergic mesolimbic brain circuit, resulting in enhanced release of
presynaptic dopamine. Such activation of the so-called “brain reward system” is hypothesized to mediate the
positive reinforcing and rewarding effects of almost all drugs of abuse [7]. Chronic regular (more than weekly)
cannabis use downregulates brain CB1 receptors; abstinence results in receptor upregulation within several days
[8]. These receptor changes are associated with an often uncomfortable or distressing cannabis withdrawal
syndrome, recognized in DSM-5 [9], which may serve as negative reinforcement to continue cannabis use in
order to suppress the withdrawal. (See "Cannabis withdrawal: Epidemiology, pathogenesis, clinical
manifestations, course, assessment, and diagnosis".)

Genetic basis — Family, twin, and adoption studies suggest that there is a substantial degree of heritability for
both initiation of cannabis use and development of cannabis use disorder [10,11]. A 2010 meta-analysis of 28
published twin studies found that the proportion of variance in who initiates cannabis use due to genetic factors
was 48 and 40 percent in men and women, respectively, due to shared environment 25 and 39 percent, and due
to unshared environment 27 and 21 percent [11]. The corresponding contributions for who develops cannabis
use disorder were 51 and 59 percent for genetic factors, 20 and 15 percent for shared environment, and 29 and
26 percent for unshared environment. The genetic contribution may be greater in adolescent than in older
cannabis users [12] and may influence all psychoactive drug use, not just specifically cannabis [10].

Several individual candidate genes have been proposed for cannabis use disorder, but there is no convincing
evidence for any single gene [13]. Three genome-wide association studies found no significant genetic
associations with cannabis dependence (DSM-IV criteria), initiation of cannabis use, or age of onset [14]. A 2016
larger (14,754 participants) genome-wide association study found significant associations between cannabis
dependence (DSM-IV criteria) and single-nucleotide polymorphisms in several genes related to neuronal calcium
homeostasis or central nervous system development [15].

Psychosocial factors — Genetic studies show that at least half the risk for initiating cannabis use or developing
cannabis use disorder comes from environmental factors (see 'Genetic basis' above). Observational studies
(both cross-sectional and longitudinal) suggest several risk factors associated with cannabis use and cannabis
use disorder, but cannot prove direct causation. These risk factors include family dysfunction (eg, parental
conflict, parental divorce), stressful life events (eg, childhood physical or sexual abuse, poor school performance,
involvement with the criminal justice system), and use of cannabis or other psychoactive substances within the
social network [16]. Protective factors associated with decreased probability of cannabis use and cannabis use
disorder include a supportive family environment, strong religious involvement, good school performance, and
absence of substance use within the social network.

PHARMACOLOGY

Types — The cannabis plant has three species or major varieties. C. sativa and C. indica contain significant
amounts of psychoactive phytocannabinoids (eg, delta-9-tetrahydrocannabinol [THC]), so are cultivated for
recreational and medicinal use. C. ruderalis contains negligible amounts of psychoactive compounds, is
cultivated for seeds and fiber (hemp), and is not considered an illegal substance. Psychoactive
phytocannabinoids are generally found only in the female plant, although in some varieties the male plant may
contain significant amounts. THC is found chiefly in the flowering heads (“buds”), with much less in the leaves
and stems. Significant products include:

● Cannabis (marijuana) usually refers to an unsorted mixture of dried flowers, leaves, and stems (typical THC
content around 6 percent) [5].

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● Sinsemilla refers to the unpollinated female plant (THC content around 13 percent).

● Hashish refers to the compressed resinous secretion of the plant (around 40 percent).

● Hash oil refers to the oil derived from the resin (around 50 percent).

● Cannabis concentrates containing up to 80 percent THC (“dabs,” “earwax”) are produced by solvent-based
extraction (often butane) of THC from plant material [17]. This results in a dense oil or wax-like substance
that can be readily vaporized in a table-top vaporizer or “e-cigarette” (so-called “electronic drug delivery
devices”) or by placing a dab at the tip of a glass or metal rod that is heated [18].

Routes of consumption — Cannabis is most commonly consumed via smoked, inhaled vapor, and oral routes
of administration. Transdermal (patch or gel) cannabis formulations are marketed in some states, but there is no
scientific evidence that these achieve pharmacologically active levels of cannabinoids in the body. Vaporizing
cannabis (“vaping”) heats the material without burning (pyrolysis). This minimizes inhalation of hot gases and
potential carcinogens compared with smoking and may produce less respiratory irritation [19,20]. Sublingual
administration is used for some medical cannabis preparations (eg, nabiximols). Intravenous and rectal
suppository administration have been reported in the literature, but appear to be extremely rare.

Route of administration substantially influences the pharmacokinetics of cannabinoids. Smoked and vaporized
cannabis have rapid absorption, with THC detectable in plasma within seconds and peak concentrations in 3 to
10 minutes [21]. This results in rapid onset of action (within one minute) and intense subjective effects. The rapid
onset and precise control over delivered dose allow for partial titration of dosing despite variations in potency
[22].

Oral cannabis has slower absorption, with peak plasma THC concentrations one to four hours after ingestion
[21], resulting in delayed and less intense effects. This may translate into less abuse liability, based on clinical
experience with oral dronabinol (synthetic THC). Naive users, experiencing no immediate effect from their initial
oral dose, may take additional doses within a short period of time, resulting in inadvertent overdose as the
cumulative dose is absorbed.

Passive (secondhand) exposure to cannabis smoke rarely produces a positive drug test and does not cause
subjective effects or impairment under normal conditions [23-25].

Pharmacokinetics — Systemic bioavailability of smoked THC is typically 15 to 30 percent, with substantial

individual variability, in part due to variations in inhalation technique [21,26]. Oral bioavailability is lower (typically
5 to 10 percent) due to extensive first pass metabolism in the liver, and also has substantial individual variability
[21].

The initial apparent volume of distribution of THC is relatively small (2 to 6 L) due to extensive protein binding
[21]. The steady-state volume of distribution is an order of magnitude greater (70 to 200 L), due to rapid
redistribution of THC, which is highly lipophilic, from blood into fatty tissue throughout the body, including brain
and adipose tissue. Regular cannabis use results in accumulation of THC in adipose tissue, from which it is
slowly released whenever blood concentrations are low. Thus, body stores of THC may be high while blood
concentrations are low, and detectable blood and urine concentrations may occur weeks after last cannabis use
[26]. This complicated pharmacokinetic profile (plus the existence of active metabolites) makes it difficult to find
significant correlations between peripheral THC concentrations and psychological effects or psychomotor
impairment, except in the acute situation soon after ingestion. As an example, a study of 602 individuals arrested
for impaired driving whose blood toxicology testing detected only THC present found that blood THC
concentration accounted for no more than 3 percent of the variance in performance on two standard road-side
psychomotor tests (finger-to-nose, eye convergence) and did not correlate with several others (walk-and-turn,

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one-leg stand, tremors, pupil reaction to light) [27]. No single blood THC concentration distinguished those with
versus without impairment.

THC is metabolized primarily by the hepatic cytochrome P-450 isozymes 3A4 and 2C9 [28]. Its predominant
metabolite is 11-OH-THC (20 percent of smoked THC, 100 percent of oral), which is then further oxidized to
THC-COOH [21,26]. OH-11-THC is pharmacologically active and readily crosses the blood-brain barrier, while
THC-COOH has no subjective effects. THC and its major metabolites are largely excreted in urine (20 to 35
percent) and feces (65 to 80 percent), which may test positive for several weeks after last cannabis intake. Less
than 5 percent of a THC dose appears unchanged in the urine.

Cannabidiol has a systemic bioavailability (range 11 to 45 percent) similar to THC when smoked, and a much
lower oral bioavailability (approximately 5 percent) [21,26]. Cannabidiol is metabolized primarily by the hepatic
cytochrome P-450 isozymes 3A4 and 2C19 [28], with an elimination half-life after chronic oral dosing of two to
five days [21,26]. Cannabidiol is excreted primarily in urine and feces.

SYNTHETIC CANNABINOIDS — Synthetic compounds with cannabinoid-like action, but not necessarily a
phytocannabinoid chemical structure, are known as synthetic cannabinoids. They include illicit, abused
substances reviewed here, as well as medications that can be legally prescribed, reviewed separately. The
clinical presentation and management of acute intoxication from synthetic cannabinoids are also reviewed
separately. (See "Synthetic cannabinoids: Acute intoxication" and "Cannabis use and disorder: Epidemiology,
comorbidity, health consequences, and medico-legal status", section on 'Medico-legal context'.)

Illicitly made synthetic cannabinoids are now a growing health problem around the world, having first appeared in
Europe in the late 2000s [29]. The compounds are sprayed on non-cannabis plant material and marketed at
convenience stores or over the Internet for legal uses (eg, incense, air freshener) under innocuous brand names
(eg, “Spice,” “K2”). As these compounds do not have the delta-9-tetrahydrocannabinol (THC) chemical structure,
they are not detected by standard drug screening tests, hence they are often termed “legal highs” [30]. New
assays that identify specific synthetic cannabinoids are being developed but are expensive and thus not widely
available. Compounds with slightly different chemical structure are constantly developed and marketed to evade
detection. More than 200 were isolated and identified as of 2016.

Little is known about the epidemiology of synthetic cannabinoid use. A 2015 secondary analysis of United States
national survey data found that 0.045 percent of 12- to 34-year-olds reported lifetime use of synthetic
cannabinoids, representing 3.6 percent those reporting use of any “new or uncommon” synthetic psychoactive
drug [31]. The prevalence may be higher than in the 2009 to 2013 sample; there was increasing prevalence of
synthetic cannabinoid use over time within the subsample, from 0 percent in 2009 to 39.7 percent in 2013.
Synthetic cannabinoid users were predominantly unmarried white men living in urban areas; more than 80
percent also used plant-derived cannabis, alcohol, and/or tobacco.

Synthetic cannabinoids first came to clinical attention because of patients with acute cannabis-like effects who
screened negative for THC [32]. Many of the adverse effects of synthetic cannabinoids are more intense or
longer lasting (sometimes days) versions of acute effects of cannabis, eg, tachycardia, agitation, sedation, and
psychosis, sometimes requiring hospitalization. Other effects are not commonly associated with cannabis use,
such as hypertension, QTc-interval prolongation [33], vomiting, delirium, catatonia, seizures, and kidney failure
[29,32].

Approximately two dozen deaths associated with synthetic cannabinoid use have been reported in the United
States through May 2015 [34], whereas there are no well-documented reports of adult deaths associated with
cannabis ingestion absent concomitant ingestion of other central nervous system depressants. Regular use of
synthetic cannabinoids is associated with a more severe withdrawal syndrome than that associated with
cannabis withdrawal. Individuals with synthetic cannabinoid withdrawal may require inpatient hospitalization
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because of seizures or cardiovascular and respiratory failure [35]. Several factors have been suggested to
account for these differences in adverse effects:

● Synthetic cannabinoids are pure agonists with very high affinity at the CB1 receptor, while THC is a partial
agonist at both CB1 and CB2 receptors.

● Synthetic cannabinoids have no apparent action at non-cannabinoid receptors, whereas cannabis contains
compounds which act on a variety of receptors.

● Cannabis contains compounds, such as cannabidiol, which appear to ameliorate or counteract effects of
THC, whereas synthetic cannabinoids are pure CB receptor agonists [36].

SUMMARY

● Cannabis use disorder appears to result from repeated activation of endogenous cannabinoid CB1 receptors
in the brain by the phytocannabinoid delta-9-tetrahydrocannabinol (THC), resulting in increased
dopaminergic activity in the mesolimbic circuit (so-called “brain reward system”). (See 'Pathogenesis'
above.)

● Psychosocial factors involved in the etiology of cannabis use disorder include family dysfunction, stressful
life events, and psychoactive substance use within the social network. (See 'Psychosocial factors' above.)

● Genetic factors account for approximately 40 to 50 percent of the variance in who initiates cannabis use and
50 to 60 percent of the variance in who develops cannabis use disorder, although no specific individual
genes have been clearly identified. (See 'Genetic basis' above.)

● Cannabis is most commonly consumed via smoking, inhaled vapor, and oral routes of administration. The
oral route has the slowest onset of action and lowest bioavailability (due to first-pass metabolism); therefore,
less abuse liability. Smoked and vaporized cannabis have rapid absorption, with THC detectable in plasma
within seconds and peak concentrations in 3 to 10 minutes [21]. This results in rapid onset of action (within
one minute) and intense subjective effects. (See 'Routes of consumption' above.)

● THC, the primary psychoactive chemical in cannabis, is highly lipophilic and stored extensively in fatty
tissue. Prolonged release from these stores as blood concentrations decline results in poor correlation
between THC blood concentration and THC effects. THC is metabolized primarily by hepatic cytochrome
P450 into both active and inactive metabolites, which may be present in urine for several weeks after the
last cannabis intake. (See 'Pharmacokinetics' above.)

● Synthetic cannabinoids have cannabinoid-like actions but not necessarily a cannabinoid chemical structure.
Their acute effects can be more intense and long-lasting than those of cannabis, in part because they are
pure agonists with high affinity at the cannabinoid 1 receptor, whereas THC is a partial agonist at both the
cannabinoid 1 and 2 receptors. This can result in acute intoxication and withdrawal syndromes that are
medically serious and require hospitalization. (See 'Synthetic cannabinoids' above.)

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Topic 109802 Version 2.0

Contributor Disclosures
David A Gorelick, MD, PhD Nothing to disclose Andrew J Saxon, MD Grant/Research/Clinical Trial Support:
Medicasafe [Medication dispensing]. Consultant/Advisory Boards: Neurocrine Biosciences [Tardive dyskinesia
(Valbenazine)]. Richard Hermann, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
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