Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet 42: 327-360

Abstract

Delta(9)-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for non-receptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15-30 minutes, and taper off within 2-3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30-90 minutes, reach their maximum after 2-3 hours and last for about 4-12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial. They are reported to be low in humans and do not preclude legitimate therapeutic use of cannabis-based drugs. Properties of cannabis that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, sedation, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and induction of apoptosis in cancer cells.

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Clin Pharmacokinet 2003; 42 (4): 327-360
R
EVIEW
A
RTICLE
0312-5963/03/0004-0327/$30.00/0
 Adis Data Information BV 2003. All rights reserved.
Pharmacokinetics and
Pharmacodynamics of Cannabinoids
Franjo Grotenhermen
Nova-Institut, H
¨
urth, Germany
Contents
Abstract ....................................................................................328
1. Taxonomy ...............................................................................329
2. Physicochemical Properties and Degradation of Dronabinol .................................330
3. Pharmacokinetics of ∆
9
-Tetrahydrocannabinol ..............................................331
3.1 Absorption ..........................................................................332
3.1.1 Inhalation .....................................................................332
3.1.2 Oral Administration .............................................................333
3.1.3 Ophthalmic Administration ......................................................334
3.1.4 Rectal Administration ...........................................................334
3.1.5 Sublingual Administration .......................................................334
3.1.6 Dermal Administration ..........................................................334
3.2 Distribution ..........................................................................334
3.2.1 Distribution to Tissues ...........................................................334
3.2.2 Distribution to Fetus and Breast Milk ..............................................335
3.3 Metabolism .........................................................................335
3.4 Time Course of Plasma Concentration of ∆
9
-Tetrahydrocannabinol and Metabolites .......337
3.5 Elimination ..........................................................................337
3.5.1 Elimination from Plasma ........................................................337
3.5.2 Excretion with Urine and Faeces .................................................338
3.6 Time–Effect Relationship ..............................................................339
3.6.1 Correlation of Time and Effects ..................................................339
3.6.2 Pharmacokinetic-Pharmacodynamic Modelling ..................................340
3.6.3 Predicting Time of Use ..........................................................340
3.7 Pharmacokinetics of Other Cannabinoids ..............................................341
3.7.1 Cannabidiol ...................................................................341
3.7.2 Nabilone ......................................................................341
3.7.3 Dexanabinol ..................................................................341
3.7.4 Metabolic Interaction of Cannabinoids ..........................................341
4. Pharmacodynamics ......................................................................342
4.1 Mechanism of Action ................................................................342
4.1.1 Cannabinoid Receptors ........................................................342
4.1.2 Endocannabinoids .............................................................342
4.1.3 Affinity for the Cannabinoid Receptor............................................343
4.1.4 Tonic Activity of the Endocannabinoid System ....................................343
4.2 Pharmacological Effects of ∆
9
-Tetrahydrocannabinol ...................................343
4.2.1 Toxicity ........................................................................343
4.2.2 Psyche, Cognition and Behaviour ................................................344
4.2.3 Central Nervous System and Neurochemistry .....................................345
4.2.4 Circulatory System .............................................................345
4.3 Effects on Some Other Organ Systems .................................................345

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328 Grotenhermen
4.3.1 Antibacterial and Antiviral Actions ...............................................345
4.3.2 Eye ...........................................................................345
4.3.3 Hormonal System and Fertility ...................................................345
4.3.4 Genetics and Cell Metabolism ..................................................345
4.3.5 Immune System ................................................................345
4.3.6 Sperm ........................................................................345
4.3.7 Digestive Tract .................................................................346
4.4 Pharmacological Activity of ∆
9
-Tetrahydrocannabinol Metabolites .......................346
4.4.1 11-Hydroxy-∆
9
-Tetrahydrocannabinol ............................................346
4.4.2 11-Nor-9-Carboxy-∆
9
-Tetrahydrocannabinol ......................................346
4.5 Pharmacological Effects of Other Cannabinoids ........................................346
4.5.1 Phytocannabinoids ............................................................346
4.5.2 Endocannabinoids .............................................................346
4.5.3 Classical Synthetic Cannabinoids ................................................346
4.5.4 Nonclassical Synthetic Cannabinoids ............................................347
4.5.5 Anandamide Analogues .......................................................347
4.5.6 Therapeutic Potential of Antagonists .............................................347
5. Tolerance and Dependency ..............................................................347
5.1 Tolerance ...........................................................................347
5.2 Withdrawal and Dependency ........................................................347
6. Therapeutic Uses .........................................................................348
6.1 Hierarchy of Therapeutic Effects .......................................................348
6.2 Established Effects ...................................................................348
6.3 Relatively Well-Confirmed Effects ......................................................348
6.4 Less Confirmed Effects ...............................................................348
6.5 Basic Research Stage ................................................................348
7. Drug Interactions.........................................................................349
8. Conclusions .............................................................................349
∆
9
-Tetrahydrocannabinol (THC) is the main source of the pharmacological
Abstract
effects caused by the consumption of cannabis, both the marijuana-like action and
the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the
non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly
discovered modulators of the endogenous cannabinoid system are also promising
candidates for clinical research and therapeutic uses. Cannabinoids exert many
effects through activation of G-protein-coupled cannabinoid receptors in the brain
and peripheral tissues. Additionally, there is evidence for non-receptor-dependent
mechanisms.
Natural cannabis products and single cannabinoids are usually inhaled or taken
orally; the rectal route, sublingual administration, transdermal delivery, eye drops
and aerosols have only been used in a few studies and are of little relevance in
practice today. The pharmacokinetics of THC vary as a function of its route of
administration. Pulmonary assimilation of inhaled THC causes a maximum
plasma concentration within minutes, psychotropic effects start within seconds to
a few minutes, reach a maximum after 15 to 30 minutes, and taper off within 2 to 3
hours. Following oral ingestion, psychotropic effects set in with a delay of 30 to
90 minutes, reach their maximum after 2 to 3 hours and last for about 4 to 12
hours, depending on dose and specific effect.
At doses exceeding the psychotropic threshold, ingestion of cannabis usually
causes enhanced well-being and relaxation with an intensification of ordinary
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Cannabinoids 329
sensory experiences. The most important acute adverse effects caused by overdos-
ing are anxiety and panic attacks, and with regard to somatic effects increased
heart rate and changes in blood pressure. Regular use of cannabis may lead to
dependency and to a mild withdrawal syndrome. The existence and the intensity
of possible long-term adverse effects on psyche and cognition, immune system,
fertility and pregnancy remain controversial. They are reported to be low in
humans and do not preclude legitimate therapeutic use of cannabis-based drugs.
Properties of cannabis that might be of therapeutic use include analgesia,
muscle relaxation, immunosuppression, sedation, improvement of mood, stimula-
tion of appetite, antiemesis, lowering of intraocular pressure, bronchodilation,
neuroprotection and induction of apoptosis in cancer cells.
O
OH
7
1
2
3
1'
2'
3'
4'
5"3"1"5'
6'
8
9
10
4
5
6
Monoterpenoid numbering
O
OH
11
9
10
10a
10b
1
2
3
5'3'1'4
56
12
13
6a
7
8
Dibenzopyran numbering
Fig. 1. Chemical structure of tetrahydrocannabinol (THC), the main cannabinoid in the cannabis plant, numbered according to the
monoterpenoid s
y
stem
(
∆
1
-THC
)
and dibenzop
y
ran s
y
stem
(
∆
9
-THC
)
.
The chemical structure of the first phytocannabi- pounds, including endogenous ligands of the recep-
noids was successfully characterised in the 1930s tors and a large number of synthetic cannabinoid
and 1940s,
[1]
but it was not until 1964 that the analogues.
chemical structure of ∆
9
-tetrahydrocannabinol
The phytocannabinoids have been numbered ac-
(∆
9
-THC), mainly responsible for the pharmacolog-
cording to the monoterpenoid system or the
ical effects of the cannabis plant,
[2,3]
had been identi-
dibenzopyran system (figure 1); the latter system
fied and synthesised.
[4]
Another scientific break-
will be employed in this review. A total of 66
through in cannabinoid research has been the detec-
phytocannabinoids have been identified, most of
tion of a system of specific cannabinoid receptors in
them belonging to several subclasses or types:
[9]
the
mammals
[5]
and their endogenous ligands
[6]
within
cannabigerol (CBG), cannabichromene (CBC), can-
the past 15 years.
nabidiol (CBD), ∆
9
-THC, ∆
8
-THC, cannabicyclol
(CBL), cannabielsoin (CBE), cannabinol (CBN),
cannabinodiol (CBDL) and cannabitriol (CBTL)
1. Taxonomy
types. A total of nine cannabinoids belong to the
∆
9
-THC group, with side chains of one, three, four
Originally, the term cannabinoid referred to the
and five carbons (figure 2 and table I).
phytocannabinoids of Cannabis sativa L. with a
typical C
21
structure and their transformation prod- The cannabinoid acids of ∆
9
-THC, CBD, CBC
ucts,
[7]
but this restricted pharmacognostic definition and CBG are the quantitatively most important can-
has been discarded in favour of a broader concept nabinoids present in the plant (see table II and figure
based on pharmacology and synthetic chemistry.
[8]
3). Their relative concentrations vary, and plants
Today the term cannabinoid may comprise all have been described that mainly contain one of these
ligands of the cannabinoid receptor and related com- cannabinoids with a C
5
side chain or contain the
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330 Grotenhermen
acids/THC ratio was reported to range between
6.1:1 and 0.5:1.
[17]
Natural ∆
9
-THC has two chiral centres at C-6a
and C-10a in the trans configuration. Usually the
acronym THC is applied to this naturally occurring
(–)-trans-isomer of ∆
9
-THC, and will be used in this
text as well. The generic name for ∆
9
-trans-te-
trahydrocannabinol is dronabinol. MarinolUse of
tradenames is for product identification only and
does not imply endorsement (Unimed Pharmaceu-
ticals, Inc.) contains synthetic dronabinol, dissolved
OH
O
R
3
R
2
R
1
Fig. 2. Cannabinoids of the ∆
9
-tetrahydrocannabinol (THC) type.
The most widespread cannabinoids are the phenolic ∆
9
-THCs with
21 carbon atoms and a C
5
side chain (R
2
= C
5
H
11
) and its two
corresponding carboxylic acids A and B with R
1
or R
3
= COOH (see
table I
)
.
in sesame oil, as capsules of 2.5, 5 and 10mg of
dronabinol.
propyl homologue (C
3
side chain) of ∆
9
-THC
(∆
9
-trans-tetrahydrocannabivarin);
[10-12]
the methyl
2. Physicochemical Properties and
(C
1
side chain) and butyl (C
4
side chain) homo-
Degradation of Dronabinol
logues are always present in very low concentra-
tions.
[13,14]
THC and many of its metabolites are highly
The cannabinoid acids of THC are devoid of
lipophilic and essentially water-insoluble.
[18]
Calcu-
psychotropic effects
[2]
and have to be decarboxyl-
lations of the n-octanol/water partition coefficient
ated to the phenols to produce marijuana-like ef-
(K
ow
) of THC at neutral pH vary between 6000
fects, e.g. by smoking the dried plant matter. The
using shake-flask methodology
[19]
and 9 440 000 by
ratio of ∆
9
-THC acids to phenolic ∆
9
-THC has been
reverse-phase high-pressure liquid chromatographic
reported to range between 2:1
[11]
and >20:1
[16]
in
estimation.
[20]
The wide range for aqueous solubility
leaves and flowers of Cannabis sativa. In plants
and K
ow
, can be attributed to the difficulty of uni-
grown in the United Kingdom from Moroccan, Sri
formly dissolving this essentially water-insoluble
Lankan and Zambian seed stock, the ∆
9
-THC acids/
substance and accurately measuring small amounts
∆
9
-THC ratio was 17:1 compared with 2:1 in the
of it. The spectrophotometric pKa is 10.6.
[18]
plants from the original areas with hotter cli-
THC is thermolabile and photolabile.
[21,22]
Stor-
mates.
[11]
In cannabis resin (hashish), the THC age leads to a cumulative decrease in THC content
Table I. Cannabinoids of the ∆
9
-trans-tetrahydrocannabinol type
Cannabinoid R
1
a
R
2
R
3
∆
9
-trans-Tetrahydrocannabinolic COOH C
5
H
11
H
acid A
∆
9
-trans-Tetrahydrocannabinolic H C
5
H
11
COOH
acid B
∆
9
-trans-Tetrahydrocannabinol H C
5
H
11
H
∆
9
-trans-Tetrahydrocannabinolic COOH or H C
4
H
9
H or COOH
acid-C
4
∆
9
-trans-Tetrahydrocannabinol-C
4
HC
4
H
9
H
∆
9
-trans-Tetrahydrocannabivarinic COOH C
3
H
7
H
acid
∆
9
-trans-Tetrahydrocannabivarin H C
3
H
7
H
∆
9
-trans-Tetrahydrocannabiorcolic COOH or H CH
3
H or COOH
acid
∆
9
-trans-Tetrahydrocannabiorcol H CH
3
H
a See figure 2 for the basic chemical structure of ∆
9
-trans-tetrahydrocannabinol.
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Cannabinoids 331
Table II. Average cannabinoid concentrations in 35 312 cannabis preparations confiscated in the US between 1980 and 1997
[15]
THC (%) CBD (%) CBC (%) CBN (%)
Marijuana 3.1 0.3 0.2 0.3
Sinsemilla 8.0 0.6 0.2 0.2
Hashish 5.2 4.2 0.4 1.7
Hashish oil 15.0 2.7 1.1 4.1
CBC = cannabichromene; CBD = cannabidiol; CBN = cannabinol; THC = ∆
9
-tetrahydrocannabinol.
through oxidation of THC to CBN.
[23,24]
Within 47 for 5 minutes at a temperature of 200–210°C has
been reported to be optimal for this purpose,
[16]
but a
weeks, the THC content of marijuana (dried leaves
few seconds in burning cannabis cigarettes are
and flowers of Cannabis sativa) decreased by 7%
equally sufficient. Slow decarboxylation of THC
with dark and dry storage at 5°C, and by 13% at
acid occurs at room temperature.
20°C.
[24]
Dronabinol rapidly degrades in acid solu-
tions. The kinetics seem to be first order and specifi-
3. Pharmacokinetics
cally hydrogen ion-catalysed,
[18]
so that significant
of ∆
9
-Tetrahydrocannabinol
degradation is assumed to occur in the normal stom-
ach with a half-life of 1 hour at pH 1.
[18]
Cannabis products are commonly either inhaled
Decarboxylation of the THC acids to the corre-
by smoking a cannabis cigarette, taken orally as
sponding phenols occurs readily over time, upon
dronabinol capsules or in baked foods or liquids
heating
[16,23]
or under alkaline conditions. Heating (figure 4). Various other routes of administration
R
3
O
OH
R
1
R
2
O
OH
R
1
R
2
OH
R
1
R
2
O
R
3
O
OR
1
R
2
R
3
R
1
= H or COOH
R
2
= C
3
or C
5
side chain
R
3
= H or CH
3
Cannabigerol type
R
1
= H or COOH
R
2
= C
3
or C
5
side chain
Cannabichromene type
R
1
= H or COOH
R
2
= C
1,
C
3,
C
4,
or C
5
side chain
R
3
= H or CH
3
Cannabidiol type
R
1
= H or C
3
R
2
= H or COOH
R
3
= C
1,
C
3,
C
4,
or C
5
side chain
Cannabinol type
Fi
g
. 3. Some ph
y
tocannabinoids.
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332 Grotenhermen
Serum protein binding
Lipoproteins, albumin
Tissue storage
Fat, protein
Hair, saliva, sweat
THC concentration in extracellular water
Absorption
THC concentration at site of action
Metabolism
Hepatic microsomal,
non-microsomal,
extrahepatic
Metabolites
Biliary excretion
Enterohepatic recirculation
Renal excretion
Glomerular filtration,
tubular secretion,
passive reabsorption
Lung, intestine, colon, skin
Administration
THC
Cannabinoid receptors,
other targets of action
THC effects
Fi
g
. 4. Pharmacokinetic properties of ∆
9
-tetrah
y
drocannabinol
(
THC
)
[
reproduced from Brenneisen
[34]
with permission
]
.
and delivery forms have been tested for therapeutic A systemic bioavailability of 23 ± 16%
[38]
and 27
purposes. The rectal route with suppositories has
± 10%
[42]
for heavy users versus 10 ± 7% and 14 ±
been applied in some patients,
[25]
and dermal
[26]
and
1% for occasional users of the drug was reported. In
sublingual
[27]
administration are under investigation.
a study with a smoking machine, patterns of canna-
Other methods include eye drops to decrease in-
bis smoking were simulated with regard to puff
traocular pressure,
[28]
as well as aerosols and inhala-
duration and volume,
[43]
resulting in 16 to 19% of
tion with vaporisers to avoid the harm associated
with smoking.
[29,30]
The kinetics of cannabinoids are
much the same for females and males,
[31]
as well as
for frequent and infrequent users.
[32,33]
3.1 Absorption
3.1.1 Inhalation
THC is detectable in plasma only seconds after
the first puff of a cannabis cigarette
[35]
with peak
plasma concentrations being measured 3 to 10 min-
utes after onset of smoking (figure 5).
[35-40]
Systemic
bioavailability generally ranges between about 10%
and 35%, and regular users are more efficient (table
III).
[38]
Bioavailability varies according to depth of
inhalation, puff duration and breathhold.
0
20
40
60
80
100
120
140
160
180
Time during and after smoking (h)
Concentration (µg/L)
6543210
THC
11-OH-THC
THC-COOH
Fig. 5. Mean plasma concentrations of ∆
9
-tetrahydrocannabinol
(THC), 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC
(THC-COOH) of six subjects during and after smoking a cannabis
ci
g
arette containin
g
about 34m
g
of THC.
[35]
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Cannabinoids 333
Table III. Systemic bioavailability of ∆
9
-tetrahydrocannabinol (THC)
Subjects Systemic bioavailability (%) Formulation Reference
average range
Oral
11 frequent or infrequent 6 ± 3 4–12 THC in chocolate cookie 39
users
6 men, 6 women 10-20 THC in sesame oil 31
7 men, 10 women 7 ± 3 2–14 THC in sesame oil 41
Inhalational
9 heavy users 23 ± 6 6–56 Marijuana cigarette 38
9 light users 10 ± 7 2–22 Marijuana cigarette 38
5 heavy users 27 ± 10 16–39 Marijuana cigarette 42
4 light users 14 ± 1 13–14 Marijuana cigarette 42
11 frequent or infrequent 18 ± 6 8–24 THC in cigarette 39
users
Rectal
2 patients with spasticity 190–220% of oral Suppository with THC- 25
bioavailability hemisuccinate
THC in the mainstream smoke. If the whole ciga- gastrointestinal tract in an oil vehicle
[31]
and
rette was smoked in one puff the percentage of THC 90–95% if taken in a cherry syrup vehicle,
[48]
but it is
in the mainstream increased to 69%. About 30% is unclear from these data how much of this radioactiv-
assumed to be destroyed by pyrolysis. With smok- ity belongs to unchanged THC and how much to
ing, additional THC is lost in the butt, in sidestream breakdown products.
smoke, and by incomplete absorption in the lungs.
An extensive first-pass liver metabolism further
Smoking a pipe that produces little sidestream
reduces the oral bioavailability of THC, i.e. much of
smoke may also result in high effectiveness, with
the THC is initially metabolised in the liver before it
45% of THC transferred via the mainstream smoke
reaches the sites of action. Ingestion of THC 20mg
in one smoker tested.
[23]
3.1.2 Oral Administration
With oral use, absorption is slow and erratic,
resulting in maximal plasma concentrations usually
after 60–120 minutes (figure 6).
[31,39,44]
In several
studies, maximal plasma concentrations were ob-
served as late as 4 hours
[45]
and even 6 hours in some
cases.
[39,41,46]
Several subjects showed more than
one plasma peak.
[37,39,41]
∆
9
-THC is expected to be degraded by the acid of
the stomach and in the gut.
[18]
At low pH, isomerisa-
tion to ∆
8
-THC and protonation of the oxygen in the
pyran ring may occur with cleavage to substituted
CBDs.
[18]
It has been suggested that a somewhat
higher bioavailability is obtained in an oil formula-
tion.
[47]
However, absorption seems to be nearly
complete in different vehicles. 95% of total radioac-
tivity of radiolabelled THC was absorbed from the
0
5
10
15
20
25
30
35
40
45
50
55
60
Time after oral ingestion (h)
Concentration (µg/L)
024681012
THC
11-OH-THC
THC-COOH
Fig. 6. Mean plasma concentrations of ∆
9
-tetrahydrocannabinol
(THC), 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC
(THC-COOH) of six cancer patients after ingestion of one oral dose
of THC 15mg (estimated from single graphs for each patient of
Frytak et al.,
[46]
with permission). The plasma courses of THC show-
ed considerable interindividual variation (see figure 8 for the individ-
ual courses of THC plasma concentrations of three patients
)
.
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334 Grotenhermen
in a chocolate cookie
[39]
and administration of About 90% of THC in the blood is distributed to
dronabinol 10mg
[41]
resulted in a very low systemic the plasma, another 10% to red blood cells.
[54]
bioavailability of 6 ± 3% (range 4–12%)
[39]
or 7 ± 95–99% of plasma THC is bound to plasma pro-
3% (range 2–14%),
[41]
respectively, with a high in- teins, mainly to lipoproteins and less to albu-
terindividual variation. min.
[32,54-56]
The time course of plasma concentrations of can-
3.1.3 Ophthalmic Administration
nabinoids has been described to fit to open two-
A study in rabbits with THC in light mineral oil
compartment,
[31,57]
three-compartment
[44,58,59]
or
determined a variable systemic bioavailability of
four-compartment
[32]
models. Even five- and six-
6–40% with ophthalmic administration.
[49]
Plasma
compartment models have been found in computer
concentrations peaked after 1 hour and remained
models to best fit the THC plasma course in ani-
high for several hours.
mals.
[53]
3.1.4 Rectal Administration
The apparent (initial) volume of distribution of
With rectal application, systemic bioavailability
THC is small for a lipophilic drug, equivalent to the
strongly differed depending on suppository formula-
plasma volume of about 2.5–3L, reflecting high
tions. Among formulations containing several polar
protein binding that complicates initial disposition.
esters of THC in various suppository bases, THC-
It was reported to be 2.55 ± 1.93L in drug-free
hemisuccinate in Witepsol H15 showed the highest
users
[32]
and 6.38 ± 4.1L in regular users.
[32]
The
bioavailability in monkeys and was calculated to be
steady-state volume of distribution has been esti-
13.5%.
[50]
The rectal bioavailability of this formula-
mated to be more than 100 times larger, in the range
tion was calculated to be about as twice as high as
of about 10 L/kg.
[31,32,57]
These early data have been
oral bioavailability in a small clinical study.
[25]
questioned because of the possible inaccuracy of the
quantification methods used. Based on pharmaco-
3.1.5 Sublingual Administration
kinetic data of two studies that used gas chromatog-
Clinical studies are under way using a liquid
raphy-mass spectrometry (GC-MS) for analysis of
cannabis extract applied under the tongue. A phase I
THC concentration, an average volume of distribu-
study in six healthy volunteers receiving up to 20mg
tion of 236L (or 3.4 L/kg assuming 70kg
of THC was reported to result in ‘relatively fast’
bodyweight) has been calculated.
[60]
Even smaller
effects.
[27]
In phase II studies, THC plasma concen-
steady-state volumes of distribution of about 1 L/kg
trations of up to 14 µg/L were noted.
[51]
have been reported using GC-MS.
[33]
This volume is
3.1.6 Dermal Administration
still about 20 times the plasma volume, since the
In a study using the more stable ∆
8
-THC isomer,
majority of the lipophilic drug is in the tissues.
the permeability coefficient of THC was significant-
ly enhanced by water and by oleic acid in propylene
3.2.1 Distribution to Tissues
glycol and ethanol,
[52]
resulting in significant THC
The lipophilicity of THC with high binding to
concentrations in the blood of rats. Studies designed
tissue and in particular to fat causes a change of
to develop transdermal delivery of cannabinoids
distribution pattern over time.
[61]
THC rapidly pene-
found a mean effective permeability coefficient for
trates highly vascularised tissues, among them liver,
∆
9
-THC in propylene glycol of 6.3 × 10
–6
cm/h.
[26]
heart, fat, lung, jejunum, kidney, spleen, mammary
gland, placenta, adrenal cortex, muscle, thyroid and
3.2 Distribution
pituitary gland, resulting in a rapid decrease in plas-
Tissue distribution of THC and its metabolites is ma concentration.
[62]
Only about 1% of THC admin-
assumed to be governed only by their physicochemi- istered intravenously is found in the brain at the time
cal properties, with no specific transport processes of peak psychoactivity.
[63]
The relatively low con-
or barriers affecting the concentration of the drug in centration in the brain is probably due to high perfu-
the tissues.
[53]
sion rate of the brain moving THC in and out of the
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Cannabinoids 335
brain rapidly.
[64]
Penetration of the metabolite ted that the placenta plays a major role in the vari-
ability of fetal exposure to cannabinoids.
[77]
11-hydroxy-∆
9
-tetrahydrocannabinol (11-OH-
THC) into the brain seems to be faster and higher
THC passes into the breast milk. In monkeys,
than that of the parent compound.
[63,65]
Thus, it can 0.2% of the THC ingested by the mother appeared in
the milk.
[78]
Long-term administration leads to ac-
be expected that 11-OH-THC will significantly con-
cumulation.
[79]
In a human female, the THC concen-
tribute to the overall central effects of THC, espe-
tration in milk was 8.4 times higher than in plasma,
cially with oral use.
in the low µg/L range.
[79]
Thus, a nursing infant
Subsequently, intensive accumulation occurs in
might ingest daily THC amounts in the range of
less vascularised tissues and finally in body fat,
[66-68]
about 0.01–0.1mg from the milk of a mother who is
the major long-term storage site, resulting in con-
consuming one or two cannabis cigarettes a day.
centration ratios between fat and plasma of up to
10
4
:1.
[69]
The exact composition of the material
3.3 Metabolism
accumulated in fat is unknown,
[47]
among them be-
ing unaltered THC and its hydroxy metabolites.
[68]
Metabolism of THC occurs mainly in the liver by
A substantial proportion of the deposit in fat seems
microsomal hydroxylation and oxidation catalysed
to consist of fatty acid conjugates of 11-OH-
by enzymes of the cytochrome P450 (CYP) com-
THC.
[70,71]
plex;
[80,81]
a member of the CYP2C subfamily of
isoenzymes plays the major role in humans.
[82]
In
3.2.2 Distribution to Fetus and Breast Milk
rats, more than 80% of intravenous THC was meta-
In animals and humans, THC rapidly crosses the
bolised within 5 minutes.
[83]
placenta.
[72]
The course of THC concentrations in
Metabolic rates show relevant interspecies differ-
fetal blood closely approximates that in the maternal
ences
[84,85]
that may be attributed to different
blood, though fetal plasma concentrations were
profiles of CYP isoenzymes.
[85]
This fact may be in
found to be lower than maternal concentrations in
part responsible for some problems of interspecies
several species.
[73-76]
The metabolites 11-OH-THC
extrapolation of pharmacological and toxicological
and 11-nor-9-carboxy-∆
9
-tetrahydrocannabinol effects.
[86]
In humans, allylic oxidation, epoxidation,
aliphatic oxidation, decarboxylation and conjuga-
(THC-COOH) cross the placenta much less effi-
tion have been described.
[64]
ciently than THC.
[74,76]
Following oral intake, THC
plasma concentrations in the fetus are about one-
Nearly 100 metabolites have been identified for
tenth of the maternal plasma concentration.
[75]
In
THC.
[85]
Besides the liver, other tissues are also able
comparison, the fetal concentration is about one- to metabolise cannabinoids but to a much lesser
degree, among them the heart and the lung.
[87-89]
third of the maternal plasma concentration after
intravenous or inhaled THC.
[73,76]
Thus, oral intake
Major metabolites are monohydroxylated com-
may have less effect on the fetus compared with
pounds. In humans
[90,91]
and many other spe-
inhalation. A study with dizygotic twins demonstra-
cies,
[85,87]
C-11 is the major site attacked (figure 7).
O
11
CH
3
OH
CH
2
OH COOH CO
-
O
-
Glucuronide
Fatty acid conjugate
HO
8
Fi
g
. 7. Main metabolic pathwa
y
s of ∆
9
-tetrah
y
drocannabinol.
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336 Grotenhermen
Hydroxylation results in 11-OH-THC and further Average plasma clearance rates have been report-
ed to be 11.8 ± 3.0 L/h (197 ± 50 ml/min) for women
oxidation in THC-COOH, which may be glucuroni-
and 14.9 ± 3.7 L/h (248 ± 62 ml/min) for men,
[31]
dated to 11-nor-9-carboxy-THC glucuronide. Long-
whereas others have determined higher mean clear-
chain fatty acid conjugates of 11-OH-THC are pro-
ance rates of about 36 L/h (600 ml/min) for naive
posed to be a form in which THC may be stored
THC users and about 60 L/h (1000 ml/min) for
within tissues.
[92]
The C-8 position is also attacked
regular users (see table IV).
[32]
The latter values are
in humans but to a much lesser degree than C-11.
[91]
similar to the volume of hepatic blood flow,
[32,42]
Table IV. Pharmacokinetic data for ∆
9
-tetrahydrocannabinol
Subjects Dose (mg) AUC (µg • min/ C
max
(µg/L) t
1
/2β
(h) Vd (L) CL (ml/min) References
L)
Intravenous
4 nonusers 0.5 57 ± 4 658 ± 174 57
5 regular users 0.5 27 ± 1 597 ± 76 57
6 males (drug 2 19.6 ± 4.1 626 ± 296 605 ± 149 32
free)
6 males (long- 2 18.7 ± 4.2 742 ± 331 977 ± 304 32
term)
6 males 4 70 ± 30 36 734 ± 444 248 ± 62 31
6 females 2.2 85 ± 26 29 523 ± 217 197 ± 50 31
11 males 5 4330 ± 620 161-316 37 39
9 heavy users 5 4300 ± 1670 288 ± 119 38
9 light users 5 6040 ± 2.21 302 ± 95 38
5 heavy users 5 5180 ± 830 >20 980 ±150 42
4 light users 5 5460 ± 1180 >20 950 ± 200 42
4 heavy users 5 9908 ± 3785 438 ± 36 1.9 ± 0.3 75 ± 16 777 ± 690 33
4 light users 5 7094 ± 2248 386 ± 29 1.6 ± 0.5 74 ± 35 771 ± 287 33
Oral
6 males 20 14.5 ± 9.7 25 31
6 females 15 9.4 ± 4.5 25 31
11 males 20 1020 ± 320 4.4–11 37 39
3 males 3 × 15 4–646
3 males, 3 15 3–546
females
20 AIDS 2 × 2.5 2.01 44
patients (0.58–12.48)
7 men, 10 10 610 ± 310 4.7 ± 3.0 41
women
Inhalational
11 males 19 1960 ± 650 33–118 37 39
9 heavy users 19 2160 ± 1030 98 ± 44 38
9 light users 19 1420 ± 740 67 ± 38 38
5 heavy users 10 2450 ± 530 42
4 light users 10 1420 ± 340 42
6 males 15.8 84 (50–129) 35
6 males 33.8 162 (76–267) 35
AUC = area under the concentration-time curve; CL = systemic clearance; C
max
= maximum plasma concentration; t
1
/2β
= plasma
elimination half-life; Vd = volume of distribution.
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Cannabinoids 337
indicating that the limiting step of the metabolic rate study with dronabinol 2.5 mg/day, mean maximal
is controlled by hepatic blood flow. These high THC concentrations were 2.01 µg/L compared with
clearance rates explain the high degree of first-pass 4.61 µg/L for 11-OH-THC.
[44]
The course of THC
metabolism and the much higher concentration of plasma concentrations shows a high interindividual
11-OH-THC after oral administration compared variation (figure 8).
with inhalation.
3.5 Elimination
3.4 Time Course of Plasma Concentration of
∆
9
-Tetrahydrocannabinol and Metabolites
3.5.1 Elimination from Plasma
About 6 hours after intravenous administration of
Intravenous infusion of THC 5mg within 2 min-
THC a pseudoequilibrium is reached between plas-
utes caused average plasma concentrations at 2 min-
ma and tissues.
[64]
The concentration in plasma usu-
utes after the end of infusion of 438 µg/L in frequent
ally has dropped below 2 µg/L at this time and than
and of 386 µg/L in infrequent users, that fell rapidly
decreases more slowly with increasing time from
to an average of 25 and 20 µg/L at 90 minutes.
[33]
use.
[35,40]
The course of plasma THC concentrations after
After smoking a low dose cannabis cigarette
inhalation resembles that after intravenous adminis-
(about 16mg of THC), the detection limit of 0.5 µg/
tration.
[35,40]
Smoking a single cannabis cigarette
L of THC in plasma was reached after 7.2 hours
containing about 16 or 34mg of THC caused aver-
(range 3–12 hours), and following a high dose ciga-
age peak concentrations of 84.3 µg/L (range
rette (about 34mg of THC) a plasma concentration
50.0–129.0 µg/L) for the lower dose and 162.2 µg/L
of 0.5 µg/L of THC was reached within 12.5 hours
(range 76.0–267.0 µg/L) for the higher dose, then
(range 6–27 hours).
[35]
THC-COOH was detectable
rapidly decreased to low concentrations of about
for a considerably longer time: for 3.5 days (range
1–4 µg/L within 3–4 hours (figure 5).
[35]
2–7 days) after the low dose and for 6.3 days (range
The maximal THC plasma concentration after
3–7 days) after smoking the high dose.
[35]
smoking a marijuana cigarette (3.55% THC) was
The major reason for the slow elimination of
reported to exceed the maximal THC-COOH con-
THC from the plasma is the slow rediffusion of THC
centration by 3-fold and the maximal 11-OH-THC
from body fat and other tissues into the blood.
[53]
concentration by 20-fold.
[35]
However, THC/
The true elimination half-life of THC from the
11-OH-THC ratios declined and reached a ratio of
plasma is difficult to calculate, as the equilibrium
about 2:1 after 2–3 hours.
[35]
Peak concentrations for
THC were observed 8 minutes (range 6–10 minutes)
after onset of smoking, whereas 11-OH-THC peak-
ed at 15 minutes (range 9–23 minutes) and THC-
COOH at 81 minutes (range 32–133 minutes).
[35]
After oral administration, the THC plasma con-
centration shows a flat course with peaks of 4.4–11
µg/L after THC 20mg,
[39]
2.7–6.3 µg/L after THC
15mg
[46]
and 0.58–12.48 µg/L after THC 2.5mg
(figure 6).
[44]
Much higher amounts of 11-OH-THC
are formed than with inhalational or intravenous
administration.
[25,31,46]
In a study by Wall et al., the
ratio of THC and 11-OH-THC plasma concentra-
tions in men and women was about 2:1 to 1:1.
[31]
In
several clinical studies,
[44,46]
11-OH-THC concen-
trations even exceeded THC concentrations. In a
0
1
2
3
4
5
Time after oral ingestion (h)
Concentration (µg/L)
Patient 3
Patient 5
Patient 6
121086420
Fig. 8. Plasma concentrations of ∆
9
-tetrahydrocannabinol (THC) of
three of the six cancer patients of figure 6 after ingestion of one oral
dose of THC 15mg (estimated from graphs of figure 2 of Frytak et
al.,
[46]
with permission
)
.
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338 Grotenhermen
Table V. Mean cumulative cannabinoid excretion
[31]
Subjects/route Urine (%) Faeces (%) Total (%) at 72h % of total in urine
at 72h
24h 72h 24h 72h
Women/ 11 ± 2 16 ± 39 ± 11 26 ± 19 42 38.1
intravenous
Men/intravenous 10 ± 5 15 ± 4 14 ± 11 35 ± 11 50 30.0
Women/oral 12.5 ± 3.0 15.9 ± 3.6 9 ± 11 48 ± 6 63.9 24.9
Men/oral 10.3 ± 2.1 13.4 ± 2.0 24 ± 42 53 ± 18 66.4 20.2
ratio plasma/fatty tissue is reached only slowly, unchanged drug in the faeces.
[31,32]
After 3 days,
resulting in very low plasma concentrations that are
overall excretion rates were about 65% following
difficult to analyse. In a study by Wall et al., the
oral and about 45% with intravenous administration
half-life of the terminal phase (t
1
/2β
) ranged from 25
(see table V).
[31]
to 36 hours for THC, from 12 to 36 hours for
A single dose of THC may result in detectable
11-OH-THC and from 25 to 55 hours for THC-
metabolites in urine for up to 12 days,
[45]
usually for
COOH after oral or intravenous administration in
3–5 days.
[94]
The average time to the first negative
men and women.
[31]
The plasma concentration was
result in urine screening for THC metabolites
followed for 72 hours in this study, not long enough
(enzyme immunoassay with a cut-off calibration of
to determine the half-life accurately. Similar elimi-
20 µg/L) was 8.5 days (range 3–18 days) for infre-
nation half-lives for THC in the range of 20–30
quent users and 19.1 days (range 3–46 days) for
hours determined over similar periods have been
regular users.
[95]
Since urine excretion of metabo-
reported by others.
[32,42,57]
lites does not decrease monotonously, urine screen-
Longer half-lives of THC plasma elimination
ings may fluctuate between positive and negative
have been determined after higher doses and longer
results for several days. The average time until the
periods of measurement in animals
[69]
and
last positive result was 12.9 days (3–29 days) for
humans,
[93]
up to 12.6 days with 4 weeks of observa-
light users and 31.5 days (4–77 days) for heavy
tion.
[93]
However, it is unclear whether THC could
users.
[95]
always be reliably distinguished from its metabo-
A urinary excretion half-life of THC-COOH of
lites, thus overestimating the length of the half-
about 30 hours was observed with a 7-day monitor-
life.
[33]
Kelly and Jones (1992) measured a t
1
/2β
for
ing period and of 44–60 hours with a 14-day
THC of only 117 minutes for frequent and 93 min-
period.
[96]
Other groups calculated similar average
utes for infrequent users.
[33]
urinary excretion half lives of about 2 days with a
The elimination half-life for THC metabolites
12-day monitoring period
[33]
and of about 3 days
from plasma is longer than the elimination half-life
(range 0.9–9.8 days) when THC-COOH was mea-
of the parent molecule. In a study by Hunt and
sured for 25 days.
[97]
Jones,
[32]
the medium t
1
/2β
of THC for frequent users
Mainly acids are excreted with the urine,
[98,99]
the
was about 19 hours and of the overall metabolites 53
main metabolite being the acid glucuronide of THC-
hours. In the study by Kelly and Jones (1992), the
COOH.
[100]
Free THC-COOH is not excreted in
plasma elimination half-life for THC-COOH was
significant concentrations.
[33,45,101]
Several authors
5.2 ± 0.8 days for frequent and 6.2 ± 6.7 days for
reported that the concentrations of THC and 11-OH-
infrequent cannabis users.
[33]
THC in urine were insignificant,
[18,102]
but a recent
3.5.2 Excretion with Urine and Faeces
study found significant concentrations of these neu-
THC is excreted within days and weeks, mainly tral cannabinoids by using an enzymatic hydrolysis
as acid metabolites, about 20–35% in urine and step in the extraction protocol, with THC concentra-
65–80% in faeces, less than 5% of an oral dose as tions peaking at 21.5 µg/L (range 3.2–53.3 µg/L) 2
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Cannabinoids 339
hours after smoking THC 27mg in a cannabis ciga- 3.6 Time–Effect Relationship
rette, 11-OH-THC peaking at 77.3 ± 29.7 µg/L after
3.6.1 Correlation of Time and Effects
3 hours and THC-COOH peaking at 179.4 ± 146.9
Peak ‘highs’ after intravenous and inhalational
µg/L after 4 hours (figure 9).
[103]
administration were noted after 20–30 minutes, and
Renal clearance has been reported to decrease decreased to low levels after 3 hours and to baseline
after 4 hours (figure 10).
[36-38]
Maximum increase of
from a maximum of 1.2 L/h (20 ml/min) at approxi-
heart rate was noted earlier, within a few (1–5)
mately 100 minutes to 0.06 L/h (1 ml/min) after 4
minutes decreasing to baseline after 3 hours.
[38]
Con-
days of THC administration.
[32]
The high lipophilici-
junctival reddening was also noted within a few
ty of THC, resulting in high tubular reabsorption,
minutes and subsided in some participants by 3
hours after smoking.
[42]
Duration of maximal effects
explains the low renal excretion of the unchanged
is dose dependent, and was found to be 45 minutes
drug.
[18]
after THC 9mg
[105]
and more than 60 minutes with
Excretion is delayed by an extensive enterohepat-
higher doses.
[106]
ic recirculation of metabolites.
[31,102]
Due to this
Following inhalation, THC plasma concentra-
tions have already dropped significantly before
marked enterohepatic recirculation and the high pro-
maximal psychotropic effects are achieved.
[36,39]
It
tein binding of cannabinoids, they are predominant-
has been proposed that the first hour represents the
ly excreted with the faeces. In contrast to urine
distribution phase
[60]
and that after 1 hour the central
excretion, the acid and neutral THC metabolites in
compartment has reached equilibrium with the ef-
fect compartment.
[36]
Hence, about 1–4 hours after
the faeces are only present in the nonconjugated
smoking there is a good correlation between plasma
form.
[31,104]
concentration and effects.
[36,107,108]
After oral use (THC 20mg in a cookie), redden-
ing of the conjunctivae occurred within 30–60 min-
utes and was maximal from 60 to 180 minutes,
gradually lessening thereafter.
[39]
As with inhala-
tion, the pulse rate often returned to baseline or
below even while the participants felt ‘high’.
[39]
Psychotropic effects after oral use set in after 30–90
minutes,
[31,37]
were maximal between 2 and 4 hours,
20
40
60
80
100
120
140
160
180
0123456
Time after smoking (h)
Concentration (µg/L)
0
THC
11-OH-THC
THC-COOH
Fig. 9. Mean urine concentrations of unchanged ∆
9
-tetrahydrocan-
nabinol (THC) and its major metabolites 11-hydroxy-THC (11-OH-
THC) and 11-nor-9-carboxy-THC (THC-COOH) after smoking a
cannabis cigarette containing about 27mg of THC by eight subjects
with self-reported history of light marijuana use (one to three ciga-
rettes per week or less). One subject later admitted regular use and
presented with high baseline concentrations of 11-OH-THC and
THC-COOH.
[103]
0
1
2
3
4
5
6
7
8
9
10
0123456
Time after administration (h)
Subjective high
Intravenous (5mg)
Smoked (19mg)
Oral (20mg)
Fig. 10. Time course of subjective effects following three modes of
administration of ∆
9
-tetrahydrocannabinol. A rating of the degree of
‘hi
g
h’ was made b
y
sub
j
ects on a 0–10 scale.
[37,39]
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340 Grotenhermen
and declined to low levels after 6 hours.
[37]
Maximal
psychotropic effects were usually delayed for 1–3
hours, when plasma concentrations had already
started to fall.
[37]
3.6.2
Pharmacokinetic-Pharmacodynamic Modelling
With both inhalational and oral use, the associa-
tion between THC concentrations in the plasma and
subsequent psychotropic effects describes a hystere-
sis over time (figure 11). The intensity of THC
effects depends on the concentration in the effect
compartment. Although THC quickly crosses the
blood-brain barrier,
[109]
plasma concentrations are
already falling while brain concentrations are still
Dose
k
1e
A
e
, V
e
effect
V
1
central
V
2
tissue
k
e0
k
12
k
21
k
10
K
a
Fig. 12. Kinetic and dynamic model for ∆
9
-tetrahydrocannabinol
(THC).
[36]
K
a
, k
12
, k
21
and k
10
describe THC kinetics in the empirical
two-compartment model. The rate constants k
1e
and k
e0
characteri-
se the effect compartment. A
e
is the amount of THC in the effect
compartment. V
e
, V
1
and V
2
are the volumes of the respective
compartments.
rising.
[109-111]
In monkeys, an intravenous dose of
radiolabelled THC resulted in peak radioactivity
levels in the brain after 15–60 minutes, in accor-
dance with the time of maximal effect after intrave-
E
kAkV
kAkV C
eee
eee ss
(/)
(/)
,
011
01150
•
•
•
•
nous and inhalational administration in humans.
[110]
The steady-state plasma concentration at 50% of
Chiang and Barnett (1984)
[36]
have proposed a kinet-
the maximum psychotropic effect (C
ss,50
) was as-
ic and dynamic model based on an open two-com-
partment model (figure 12). certained to be 25–29 µg/L by using cannabis ciga-
rettes of three different potencies.
[36]
The elimina-
According to the Hill equation, there is a relation-
tion rate constant from the effect compartment (k
e0
)
ship between the intensity of the psychotropic ef-
was 0.03–0.04 min
–1
, and the sigmoid parameter γ
fects (E) and the amount of THC in the effect
(the degree of sigmoidicity of the effect/amount
compartment (A
e
):
relationship) was 1.5–2.0. The transfer rate constant
k
21
from the tissue compartment was much smaller
(0.0078–0.012 min
–1
) than the elimination rate con-
stant. Thus, the time course of effects must precede
the time course of the THC amount in the tissue
compartment.
[36]
The rate constant k
10
probably
consists of a mixture of constants for metabolism
and distribution between the central and deep tissue
compartments.
[36]
3.6.3 Predicting Time of Use
Several methods and models have been proposed
for predicting time of administration. They are
based on THC plasma concentrations
[112,113]
or the
ratio of THC and its metabolites THC-COOH and
11-OH-THC in the plasma.
[45,114-116]
The higher the
THC-COOH/THC ratio the longer time has passed
since consumption.
0
1
2
3
4
5
Plasma concentration (µg/L)
Subjective high
6543210
Fig. 11. Phase plot of subjective ‘high’ versus plasma ∆
9
-te-
trahydrocannabinol (THC) concentration from 0 to 360 minutes
after oral ingestion of THC 15mg in a chocolate cookie.
[37]
Every
solid point in the figure marks 30 minutes of time. The maximum
THC plasma concentration (5.7 µg/L) was reached after 60 min-
utes, whereas the maximum subjective ‘high’ (on a 0–10 scale; see
fi
g
ure 10
)
was noted 2–4 hours after intake of the cannabinoid.
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Cannabinoids 341
3.7.2 Nabilone
In urine, THC concentrations above 2 µg/L were
The absorption of oral nabilone (as a
proposed as a marker for cannabis use within 5
polyvinylpyrrolidone coprecipitate) is nearly com-
hours after smoking (figure 9).
[103]
Others suggested
plete,
[123]
with plasma concentrations peaking at 1–4
that 8β,11-dihydroxy-THC showed promise as a
hours. Nabilone was reported to disappear from
urine marker for recent use,
[113]
whereas Manno et
plasma relatively fast, with a half-life of about 2
al. detected 8β,11-dihydroxy-THC only in the urine
hours,
[123,124]
and total radioactivity disappeared
of a regular user and not in the urine of the light
slowly with a half-life of 30 hours.
[123]
Circulating
users in his study.
[103]
metabolites in plasma include isomeric carbinols
3.7 Pharmacokinetics of
with long half lives formed by reduction of the
Other Cannabinoids
ketone at C-9.
[124-126]
3.7.3 Dexanabinol
The pharmacokinetics of other cannabinoids re-
The pharmacokinetics of the synthetic nonp-
semble the kinetics of THC.
[117]
Pharmacokinetics
sychotropic cannabinoid dexanabinol (HU-211)
will be reviewed briefly for the phytocannabinoid
were evaluated with doses of 48, 100 and 200mg as
cannabidiol, for nabilone, a synthetic ketocannabi-
short intravenous infusions in healthy volunteers.
noid that is available on prescription in several
The plasma course was best fitted to a three-com-
countries, and for dexanabinol, a nonpsychotropic
partment model with a t
1
/2β
of approximately 9
analogue of ∆
8
-THC under clinical investigation.
hours.
[59]
The plasma clearance of the drug (about
3.7.1 Cannabidiol
102 L/h [1700 ml/min]) and the volume of distribu-
Average systemic bioavailability of inhaled CBD
tion (about 15 L/kg) were somewhat higher than
in a group of cannabis users was 31% (range
seen with THC.
11–45%).
[118]
The plasma pattern was similar to that
3.7.4 Metabolic Interaction of Cannabinoids
of THC. After oral administration of CBD 40mg, the
Metabolic interaction between cannabinoids has
plasma course over 6 hours was in the same range as
been observed, but only cannabidiol seems to have a
the course after THC 20mg.
[119]
Daily oral doses of
significant effect on THC by inhibiting hepatic
CBD 10 mg/kg per day for 6 weeks in patients with
microsomal THC metabolism through inactivation
Huntington’s disease resulted in mean weekly plas-
of the CYP oxidative system.
[127-130]
ma concentrations of 5.9–11.2 µg/L.
[120]
In rats re-
ceiving intravenous THC and CBD (each 1 mg/kg Treatment of mice with high doses of CBD (120
bodyweight), brain concentrations of unchanged mg/kg) resulted in changes of metabolism of THC
CBD were higher than that of THC 5 minutes after (12 mg/kg) and modest elevation of THC blood
administration.
[83]
The volume of distribution was concentrations.
[131]
Brain concentrations of THC in-
about 30 L/kg, greater than for THC,
[118]
and the creased by nearly 3-fold.
[131]
However, there was no
plasma clearance was similar to that of THC, rang- or minimal effect of CBD on THC plasma concen-
ing from 58 to 94 L/h (960 to 1560 ml/min).
[118]
An trations in humans.
[119,132]
Repeated administration
average t
1
/2β
of 24 hours (range 18–33 hours) during of THC and THC metabolites,
[133,134]
other cannabi-
an observation period of 72 hours was determined noid receptor agonists
[135]
and even CBD
[133]
in-
after intravenous injection of 20mg.
[118]
creased the activity of CYP by enzyme induction,
thus decreasing the inactivating effect caused by
The metabolic pattern is similar to that of
CBD.
THC.
[121,122]
Several cyclised cannabinoids were
identified, among them ∆
9
-THC, ∆
8
-THC and can- In humans, pretreatment with oral CBD 40mg
nabinol.
[121]
The excretion rate of metabolites in resulted in a delayed, longer and only slightly rein-
urine (16% in 72 hours) is similar to that of THC,
[122]
forced action of oral THC 20mg.
[136]
However, si-
whereas unlike THC a high percentage of un- multaneous administration of CBD and THC result-
changed CBD is excreted in the faeces.
[122]
ed in a significant block of several THC effects,
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342 Grotenhermen
among them anxiety and other subjective alterations (5-HT
3
) receptor ion channels,
[146]
and some CB
1
caused by THC
[137]
and tachycardia,
[138]
presumably receptors are negatively coupled to M-type potassi-
due to antagonistic interaction of CBD at the CB
1
um channels.
[147]
Under certain conditions, they may
receptor.
[139]
also activate adenylate cyclase through stimulating
G proteins (G
s
proteins).
[148]
4. Pharmacodynamics
CB
1
receptors are found mainly on neurons in the
brain, spinal cord and peripheral nervous system,
but are also present in certain peripheral organs and
4.1 Mechanism of Action
tissues, among them endocrine glands, leucocytes,
spleen, heart and parts of the reproductive, urinary
The majority of phytocannabinoid effects are me-
and gastrointestinal tracts.
[145]
diated through agonistic or antagonistic actions at
CB
2
receptors occur principally in immune cells,
specific receptors sites. Cannabinoid receptors and
among them leucocytes, spleen and tonsils,
[146]
and
their endogenous ligands together constitute the ‘en-
there is markedly more mRNA for CB
2
than for CB
1
dogenous cannabinoid system’ or the ‘endocannabi-
in the immune system. Levels of CB
1
and CB
2
noid system’ that is teleologically millions of years
mRNA in human leucocytes have been shown to
old.
[140]
vary with cell type (B cells > natural killer cells >
Some non-receptor-mediated effects of phyto-
monocytes > polymorphonuclear neutrophils, CD4+
cannabinoids and synthetic derivatives have also
and CD8+ cells).
[149]
been described e.g. effects on the immune sys-
There is some evidence for the existence of one
tem,
[141]
neuroprotective effects in ischaemia and
or more additional cannabinoid receptor sub-
hypoxia,
[142]
and some effects on circulation.
[143]
types.
[150-152]
The antiemetic effects of THC are in part non-
Activation of the CB
1
receptor produces marijua-
receptor-mediated, the rationale for the clinical use
na-like effects on psyche and circulation, whereas
of THC as an antiemetic in children receiving cancer
activation of the CB
2
receptor does not. Hence,
chemotherapy.
[144]
Due to the lower CB
1
receptor
selective CB
2
receptor agonists have become an
density in the brain of children compared with
increasingly investigated target for therapeutic uses
adults, they tolerated relatively high doses of
of cannabinoids, among them analgesic, anti-in-
∆
8
-THC in a clinical study without significant ad-
flammatory and antineoplastic actions.
[153,154]
verse effects.
[144]
It is possible that some of these
effects are mediated by cannabinoid receptor sub-
types that have not yet been identified.
4.1.2 Endocannabinoids
The identification of cannabinoid receptors was
4.1.1 Cannabinoid Receptors
followed by the detection of endogenous ligands for
To date, two cannabinoid receptors have been
these receptors, endogenous cannabinoids or endo-
identified, CB
1
receptors (cloned in 1990) and CB
2
cannabinoids, a family of endogenous lipids (figure
receptors (cloned in 1993),
[145]
both coupled through
13).
[6,155,156]
The most important of these endocan-
inhibiting G proteins (G
i
proteins), negatively to
nabinoids are arachidonylethanolamide
adenylate cyclase and positively to mitogen-activat-
(anandamide) and 2-arachidonylglycerol, both of
ed protein kinase. Activation of G
i
proteins causes
which are thought to serve as neurotransmitters or
inhibition of adenylate cyclase, thus inhibiting the
neuromodulators.
[146,157]
Endocannabinoids are re-
conversion of AMP to cyclic AMP.
leased from cells in a stimulus-dependent manner by
CB
1
receptors are also coupled to ion channels
cleavage of membrane lipid precursors.
[155]
After
through G
i/o
, negatively to N-type and P/Q-type
calcium channels and positively to A-type and in-
wardly rectifying potassium channels.
[146]
They may
also mobilise arachidonic acid and close serotonin
Gro15
Fi
g
. 13. Ma
j
or endocannabinoids.
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Cannabinoids 343
release, they are rapidly deactivated by uptake into 4.2 Pharmacological Effects
of ∆
9
-Tetrahydrocannabinol
cells via a carrier-mediated mechanism and
enzymatic hydrolysis by fatty acid amide hydrolase
(FAAH).
[155,158]
In mice, lack of FAAH resulted in
The pharmacological activity of ∆
9
-THC is stere-
supersensitivity to anandamide and enhanced en-
oselective, with the natural (–)-trans isomer
dogenous cannabinoid signalling.
[159]
(dronabinol) being 6–100 times more potent than the
(+)-trans isomer depending on the assay.
[2]
4.1.3 Affinity for the Cannabinoid Receptor
The activation of the cannabinoid system through
Cannabinoids show different affinity to CB
1
and
THC and other phytocannabinoids, synthetic and
CB
2
receptors. Synthetic cannabinoids have been
endogenous cannabinoids causes numerous actions
that have been extensively reviewed (see table
developed that act as highly selective agonists or
VI).
[2,3,170-175]
Additional non-receptor-mediated ef-
antagonists at one of these receptor types.
[146,160,161]
fects have come into focus as well.
[142]
Some effects
∆
9
-THC has approximately equal affinity for the
of cannabinoid receptor agonists show a biphasic
CB
1
and CB
2
receptor, whereas anandamide has
behaviour in dependency on dose, e.g. low doses of
marginal selectivity for CB
1
receptors.
[161]
How-
anandamide stimulated phagocytosis and stimulated
ever, the efficacy of THC and anandamide is less at
behavioural activities in mice, whereas high doses
CB
2
than at CB
1
receptors. As a partial (low-effi-
decreased activities and caused inhibitory effects on
cacy) agonist, THC can behave either as an agonist
immune functions.
[176]
or antagonist at CB
2
receptors.
[146]
4.2.1 Toxicity
4.1.4 Tonic Activity of the
Endocannabinoid System
The median lethal dose (LD
50
) of oral THC in
rats was 800–1900 mg/kg depending on sex and
The endogenous cannabinoid system has been
strain.
[177]
There were no cases of death due to
demonstrated to be tonically active in several condi-
toxicity following the maximum oral THC dose in
tions. Endocannabinoid levels have been demon-
dogs (up to 3000 mg/kg THC) and monkeys (up to
strated to be increased in a pain circuit of the brain
9000 mg/kg THC).
[177]
Acute fatal cases in humans
(periaqueductal gray) following painful stimuli.
[162]
have not been substantiated. However, myocardial
Tonic control of spasticity by the endocannabinoid
infarction may be triggered by THC due to effects
system has been observed in chronic relapsing ex-
on circulation.
[178,179]
perimental autoimmune encephalomyelitis
(CREAE) in mice, an animal model of multiple
Adverse effects of medical cannabis use are with-
sclerosis.
[163]
An increase of cannabinoid receptors in the range of effects tolerated for other medica-
tions.
[173,174]
It is controversial whether heavy regu-
following nerve damage was demonstrated in a rat
lar consumption may impair cognition,
[180,181]
but
model of chronic neuropathic pain
[164]
and in a
this impairment seems to be minimal if it ex-
mouse model of intestinal inflammation.
[165]
This
ists.
[182,183]
Long-term medical use of cannabis has
may increase the potency of cannabinoid agonists
been reported to be well tolerated without signif-
used for the treatment of these conditions. Tonic
icant physical or cognitive impairment.
[184]
There is
activity has also been demonstrated with regard to
conflicting evidence that infants exposed to THC in
appetite control
[166]
and with regard to vomiting in
utero experience developmental and cognitive im-
emetic circuits of the brain.
[167]
Elevated endocan-
pairment.
[185]
Cannabis can induce a schizophrenic
nabinoid levels have been detected in cerebrospinal
psychosis in vulnerable persons, presumably with-
fluid of schizophrenic patients.
[168]
In other models,
out increasing the incidence of the disease.
[172,186]
tonic or enhanced activity could not be demonstra-
ted, e.g. in a rat model of inflammatory hyperalge-
The harmful effects of combustion products pro-
sia.
[169]
duced by smoking cannabis have to be distinguished
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344 Grotenhermen
Table VI. Physiological effects of ∆
9
-tetrahydrocannabinol. These dose-dependent effects have been observed in clinical studies, in vivo or
in vitro
Body system Effects
Psyche and perception Fatigue, euphoria, enhanced well-being, dysphoria, anxiety,
reduction of anxiety, depersonalisation, increased sensory
perception, heightened sexual experience, hallucinations, alteration
of time perception, aggravation of psychotic states, sleep
Cognition and psychomotor performance Fragmented thinking, enhanced creativity, disturbed memory,
unsteady gait, ataxia, slurred speech, weakness, deterioration or
amelioration of motor coordination
Nervous system Analgesia, muscle relaxation, appetite stimulation, vomiting,
antiemetic effects, neuroprotection in ischaemia and hypoxia
Body temperature Decrease of body temperature
Cardiovascular system Tachycardia, enhanced heart activity, increased output, increase in
oxygen demand, vasodilation, orthostatic hypotension, hypertension
(in horizontal position), inhibition of platelet aggregation
Eye Reddened conjunctivae, reduced tear flow, decrease of intraocular
pressure
Respiratory system Bronchodilation
Gastrointestinal tract Hyposalivation and dry mouth, reduced bowel movements and
delayed gastric emptying
Hormonal system Influence on luteinising hormone, follicle-stimulating hormone,
testosterone, prolactin, somatotropin, thyroid-stimulating hormone,
glucose metabolism, reduced sperm count and sperm motility,
disturbed menstrual cycle and suppressed ovulation
Immune system Impairment of cell-mediated and humoral immunity, immune
stimulation, anti-inflammatory and antiallergic effects
Fetal development Malformations, growth retardation, impairment of fetal and postnatal
cerebral development, impairment of cognitive functions
Genetic material and cancer Antineoplastic activity, inhibition of synthesis of DNA, RNA and
proteins
from the effects of cannabis or single cannabi- Acute THC intoxication impairs learning and
noids.
[174]
memory,
[191-193]
and adversely affects psychomotor
and cognitive performance,
[186]
reducing the ability
4.2.2 Psyche, Cognition and Behaviour
to drive a car and to operate machinery. Reduced
In many species the behavioural actions of low
reaction time also affects the response of the pupil of
doses of THC are characterised by a unique mixture
the eye. A brief light flash causes a decreased ampli-
of depressant and stimulant effects in the CNS.
[2]
tude of constriction and a reduced velocity of con-
In humans, THC intoxication is usually described
striction and dilation.
[194]
as a pleasant and relaxing experience. Use in a social
The most conspicuous psychological effects of
context may result in laughter and talkativeness.
THC in humans have been divided into four groups:
Occasionally there are unpleasant feelings such as
anxiety that may escalate to panic. A sense of en-
affective (euphoria and easy laughter), sensory (in-
hanced well-being may alternate with dysphoric
creased perception of external stimuli and of the
phases. THC improves taste responsiveness and en-
person’s own body), somatic (feeling of the body
hance the sensory appeal of foods.
[187]
It may induce
floating or sinking in the bed) and cognitive (distor-
sleep.
[188,189]
Whole cannabis preparations and THC
tion of time perception, memory lapses, difficulty in
produce similar subjective effects if administered
concentration).
[195]
via the same routes (oral, inhalation).
[190]
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Cannabinoids 345
4.2.3 Central Nervous System and Neurochemistry
4.3 Effects on Some Other Organ Systems
Most effects of THC (e.g. analgesia, appetite
4.3.1 Antibacterial and Antiviral Actions
enhancement, muscle relaxation and hormonal ac-
Antibacterial actions have been demonstrated for
tions) are mediated by central cannabinoid recep-
CBD, CBG and THC.
[208]
Incubation with THC
tors, their distribution reflecting many of the medici-
reduced the infectious potency of herpes simplex
nal benefits and adverse effects.
[146,191,196]
viruses.
[209]
Cannabinoids interact with a multitude of neuro-
4.3.2 Eye
transmitters and neuromodulators,
[2,197]
among them
The evidence of cannabinoid receptors at differ-
acetylcholine, dopamine, γ-aminobutyric acid
ent sites (anterior eye, retina, corneal epithelium)
(GABA), histamine, serotonin, glutamate, norepine-
suggests that cannabinoids influence different phys-
phrine, prostaglandins and opioid peptides. A num-
iological functions in the human eye.
[210]
Vasodila-
ber of pharmacological effects can be explained (at
tion in the eye is observed as conjunctival reddening
least in part) on the basis of such interactions. For
after THC exposure.
[2]
THC and some other can-
example, tachycardia and hyposalivation with dry
nabinoids decrease intraocular pressure.
[210,211]
mouth
[187,198]
are mediated by effects of THC on
4.3.3 Hormonal System and Fertility
release and turnover of acetylcholine.
[198]
In a rat
THC interacts with the hypothalamic-pituitary-
model, cannabinoid agonists inhibited activation of
adrenal axis, influencing numerous hormonal pro-
serotonin 5-HT
3
receptors, explaining the antiemet-
cesses.
[212]
Minor changes in human hormone levels
ic properties of cannabinoids by interactions with
due to acute cannabis or THC ingestion usually
serotonin.
[199]
Therapeutic effects on movement and
remain in the normal range.
[3]
Tolerance develops to
spastic disorders could be ascribed in part to interac-
these effects, however, and even regular cannabis
tions with GABAergic, glutaminergic and dopamin-
users demonstrate normal hormone levels.
ergic transmitter systems.
[200,201]
4.3.4 Genetics and Cell Metabolism
THC can inhibit DNA, RNA, and protein synthe-
4.2.4 Circulatory System
sis, and can influence the cell cycle. However, very
THC can induce tachycardia
[195]
and increase car-
high doses are required to produce this effect in
diac output with increased cardiac work and oxygen
vitro.
[213]
Cannabinoid agonists inhibited human
demand.
[202]
It can also produce peripheral vasodila-
breast cancer cell proliferation in vitro,
[214,215]
and,
tion, orthostatic hypotension
[3,203]
and reduced plate-
directly applied at the tumour site, showed antine-
oplastic activity against malignant gliomas in
let aggregation.
[204]
There was no change of mean
rats.
[216]
global cerebral blood flow after smoking cannabis,
but increases and decreases in several regions.
[205]
4.3.5 Immune System
The tachycardic effect of THC is presumably based
Animal and cell experiments have demonstrated
on vagal inhibition and can be attenuated by β-
that THC exerts complex effects on cellular and
blockers.
[195]
Due to the development of tolerance,
humoral immunity.
[217,218]
It is not clear whether and
long-term use can lead to bradycardia.
[203]
The en-
to what extent these effects are of clinical relevance
in humans with respect to beneficial (inflamma-
dogenous cannabinoid system seems to play a major
tion,
[219,220]
allergies, autoimmune processes
[218]
)
role in the control of blood pressure. Endocannabi-
and undesirable (decreased resistance towards
noids are produced by the vascular endothelium,
pathogens and carcinogens) effects.
[217]
circulating macrophages and platelets.
[206]
Vascular
resistance in the coronaries and the brain is lowered
4.3.6 Sperm
primarily by direct activation of vascular cannabi-
After several weeks of daily smoking eight to ten
noid CB
1
receptors.
[207]
cannabis cigarettes, a slight decrease in sperm count
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346 Grotenhermen
was observed in humans, without impairment of tory
[240]
effects have been observed. It reduced in-
their function.
[221]
In animal studies, high doses of traocular pressure,
[241]
was neuroprotective
[142]
and
cannabinoids inhibited the acrosome reaction.
[222]
antagonised the psychotropic and several other ef-
fects of THC.
[137]
Anxiolytic and antipsychotic
4.3.7 Digestive Tract
properties might prove useful in psychiatry.
[137,236]
Anandamide induces overeating in rats through a
The nonpsychotropic cannabinoids CBG and
CB
1
receptor mediated mechanism.
[223]
Cannabi-
CBC show sedative effects. CBG has been observed
noid-induced eating is ascribed to an increase of the
to decrease intraocular pressure,
[211]
showed an-
incentive value of food.
[224]
Cannabinoid agonists
titumour activity against human cancer cells
[242]
and
inhibit gastrointestinal motility and gastric emptying
has antibiotic properties.
in rats.
[225]
In a study with humans, THC caused a
significant delay in gastric emptying.
[226]
In addi-
4.5.2 Endocannabinoids
tion, CB
1
agonists inhibited pentagastrin-induced
Anandamide (arachidonyl-ethanolamide), an en-
gastric acid secretion in the rat,
[227]
mediated by
docannabinoid, produces pharmacological effects
suppression of vagal drive to the stomach through
similar to those of THC. However, there are appar-
activation of CB
1
receptors.
[228]
ently some significant differences with THC. Under
certain circumstances, anandamide acts as a partial
4.4 Pharmacological Activity of
agonist at the CB
1
receptor,
[243]
and very low doses
∆
9
-Tetrahydrocannabinol Metabolites
of anandamide antagonised the actions of THC. It is
assumed that low doses of anandamide activated
4.4.1 11-Hydroxy-∆
9
-Tetrahydrocannabinol
stimulating G
s
protein pathways and not inhibiting
11-OH-THC is the most important psychotropic
G
i
proteins, or caused an allosteric modulation of the
metabolite of ∆
9
-THC, with a similar spectrum of
cannabinoid receptor.
[243]
actions and similar kinetic profiles as the parent
molecule.
[122,229,230]
After intravenous administra-
4.5.3 Classical Synthetic Cannabinoids
tion in humans, 11-OH-THC was equipotent to THC
Among the classical synthetic cannabinoids that
in causing psychic effects and reduction in intraocu-
retain the phytocannabinoid ring structures and their
lar pressure.
[230]
In some pharmacological animal
oxygen atoms are nabilone, HU-210 and dexanabi-
tests, 11-OH-THC was three to seven times more
nol. Nabilone is available on prescription in several
potent than THC.
[231]
countries with a similar pharmacological profile as
4.4.2 11-Nor-9-Carboxy-∆
9
-Tetrahydrocannabinol
THC (figure 14).
[244]
HU-210, an analogue of
THC-COOH is the most important nonpsycho-
∆
8
-THC with a dimethylheptyl side chain, is be-
tropic metabolite of ∆
9
-THC. It possesses anti-in-
tween 80 and 800 times more active than
flammatory and analgesic properties by mechanisms
THC,
[245,246]
while its enantiomer dexanabinol
similar to those of nonsteroidal anti-inflammatory
(HU-211) is completely devoid of psychoactivi-
drugs.
[232-234]
THC-COOH antagonises some effects
ty.
[247]
Dexanabinol is an N-methyl-D-aspartate
(for example the cataleptic effect in mice) of the
(NMDA) antagonist with neuroprotective properties
parent drug through an unknown mechanism.
[235]
in hypoxia and ischaemia.
[248]
It is under clinical
investigation for the treatment of brain injuries and
4.5 Pharmacological Effects of
stroke.
[248]
CT-3 or ajulemic acid, a derivative of the
Other Cannabinoids
∆
8
-THC metabolite THC-COOH, is under clinical
investigation for inflammation and pain.
[65,249]
4.5.1 Phytocannabinoids
Cannabidiol (CBD) is a nonpsychotropic can-
nabinoid, for which sedating,
[236]
antiepileptic,
[237]
antidystonic,
[238]
antiemetic
[239]
and anti-inflamma-
Gro14
Fi
g
. 14. Classical s
y
nthetic cannabinoids.
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Cannabinoids 347
4.5.4 Nonclassical Synthetic Cannabinoids
5. Tolerance and Dependency
Levonantradol, which was under clinical investi-
gation for the treatment of pain
[250]
and the adverse
5.1 Tolerance
effects of chemotherapy
[251]
and radiotherapy,
[252]
is
a nonclassical cannabinoid with a more radical
Tolerance develops to most of the effects of
change from the typical structure. Other nonclassi-
THC,
[261]
among them the cardiovascular, psycho-
cal cannabinoids are the aminoalkylindol
logical and skin hypothermic effects,
[262,263]
analge-
WIN-55,212-2, which has a 6.75-fold bias towards
sia,
[264]
immunosuppression,
[265]
corticosteroid re-
the CB
2
receptor
[253]
and the bicyclic cannabinoid
lease,
[266]
and disruption of the hypothalamo-hypo-
analogue CP-55,940, a widely-used agonist for the
physeal axis,
[267]
causing alterations in
testing of cannabinoid receptor affinity with a poten-
endocannabinoid formation and content in the
cy 4–25 times greater than that of THC depending
brain.
[268]
In a 30-day study volunteers received
on assay.
[254]
daily oral doses of THC 210mg and developed toler-
ance to cognitive and psychomotor impairment and
4.5.5 Anandamide Analogues
to the psychological ‘high’ by the end of the
study.
[262]
After a few days an increased heart rate
Several anandamide congeners have been syn-
was replaced by a normal, or slowed, heart rate.
thesised,
[160]
among them (R)-(+)-α-metha-
Tolerance also develops to orthostatic hypoten-
nandamide that possesses both a 4-fold higher affin-
sion.
[203]
ity for the CB
1
receptor and a greater catabolic
resistance than anandamide. Fatty acid-based com-
Tolerance can mainly be attributed to pharmaco-
pounds have been synthesised that mimic the struc-
dynamic changes, presumably based on receptor
ture of anandamide, but act as inhibitors of the
downregulation and/or receptor desensitisa-
catabolic amidase enzyme FAAH.
[158]
tion.
[268,269]
Rate and duration of tolerance varies
with different effects. Rats receiving THC over a
AM-404 is a synthetic fatty amide that acts as a
period of 5 days exhibited a decreased specific bind-
selective inhibitor of anandamide transport, thus
ing ranging from 20% to 60% in different receptor
preventing cellular reuptake of anandamide
[255]
and
sites of the brain compared with controls.
[261]
How-
increasing circulating anandamide concentra-
ever, in another study no significant alteration in
tions.
[155]
receptor binding was observed after chronic admin-
istration of THC, resulting in 27-fold behavioural
4.5.6 Therapeutic Potential of Antagonists
tolerance.
[270]
Long-term administration of
When administered by themselves, cannabinoid
anandamide also resulted in behavioural tolerance
receptor antagonists (e.g. SR141716A; figure 15)
without receptor downregulation,
[271]
and it was pro-
may behave as inverse agonists in several bioassay
posed that desensitisation of the CB
1
receptor might
systems and produce effects that are opposite in
account for this observation.
[271]
Tolerance has been
direction from those produced by cannabinoid re-
observed to occur together with modified biotrans-
ceptor agonists, e.g. hyperalgesia
[256]
and improve-
formation activities with regard to mitochondrial
ment of memory.
[257]
Possible therapeutic potential
oxygen consumption, mono-oxygenase activities
was proposed for obesity,
[258]
schizophrenia,
[35]
in
and the content of liver microsomal CYP.
[135]
How-
conditions with lowered blood pressure,
[207]
Parkin-
ever, only a small proportion of tolerance can be
son’s disease,
[259]
Huntington’s disease
[260]
and to
attributed to changes in metabolism.
[32]
improve memory in Alzheimer’s disease.
[35]
5.2 Withdrawal and Dependency
After abrupt cessation of long-term administra-
tion of high doses of THC, withdrawal has been
Gro19
Fig. 15. Cannabinoid receptor antagonists, SR 141716A (a) and
SR 144528
(
b
)
.
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348 Grotenhermen
observed in humans.
[262,272]
Subjects complained of Nabilone is approved for nausea and vomiting asso-
inner unrest, irritability and insomnia, and presented ciated with cancer chemotherapy.
‘hot flashes’, sweating, rhinorrhoea, loose stools,
6.3 Relatively Well-Confirmed Effects
hiccups and anorexia. Withdrawal symptoms in
humans are usually mild and the risk for physical
Spasticity due to spinal cord injury
[25,290,291]
and
and psychic dependency is low compared with opi-
multiple sclerosis,
[25,291-296]
chronic painful condi-
oids, tobacco, alcohol and benzodiazepines.
[273-275]
tions, especially neurogenic pain,
[290,291,297-301]
A review of several indicators of the abuse potential
movement disorders (including Tourette’s syn-
of oral dronabinol in a therapeutic context found
drome, dystonia and levodopa-induced dyskine-
little evidence of such a problem.
[276]
sia),
[200,302-308]
asthma
[30,309,310]
and glauco-
ma
[28,311-314]
can be regarded as relatively well-con-
6. Therapeutic Uses
firmed effects with small placebo-controlled trials
Cannabis preparations have been employed in the
demonstrating benefits. However, results were
treatment of numerous diseases, with marked differ-
sometimes conflicting.
ences in the available supporting data.
[171,173,174,277]
Besides phytocannabinoids, several synthetic can-
6.4 Less Confirmed Effects
nabinoid derivatives that are devoid of psychotropic
effects are under clinical investigation, and modula- There are several indications in which mainly
tors of the endocannabinoid system (such as reup- only case reports suggest benefits. These are aller-
take inhibitors and antagonists at the CB
1
or CB
2
gies,
[315]
inflammation,
[174]
epilepsy,
[316]
intractable
receptor) will presumably follow. hiccups,
[317]
depression,
[287]
bipolar disorders,
[318]
anxiety disorders,
[174]
dependency on opioids and
6.1 Hierarchy of Therapeutic Effects
alcohol,
[315,319]
withdrawal symptoms
[319]
and dis-
turbed behaviour in Alzheimer’s disease.
[320]
Possible indications for cannabis preparations
have been extensively reviewed.
[171,173,174,277-281]
To
6.5 Basic Research Stage
do justice to the scientific evidence with regard to
different indications, a hierarchy of therapeutic ef-
Basic research shows promising possible future
fects can be devised, with established effects, rela-
therapeutic indications, among them neuroprotect-
tively well-confirmed effects, less confirmed effects
ion in hypoxia and ischaemia due to traumatic head
and a basic research stage. However the history of
injury, nerve gas damage and stroke.
[142,248]
Some
research into the therapeutic benefits of cannabis
immunological mechanisms of THC hint of possible
and cannabinoids has demonstrated that the scien-
benefits in basic mechanisms of T helper 1 dominat-
tific evidence for a specific indication does not
ed autoimmune diseases, such as multiple sclerosis,
necessarily reflect the actual therapeutic potential
arthritis and Crohn’s disease.
[218]
Other fields of
for a given disease, but sometimes obstacles to
research are disorders of blood pressure
[207,321]
and
clinical research.
antineoplastic activity.
[154,322]
Cannabinoids seem to
be able to control the cell survival/death deci-
6.2 Established Effects
sion.
[323]
Thus, cannabinoids may induce prolifera-
Dronabinol is approved for use in refractory nau- tion, growth arrest or apoptosis in a number of cells
sea and vomiting caused by antineoplastic drugs in depending on dose.
[323]
Several effects observed in
cancer
[144,282-284]
and for appetite loss in anorexia and animal studies provide the basis for further research,
cachexia of HIV/AIDS patients.
[285-287]
These effects among them effects against diarrhoea in mice,
[324]
can be regarded as established effects for THC and inhibition of bronchospasms provoked by chemical
cannabis. THC is also effective in cancer cachex- irritants in rats
[325]
and stabilisation of respiration in
ia
[288]
and nausea induced by syrup of ipecac.
[289]
sleep-related breathing disorders (e.g. apnoea).
[326]
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Cannabinoids 349
7. Drug Interactions analgesic effect of opioids,
[333]
the antiemetic effect
of the phenothiazines
[283]
and the antiepileptic action
Interactions with other drugs may depend on
of benzodiazepines.
[334]
THC may antagonise the
activity on similar effector systems or metabolic
antipsychotic actions of neuroleptics
[331]
and may
interactions.
[327]
improve their clinical responsiveness in motor dis-
Since cannabinoids are strongly bound to pro-
orders.
[335]
teins, interactions with other protein-bound drugs
Indomethacin, aspirin (acetylsalicylic acid) and
may also occur. They might also interact with drugs
other nonsteroidal anti-inflammatory drugs ant-
that, such as THC, are metabolised by enzymes of
agonise the effects of THC. Indomethacin signifi-
the CYP complex. However, there was only a minor
cantly reduced subjective ‘high’,
[336]
tachycardia
[336]
influence of cannabis smoking and oral dronabinol
and decrease of intraocular pressure following topi-
on the pharmacokinetic parameters of antiretroviral
cal THC (eye drops).
[337]
These interactions reflect
medications used in HIV infection and metabolised
the fact that several THC effects are at least in part
by CYP enzymes, and the use of cannabinoids is
mediated by prostaglandin-mediated processes.
[2,337]
unlikely to affect antiretroviral efficacy.
[328]
Cessa-
tion of tobacco and cannabis smoking was reported
8. Conclusions
to result in elevated blood concentrations of anti-
psychotic medication (clozapine or olanzapine) due
The discovery, within the past 15 years, of a
to cessation of induction of CYP1A2 by smoke
system of specific cannabinoid receptors in humans
constituents.
[329]
and their endogenous ligands has strongly stimulat-
Other medicines may enhance or attenuate cer-
ed cannabinoid research, with about 650 articles
tain actions of THC, or certain actions of these
published in Medline-listed journals in 2001 com-
medicines may be enhanced or attenuated by
pared with about 250 in 1986. It has become appar-
THC.
[330,331]
Moreover, it is possible that certain
ent that the endocannabinoid system plays a major
effects are enhanced and others reduced, as is the
role in signal transduction in neuronal cells, and
case with phenothiazines used against the adverse
arachidonylethanolamide (anandamide) seems to be
effects of cancer chemotherapy. In a study by Lane
a central inhibitory compound in the central nervous
et al., a combination of prochlorperazine and
system.
[338]
dronabinol was more effective in reducing unwant-
Mechanisms of action of cannabinoids are com-
ed effects of the antineoplastic medication than the
plex, not only involving activation of and interaction
phenothiazine alone, and the incidence of cannabi-
at the cannabinoid receptor, but also activation of
noid-induced adverse effects was decreased when
vanilloid receptors,
[322]
influence of endocannabi-
dronabinol was combined with prochlorperazine,
noid concentration,
[339]
antioxidant activity,
[142]
met-
which also has antipsychotic properties.
[283]
Canna-
abolic interaction with other compounds, and sever-
bis, caffeine and tobacco reduced the blood pressure
al others. There is still much to learn about the
reactivity protection of ascorbic acid, probably
physiological role of the natural ligands for the CB
through their dopaminergic effects.
[332]
receptor, about the long-term effects of cannabis
Of greatest clinical relevance is reinforcement of
use, and even some controversial findings on can-
the sedating effect of other psychotropic substances
nabinoid pharmacokinetics remain to be solved.
(alcohol, benzodiazepines), and the interaction with
However, because of the millennia-long use of
substances that act on heart and circulation (such as
cannabis for recreational, religious and medicinal
amphetamines, adrenaline, atropine, β-blockers, di-
purposes, which in recent decades has been accom-
uretics and tricyclic antidepressants).
[330,331]
panied by research in several disciplines, we do not
A number of additive effects may be desirable, expect to encounter with the medicinal use of can-
such as the enhancement of muscle relaxants, bron- nabinoids the same unpleasant surprises that occa-
chodilators and antiglaucoma medication,
[210]
the sionally occur with newly designed synthetic drugs.
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350 Grotenhermen
6. Devane WA, Hanus L, Breuer A, et al. Isolation and structure of
Many people who suffer from severe illnesses
a brain constituent that binds to the cannabinoid receptor.
have discovered cannabis as a beneficial remedy,
Science 1992; 258 (5090): 1946-9
and surveys in Europe and North America show that 7. Razdan RK. Structure-activity relationships in cannabinoids.
Pharmacol Rev 1986; 38: 75-149
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cism.
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Aside from phytocannabinoids and cannabis
13. Harvey DJ. Characterization of the butyl homologues of
preparations, cannabinoid analogues that do not
delta1-tetrahydrocannabinol, cannabinol and cannabidiol in
bind to the CB
1
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samples of cannabis by combined gas chromatography and
mass spectrometry. J Pharm Pharmacol 1976; 28 (4): 280-5
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14. Vree TB, Breimer DD, van Ginneken CA, et al. Identification in
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24 (1): 7-12
actions comprise the concurrent administration of
15. ElSohly MA, Ross SA, Mehmedic Z, et al. Potency trends of
THC and CBD, the design of CB
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∆9-THC and other cannabinoids in confiscated marijuana from
that do not cross the blood-brain barrier, and the
1980-1997. J Forensic Sci 2000; 45 (1): 24-30
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nabinoide in Cannabis sativa L. und in Cannabisprodukten
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