Cannabinoids in bipolar affective disorder: a review and discussion of their therapeutic potential (2005

ashton 2005 cannabis j psychopharm

 

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Cannabinoids in bipolar affective
disorder: a review and discussion
of their therapeutic potential
C. H. Ashton Department of Psychiatry, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle
upon Tyne, UK.
P. B. Moore Department of Psychiatry, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon
Tyne, UK.
P. Gallagher Department of Psychiatry, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle
upon Tyne, UK.
A. H. Young Department of Psychiatry, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle
upon Tyne, UK.

Bipolar affective disorder is often poorly controlled by prescribed drugs.
Cannabis use is common in patients with this disorder and anecdotal
reports suggest that some patients take it to alleviate symptoms of both
mania and depression. We undertook a literature review of cannabis use
by patients with bipolar disorder and of the neuropharmacological
properties of cannabinoids suggesting possible therapeutic effects in
this condition. No systematic studies of cannabinoids in bipolar disorder
were found to exist, although some patients claim that cannabis
relieves symptoms of mania and/or depression. The cannabinoids
∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD) may exert
sedative, hypnotic, anxiolytic, antidepressant, antipsychotic and

anticonvulsant effects. Pure synthetic cannabinoids, such as dronabinol
and nabilone and specific plant extracts containing THC, CBD, or a
mixture of the two in known concentrations, are available and can be
delivered sublingually. Controlled trials of these cannabinoids as
adjunctive medication in bipolar disorder are now indicated.
Keywords
bipolar disorder, cannabidiol, cannabinoids, cannabis, CBD, depression,
dronabinol, mania, nabilone, tetrahydrocannabinol, THC

Abstract

Corresponding author: Professor C. H. Ashton, Department of Psychiatry, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK.
Email: c.h.ashton@ncl.ac.uk
Review

widespread, especially in children with psychological difficulties

and in pain management. Nevertheless, the consequences of extend-
ing the use of controlled substances need careful consideration.

It is well known that there is a high prevalence of comorbid

drug abuse in people with BAD (Brown et al., 2001). A 61% life-
time prevalence of substance abuse in Bipolar I patients and 48%

in Bipolar II patients has been reported compared to 6% in the gen-
eral population (Regier et al., 1990). Some studies have provided

data on individual drugs that are abused by these patients (Estroff
et al., 1985; Miller et al., 1989; Regier et al., 1990; Marken et al.,
1992; Mueser et al., 1992; Sonne et al., 1994; Winokur et al.,
1998). The results indicate high rates of lifetime use of cannabis
(30–64%) and stimulants (amphetamines 31–39%, cocaine
15–39%) and lower rates for opiates (6–25%). The extent to which
bipolar patients use cannabis as self-medication is not clear,

although anecdotal reports suggest that some patients find it allevi-
ates both depression (Gruber et al., 1996) and mania (Grinspoon

and Bakalar, 1998). Although cannabis can cause adverse effects,
including psychosis and mania, some cannabinoids have properties
that could be of value in psychiatric disorders, and a literature
review was therefore undertaken to investigate their therapeutic
potential in bipolar affective disorder.
Methods
Electronic searches for relevant papers were performed, employing
Medline (1966 to present), Embase (1980 to present), ISI Web of
Science (1990 to present) and Psychoinfo (earliest available to
present). Search terms were ‘bipolar’, ‘manic depression’, ‘mania’,
‘antidepressant’, ‘antimanic’, ‘mood stabilizer’, ‘cannabinoid’,
tetrahydrocannabinol’, ‘THC’, ‘cannabidiol’, ‘CBD’, ‘cannabis,
“marijuana”, ‘nabilone’ and ‘dronabinol’.

In addition, Medline reviews and investigations of pharma-
cological, psychiatric and therapeutic effects of cannabis/cannabi-
noids (1970–2003) were consulted and a manual searching of all

relevant articles was performed.
Results

The literature search revealed no systematic studies of the thera-
peutic use of cannabis or cannabinoids in BAD, although there are

several anecdotal reports. Grinspoon and Bakalar (1998) described
five cases in which cannabis appeared to alleviate mania. For
example, one woman with BAD quoted in their report chose
cannabis over alcohol to control her manic behaviour: ‘A few puffs
of this herb and I can be calm … this drug seems harmless
compared to other drugs I have tried, including tranquillisers and
lithium’. A husband, describing his wife with BAD said: ‘My wife

functions much better when she uses marijuana. When she is hypo-
manic, it relaxes her, helps her sleep, and slows her speech down.

When she is depressed and would otherwise lie in bed all day, the
marijuana makes her more active … Lithium is also effective, but
it doesn’t always keep her in control’.

Personal observation of a patient attending the local outpatients
also indicated an apparent antimanic effect of cannabis. The patient

was a 39-year-old male who had been diagnosed 10 years previ-
ously as having BAD. His illness mainly took the form of manic

episodes for which he had a history of five hospital admissions.
These episodes were difficult to control because the patient was

intolerant of antipsychotic drugs, including quetiapine and risperi-
done, and non-compliant with lithium and sodium valproate.

Diazepam controlled his symptoms but he often used up his
2-week prescription for 30 mg daily in 1 week.
A recent manic episode was associated with a severe behaviour

disturbance involving a further possible detention order. The psy-
chiatrist was called for a home visit, which he made some hours

later. To his surprise, he found the patient calm, almost serene,
sitting tranquilly in an armchair smoking a cannabis ‘spliff’. (He
offered the psychiatrist one of the same, which was declined). It
was clear that the cannabis was responsible for the rapid change in
the patient’s behaviour. He maintained that, over the years, he had
taken mainly cannabis, sometimes moderate amounts of alcohol,
occasionally ‘street’ benzodiazepines, and infrequently heroin to
regulate his mood.
Gruber et al. (1996) described five cases in which marijuana
appeared to produce a direct antidepressant effect. Three of these
patients had BAD and all but one found that marijuana relieved
their depression better than standard antidepressant drugs. Two
surveys of medicinal cannabis use in California, where this use is
legalized, showed that 15–27% of patients were prescribed it for

mood disorders, including depression, post-traumatic stress disor-
der, BAD and attention deficit disorder resistant to conventional

pharmacotherapy (Gieringer, 2003).
It is noteworthy that, in the anecdotal reports, cannabis was not
taken for the ‘high’ sought by recreational users and it is possible
that its effects are different when taken in subeuphoric doses for
medical reasons, such as in multiple sclerosis or pain conditions
(Randall, 1991; Hodges, 1993). The effects are most probably due
to cannabinoids present in cannabis smoke, including ∆9-THC,
CBD and possibly others, which have been less studied. Patients’
accounts and the advances in the understanding of cannabinoid
physiology suggest that they may have a therapeutic potential in
BAD (Pertwee, 1999a,b).
Pharmacological basis of cannabinoid effects:
the endocannabinoid system

THC and cannabinoid CB1 receptors THC is the major psychoac-
tive agent present in cannabis, and its primary metabolite, 11-OH-
THC, is even more potent (Maykut, 1985; McPartland and Russo,

2001). These cannabinoids are agonists of endogenous cannabi-
noid CB1 receptors that are present in the brain, spinal cord and

peripheral nerves. CB1 receptors are widely distributed throughout
the brain (Table 1) and are present in the cerebral cortex, including

the cingulate cortex, hippocampus, basal amygdala, corpus stria-
tum and other areas possibly involved in the pathophysiology of

BAD and its emotional and cognitive components (Drevets et al.,
1997; Strakowski et al., 1999; Altshuler et al., 2000; Phillips et al.,

294 Cannabinoids in bipolar disorder

2003; Surguladze et al., 2003). CB1 receptors belong to a family of
G-protein coupled receptors that includes receptors for aminergic

neurotransmitters (noradrenaline, dopamine, serotonin and acetyl-
choline) and act through second messenger systems. CB2 receptors

are similar to CB1 receptors but are present mainly in immune cells
in the periphery and are not considered further here.
Activation of the CB1 receptor (Fig. 1) inhibits adenylate
cyclase and decreases the production of cAMP (3,5-adenosine
monophosphate) (Pertwee, 1997), an action which affects many

intracellular processes and ultimately affects intracellular neuro-
transmission (Shiloh et al., 1999). CB1 receptors also modulate

transneuronal ion channels. They are negatively coupled to calcium
channels (N and P/Q type) and inhibit the inward flow of
calcium ions, decreasing the release of neurotransmitters, either
excitatory or inhibitory, at presynaptic nerve terminals (Pertwee,
1997). At the same time, CB1 activation enhances the outward flow
of potassium ions (through A-type potassium channels), a
G-protein coupled event that may also depend on inhibition of
cAMP production (Deadwyler et al., 1995). The result is inhibition
of neuronal depolarization, decreased action potential generation
and hence reduced impulse propagation.
CBD and anandamides The endogenous ligands for cannabinoid
receptors, both CB1 receptors in the nervous system and CB2
receptors in peripheral tissues, are a family of arachidonic acid
derivatives, sometimes termed endocannabinoids (Pertwee,

1999a,b). The two that appear to be of most physiological impor-
tance are arachidonylethanolamide (anandamide) and 2-arachidonyl

glycerol (2-AG). Anandamide is present in the brain in the same
areas as CB1 receptors. It is enzymatically synthesized in cell
membranes, binds to CB1 receptors (Van der Stelt and Di Marzo,

2003) and, in animal models, shows many of the actions of THC
(Stein et al., 1996; Martin and Cone, 1999). However, unlike THC,
the effects of anandamide are short-lived, lasting less than 15 min
after intravenous injection in the rat (Stein et al., 1996) because it
is rapidly inactivated by enzymatic hydrolysis and removed from
its site of action by neuronal uptake mechanisms (Joy et al., 1999;

Pertwee, 1997, 1999b; Piomelli et al., 2000; Alger, 2004). In addi-
tion, anandamide is synthesized and released at discrete loci on

demand by neural activity or depolarization of postsynaptic mem-
branes and then acts retrogradely as an agonist on presynaptic CB1

receptors (Piomelli et al., 2000; Christie and Vaughan, 2001;
Wilson and Nicol, 2001; Van der Stelt and Di Marzo, 2003; Alger,
2004). By contrast, the exogenous cannabinoid THC is widely
distributed, reaching all areas of CB1 receptors, is very slowly
eliminated (Agurell et al., 1986) and produces effects lasting
several hours (Maykutt, 1985).
CBD binds only minimally to CB1 receptors and is usually
described as non-psychoactive. However, the clinical observations

described below suggest that it has antipsychotic, anxiolytic, anti-
convulsant and other psychological effects (Zuardi et al., 1995;

Mechoulam et al., 2002). Its mode of action is not fully understood
but CBD has recently been shown to block the reuptake of
Cannabinoids in bipolar disorder 295

Table 1 Localization of cannabinoid CB1 receptors
Density Localization
Very dense Basal ganglia – globus pallidus, substantia
nigra pars reticulata,
entopeduncular nucleus
Cerebellum – molecular layers
Hippocampus – dentate gyrus
Dense Cerebral cortexa – layers I and VI
Hippocampus – CA pyramidal cells
Corpus striatum – caudate putamen

Moderate Hypothalamusa
Basal amygdalaa
Central grey substance
Nucleus of solitary tract
Spinal cord
Peripheral nerve terminals

Sparse Thalamus
Pons and Medulla
Some non-neural tissues, including spleen and testes
aReceptor density in the cingulate cortex, hypothalamus and amygdala is
relatively greater in the human brain than in the same areas of rat and
monkey brain (Herkenham, 1995; Pertwee, 1997).

Figure 1 Schematic diagram of signal transduction mechanisms stimu-
lated by CB1 receptors. The CB1 receptor (1) is coupled to a second mes-
senger Gi/o protein. Via this protein, activation of the receptor inhibits

the enzyme adenylate cyclase (2) and decreases the production of cAMP
(3). Via the G-protein, the inward flow of calcium ions is blocked (4),
decreasing release of neurotransmitters (5). Also via the G-protein, the
outward flow of potassium ions is enhanced (6), resulting in decreased
neuronal firing and decreased impulse transmission (7). Stimulation of
the G-protein also activates MAP kinase (8), affecting intracellular gene
expression. Other receptors on the same neurone (for monoamines
and/or opioids) may activate their own G-proteins but share a common
adenylate cyclase, which they may stimulate (9) or inhibit (10).

Anandamide is released in the post-synaptic membrane and acts retro-
gradely as an agonist on presynaptic CB1 receptors (Howlett, 1995;

Pertwee, 1997; Ameri, 1999; Joy et al., 1999; Van der Stelt and di
Marzo, 2003; Alger, 2004)

anandamide (Bisogno et al., 2001) and to inhibit its enzymatic
hydrolysis (Mechoulam et al., 2002). CBD also reduces the

hydroxylation of THC to its more psychoactive metabolite, 11-OH-
THC (McPartland and Russo, 2001). It has been shown to inhibit

serotonin reuptake and to increase catecholamine activity in rat
brain synaptosomes (McPartland and Russo, 2001), an action also
shown by anandamide (Steffens and Feuerstein, 2004). In addition,

CBD is a potent antioxidative agent and is protective against gluta-
mate toxicity, an action which is not affected by cannabinoid

receptor antagonists (Mechoulam et al., 2002). The possible con-
tribution of each of these actions to the psychological effects of

CBD is not clear.
The discovery of endocannabinoids and the realization that
these are the biological ligands of cannabinoid receptors has
opened a whole new vista in cannabinoid pharmacology. A system

of cannabinoid receptors and endocannabinoids appears to modu-
late many important physiological processes (Di Marzo et al.,

1998). These processes have yet to be clearly defined but evidence
is already accumulating that endocannabinoids are involved in the

modulation of brain reward systems (Gardner, 1999), mood, anxi-
ety and sleep (Musty et al., 1995), pain (Pertwee, 2001), cognition

and memory (Terranova et al., 1995, 1996), appetite (Williams and
Kukham, 1999; Di Marzo et al., 2001), endocrine activity
(Mendelson and Mello, 1999), cardiovascular regulation (Randall
and Kendall, 1998) and other vital functions (Musty et al., 1995;
Ameri, 1999). The basic function of the endogenous system
appears to be the regulation of interneuronal signalling, involving

complex interactions with many neurotransmitters and neuromod-
ulators, including monoamines, acetylcholine, opioids, GABA and

glutamate (Ameri, 1999).
Psychological effects of THC
The psychological effects of cannabis and THC have been
described by many authors (Paton and Pertwee, 1973; Ashton,
1999a; Johns, 2001). It is important to note that many of these are

biphasic and bidirectional, depending on dose, mode of administra-
tion, environment, expectation, personality, degree of tolerance and

other individual factors, as well as time-frame (Paton and Pertwee,
1973; Ashton et al., 1981; Ashton, 1999b). Thus, acute effects in
normal subjects can include euphoria or dysphoria, relaxation or
anxiety, excitation followed by sedation, heightened
perception followed by perceptual distortion, and increased motor
activity followed by incoordination. Synthetic THC (dronabinol)

and nabilone, a synthetic cannabinoid related to THC, exert simi-
lar actions depending on dosage and the other factors mentioned

above. In healthy subjects under placebo-controlled laboratory
conditions, THC (5 mg and 10 mg smoked in herbal cigarettes) was
shown to produce relaxation with decreased subjective ratings of
anxiety, tension and depression (Ashton et al., 1981). However,
D’Souza et al., 2004) recently found that intravenous infusions of

THC (2.5 mg and 5 mg) produced mild and transient schizophrenia-
like symptoms, anxiety, detachment, perceptual distortion and

cognitive impairment.

Patients using cannabis or synthetic THC compounds in mod-
erate doses for chronic pain conditions or multiple sclerosis have

reported improvement of mood and increased general well-being
and mental health, as well as alleviation of their other symptoms
(Martyn et al., 1995; Notcutt et al., 1997; Ashton, 1999b; Williams
and Evans, 2000; Wade et al., 2003; Svendson et al., 2004). A few
controlled studies have shown anxiolytic effects of nabilone in
some patients (Glass et al., 1980; Fabre and McLendon, 1981;
Ilaria et al., 1981) and an antidepressant effect of THC in cancer
patients (Regelson et al., 1976; Russo et al., 2003).
Many of the adverse effects of cannabis (usually attributed to its
THC content) result from relatively high dose or chronic use.

Cannabis can cause an acute psychosis in previously normal indi-
viduals, but those with mental illness are more vulnerable (Johns,

2001). Such reactions are dose-related and appear to be becoming
more common with the present-day recreational use of potent
cannabis varieties such as ‘skunk’ and netherweed (Wylie et al.,

1995). Heavy cannabis use can also lead to an acute functional psy-
chosis with marked hypomanic features (Rottenburg et al., 1982;

Johns, 2001). In patients with BAD, the duration of cannabis use is

associated positively with the duration of manic, but not depres-
sive, episodes (Strakowski et al., 2000) and substance abuse in

general appears to increase the severity of the illness (Cassidy et
al., 2001) and to increase suicide rate (Dalton et al., 2003).
Cannabis is a well-known risk factor for schizophrenia and may
precipitate the illness in genetically predisposed individuals
(Johns, 2001). It aggravates positive symptoms in schizophrenia
and may antagonize the effects of antipsychotic drugs (Negrete and
Gill, 1999). A large number of studies, as reviewed by Arsenault

et al. (2004) and Macleod et al. (2004), have implicated a dose-
related association between the use of cannabis in childhood and

adolescence with later development in young adulthood of schizo-
phrenia, depression, violence and antisocial behaviour, use of other

illicit drugs, lower educational attainment, and psychological
distress. Whether or not these associations are causal are debated
by the above authors.
Psychological effects of CBD
There is some evidence that CBD, which constitutes up to 40% of

cannabis extracts, has anxiolytic, hypnotic, antipsychotic and anti-
convulsant actions (Zuardi and Guimaraes, 1997; Mechoulam et

al., 2002). CBD antagonizes the anxiety, intoxication liability and

psychotic-like symptoms produced by high doses of THC in nor-
mal subjects (Zuardi et al., 1982; Russo, 2003) and has similar

anxiolytic effects to diazepam in a simulated public speaking test
(Zuardi and Guimaraes, 1997). Anxiolytic effects have also been
demonstrated in animal models, including the behaviour of rodents
on the elevated plus maze (Guimaraes et al., 1990). In this test, the
action of CBD, administered alone, was dose-dependent and
biphasic, similar to many other cannabinoid effects (Sulcova et al.,
1998). Biphasic hypnotic effects in rats have also been demonstrated
(Monti, 1997) and CBD significantly increased sleeping time
compared to placebo in insomniacs (Carlini and Cunha, 1981).
Antipsychotic effects of CBD were suggested by the observation

that it acted in a similar way to haloperidol in animal tests predic-
tive of antipsychotic activity (Zuardi et al., 1991, 1995). A placebo-
controlled case study of a patient with schizophrenia who was

296 Cannabinoids in bipolar disorder

intolerant of haloperidol showed antipsychotic effects of high-dose
oral CBD with 60–69% improvement in scores on the Brief
Psychiatric Rating Scale and Interactive Observation Scale for
Psychiatric Inpatients after 4 weeks of CBD therapy (Zuardi et al.,
1995). Preliminary results with CBD in additional schizophrenic
patients are reported as promising (Gerth et al., 2002).
Anticonvulsant actions of CBD, comparable to those of
diphenylhydantoin and other drugs that are clinically effective in
major seizures, have been shown in a variety of animal models
(Consroe and Snyder, 1986; Consroe and Sandyk, 1992). The
effects are not reversed by CB1 antagonists, indicating that they are
not CB1 receptor mediated. A small placebo-controlled clinical

study of oral CBD as an add-on therapy in 15 patients with uncon-
trolled secondary generalized epilepsy with temporal focus was

conducted by Cunha et al. (1980). Of the eight patients who
received CBD over 4 months, four remained almost seizure-free
and three others showed partial improvement, whereas the patients
taking placebo showed no change.
Pharmacokinetic factors
When administered orally, the absorption of both THC and CBD
is slow and erratic. Peak plasma concentrations are not reached
for 2–6 h and the biological availability is 4–12% for THC
(Grotenhermen, 2003) and 13–19% for CBD (Mechoulam et al.,
2002). Both cannabinoids undergo extensive first pass metabolism
in the liver and THC is also degraded by stomach acids. By
contrast, inhaled cannabinoids reach peak plasma concentrations
within minutes and have a bioavailability of approximately 35%
for both THC and CBD. For medicinal purposes, other modes of

administration have been investigated and sublingual liquid solu-
tions appear to be well absorbed, producing rapid effects compar-
able to inhalation (Whittle et al., 2001; Grotenhermen, 2003; Wade

et al., 2003). Using a sublingual spray of THC and CBD, Wade

et al. (2003) found that it was possible for subjects with pain con-
ditions or multiple sclerosis to self-titrate small doses that relieved

pain and muscle spasms without inducing intoxication.
After absorption, both THC and CBD are sequestrated in fatty

tissues from which they are only slowly released (the tissue half-
life is 5–7 days). Both cannabinoids form a large number of

metabolites, which are gradually eliminated over days or weeks in

the urine and faeces (Gold, 1992). There may be complex interac-
tions between the two cannabinoids. CBD inhibits some cytochrome

P450 enzymes and may inhibit the conversion of THC to its active
11-hydroxy metabolite (McPartland and Russo, 2001), but Zuardi
et al. (1982) found no effect on THC levels in humans when the
two cannabinoids were administered together. By contrast, THC
and its metabolites, and even CBD on repeated administration,
increase cytochrome P450 activity through enzyme induction
(Grotenhermen, 2003).
Discussion
Despite the sparse anecdotal data in humans and the absence of
controlled clinical trials, the evidence discussed above shows that

both THC and CBD have pharmacological properties that could be

therapeutic in patients with BAD. Furthermore, the available phar-
macokinetic evidence indicates optimal methods of administration

and dosage control. The underlying pathophysiology of BAD is

unknown, but these cannabinoids, especially when used in combi-
nation, have several characteristics (Table 2) in common with

drugs known to benefit this disorder, including antidepressants,
antipsychotics, anticonvulsants (mood-stabilizers) and anxiolytics.
THC, in some conditions and doses, has anxiolytic, hypnotic
and antidepressant effects with improvement in mood and general
well-being in normal subjects, and in patients with pain conditions,
multiple sclerosis or cancer (Regelson et al., 1976; Glass et al.,
1980; Ashton et al., 1981; Fabre and McLendon, 1981; Ilaria et
al., 1981; Paton and Pertwee, 1981; Martyn et al., 1995; Notcutt et
al., 1997; Ashton, 1999b; Wade et al., 2003). These actions could
be helpful in BAD, especially in depressive phases, which are often

accompanied by anxiety (Goodwin and Sachs, 2004). CBD antag-
onizes the psychotic-like effects and intoxication liability produced

by high doses of THC and has anxiolytic, hypnotic and anticonvul-
sant actions of its own in addition to a protective effect against glu-
tamate toxicity (Cunha et al., 1980; Carlini and Cunha, 1981;

Consroe and Snider, 1986; Guimaraes et al., 1990; Consroe and
Sandyk, 1992; Zuardi et al., 1995; Zuardi and Guimaraes, 1997;
Gerth et al., 2002; Mechoulam et al., 2002; Russo, 2003). These
actions do not appear to be mediated by CB1 receptors but may
result from enhancement of the endogenous anandamide system
and effects on THC metabolism (Mechoulam et al., 2002;
McPartland and Russo, 2001). As well as adding to the anxiolytic

effects of THC, the antipsychotic effects of CBD could be thera-
peutic in bipolar patients with psychotic symptoms, and the anti-
convulsant and protective effects against glutamate toxicity may

have a mood-stabilizing action similar to some other anticon-
vulsants of proven value in BAD (Porter et al., 1999; Ashton and

Cannabinoids in bipolar disorder 297

Table 2 Comparison of some effects of ∆9-tetrahydrocannabinol (THC)
and cannabidiol (CBD)
Actions THC CBD
Agonist action on CB1 receptors + –
Inhibition of anandamide reuptake and hydrolysis – +
Anxiolytic +a +
Psychotropic + –
Antipsychotic – +b
Anticonvulsant – +
Antidepressant (+)c –
Sedative/hypnotic + +
Antinociceptive + +
Neuroprotective (inhibition of glutamate release) + +
Antiemetic + –
Appetite stimulant + No data
Cardiovascular effectsd + +
aTHC is anxiolytic in some doses, but can be anxiogenic in higher doses
or in drug-naïve individuals. bCBD also antagonizes some psychotropic
effects of THC. c

Shown in one study in cancer patients (Regelson et al.,
1976). dTHC causes tachycardia and hypotension; CBD can cause
bradycardia and hypotension.

Young, 2003). In addition, both THC and CBD have extremely low
toxicity (British Medical Association, 1997; Mechoulam et al., 2002).
Cannabinoids have already been tested for therapeutic effects in
acute and chronic pain conditions and multiple sclerosis (Wade et
al., 2003; Svendsen et al., 2004). The evidence suggests that a
placebo-controlled trial of cannabinoids as adjunctive therapy in
BAD should now be undertaken. Such a trial might start with a
pilot investigation in treatment-resistant bipolar patients who
remain symptomatic despite standard medications, choosing patients
over the age of 18 years who have used cannabis previously (but

who undertake to abstain from cannabis during the trial). Stand-
ardized plant extracts containing THC and CBD in combination

and matching placebo have been available for clinical research
since 1988 (GW Pharmaceuticals plc, Salisbury, UK). These could
be self-administered as a 1 : 1 THC : CBD mixture or placebo and
delivered by metered dose pump action aerosol spray as described
by Wade et al. (2003). These authors found that the product was
well tolerated and that side-effects were minimal in patients with
various neurological disorders. Bipolar patients could self-titrate
their preferred dosage to control symptoms and dosage would be
minimized by limiting the amount contained in each spray to
2.5 mg of cannabinoid and the total dosage in each daily container
to 120 mg cannabinoids. Thus, the maximum amount of THC
obtainable daily would be 60 mg: a single modern cannabis ‘spliff’
contains 60–150 mg THC or more (Ashton, 1999b). Treatment
periods would possibly be for 4 weeks, perhaps in a crossover
active treatment/placebo design. Assessments would include
clinical ratings of mania and depression scores, subjective rating
scales, neuropsychological performance and a record of adverse
effects. The results would provide information on optimal dosage
regimes, duration of treatment, adverse effects and other factors.
Possible adverse effects that would require close monitoring in

such a trial include the precipitation of hypomania, mania and psy-
chosis, although these effects are unlikely to be significant with

small dose preparations and a 50% CBD content in the medication.
Neurocognitive function, which is already impaired in BAD
(El-Badri et al., 2001; Ferrier and Thompson, 2002) may be further
compromised by THC (Solowij, 1998). On the other hand, better
symptom control with the THC/CBD preparation may improve
congnition. Additive effects may occur with hypnotics, sedatives
and alcohol. Induction of cytochrome P450 enzymes may result in

interactions with drugs metabolized by the same enzymes, includ-
ing many antidepressants and antipsychotics. However, these

enzymes are already induced in BAD patients who smoke tobacco
or take cannabis. Two patients who stopped or reduced tobacco
and/or cannabis consumption when on clozapine or olanzapine
experienced adverse effects due to increased plasma levels of the
drugs, necessitating dosage adjustment (Zullino et al., 2002). A
possible interaction between lithium and marijuana was reported in
one case resulting in elevated serum lithium levels, which dropped
when the patient stopped using marijuana (Ratey et al., 1981). The
interaction was attributed to slowed gut motility caused by
marijuana which increased lithium absorption.
Tolerance and dependence can result from chronic use of
cannabis and withdrawal effects occur on ceasing use (Ashton,
1999a). However, little tolerance appears to develop to the putative

therapeutic effects that have been studied. Some patients have
found nabilone still to be effective for pain relief after 2–3 years of
regular use (Notcutt et al., 1997) and patients taking plant-based
cannabinoid extracts long-term for pain have not so far reported
tolerance (Whittle et al., 2001). Any withdrawal problems could be
minimized by tapering dosage if use was no longer required.
Similar to cannabis, THC has abuse potential and precautions may
be needed to limit patients’ overuse of the cannabinoid aerosols.
In conclusion, BAD is often poorly controlled by existing drugs
and often involves a polypharmacological medley, including lithium,
anticonvulsants, antidepressants, antipsychotics and benzodiazepines.
Many patients take street drugs in addition, including cannabis,
amphetamines, cocaine and illicitly obtained benzodiazepines in

an attempt to control their symptoms. Some claim that such self-
medication is superior to the drugs prescribed by psychiatrists.

There are good pharmacological reasons for believing that the pre-
scription of synthetic cannabinoids or standardized plant extracts

may have a therapeutic potential in BAD. We suggest that the time
is ripe for carefully managed trials of prescribed cannabinoids to
determine whether they are of value as adjunctive drugs in bipolar

patients whose symptoms are not adequately controlled by stan-
dard medications.

References
Agurell A, Halldin M, Lindgren J E, Ohlsson A, Widman M, Gillespie H,

Hollister L (1986) Pharmacokinetics and metabolism of ∆1-tetrahydro-
cannabinol and other cannabinoids with emphasis on man. Pharmacol

Rev 38: 21–43
Alger B E (2004) Endocannabinoids: getting the message across. Proc Natl
Acad Sci 101: 8512–8513
Altshuler L L, Bartzokis G, Grieder T, Curran J, Jimenez T, Leight K, Wilkins
J, Gerner R, Mintz J (2000) An MRI study of temporal lobe structures in
men with bipolar disorder or schizophrenia. Biol Psychiatry 48: 147–162
Ameri A (1999) The effects of cannabinoids on the brain. Prog Neurobiol
58: 315–348
Arsenault L, Cannon M, Witton J, Murray R M (2004) Causal association
between cannabis and psychosis: examination of the evidence. Br J
Psychiatry 184: 110–117
Ashton H (1999a) Cannabis in palliative care. CME Bull Palliat Med 1:
73–77
Ashton H (1999b) Adverse effects of cannabis and cannabinoids. Br J
Anaesth 83: 637–649
Ashton H, Young A H (2003) GABA-ergic drugs: exit stage left, enter stage
right. J Psychopharmacol 17: 174–178
Ashton H, Golding J F, Marsh V R, Millman J E, Thompson J W (1981)
The seed and the soil: effect of dosage, personality and starting state on
the response to ∆9-tetrahydrocannabinol in man. Br J Clin Pharmacol
12: 705–720
Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde D, Brandi I,
Moriello A S, Davis J B, Mechoulam R, Di Marzo V (2001) Molecular
targets for cannabidiol and its synthetic analogues: effect on vanilloid
VR1 receptors and on the cellular uptake and enzymatic hydrolysis of
anandamide. Br J Pharmacol 134: 845–852
British Medical Association (1997) Therapeutic Uses of Cannabis.
Harwood Publishers, London

Brown E, Suppes T, Adinoff B, Thomas NR (2001) Drug abuse and bipo-
lar disorder: comorbidity or misdiagnosis? J Affect Dis 65: 105–115

Carlini E A, Cunha J M (1981) Hypnotic and antiepileptic effects of
cannabidiol. J Clin Pharmacol 21: 417S–427S

298 Cannabinoids in bipolar disorder

Cassidy F, Ahearn E P, Carroll B J (2001) Substance abuse in bipolar
disorder. Bipolar Disord 3: 181–188
Christie M J, Vaughan C W (2001) Cannabinoids act backwards. Nature
410: 527–30
Committee on Safety of Medicines (2003) Current Problems in
Pharmacovigilance 29: 6
Consroe P, Sandyk R (1992) Potential role of cannabinoids for therapy of
neurological disorders. In Murphy L, Bartke A (eds), Marijuana/
Cannabinoids: Neurobiology and Neuropsychology. CRC Press, Boca
Raton, FL, pp. 459–524
Consroe P, Snyder S R (1986) Therapeutic potential of cannabinoids for
therapy of neurological disorders. In Mechoulam R (ed.), Cannabinoids
as Therapeutic Agents. CRC Press, Boca Raton, FL, pp. 21–49
Cunha J M, Carlini E A, Pereira A E, Ramos O L, Pimentel G, Gagliardi R,
Sanvito E L, Lander N, Mechoulam R (1980) Chronic administration of
CBD to healthy volunteers and epileptic patients. Pharmacologia 21:
175–185
Dalton E J, Cate-Carter T D, Mundo E, Parikh S V, Kennedy J L (2003)
Suicide risk in bipolar patients: the role of co-morbid substance use
disorders. Bipolar Disord 3: 58–61
Deadwyler S A, Hampson R E, Childers S R (1995) Functional significance
of cannabinoid recepters in brain. In Pertwee R G (ed.), Cannabinoid
Receptors. Academic Press Ltd, London, pp. 205–231
Di Marzo V, Goparaju S K, Wang L, Liu J, Batkai S, Jaral Z M, Fezza F,
Miura G I, Palmiter R D, Sugiura T, Kunos G (2001) Leptin-regulated
endocannabinoids are involved in maintaining food intake. Nature 410:
822–825

Di Marzo V, Melck D, Brisogno T, De Petrocellos L (1998) Endo-
cannabinoids: endogenous cannabinoid receptor ligands with neuro-
modulatory action. Trends Neurosci 21: 521–528

D’Souza D C, Perry E, MacDougall L, Ammerman Y, Cooper T, Wu,Y, Braley
G, Gueorguieva R, Krystal J H (2004) The psychotomimetic effects of

intravenous delta-9-tetrahydrocannabinol in healthy individuals: implica-
tions for psychosis. Neuropsychopharmacology 29: 1558–1572

Drevets W C, Price J L, Simpson J R (1997) Subgenual prefrontal cortex
abnormalities in mood disorders. Nature 386: 824–827
El-Badri S M, Ashton C H, Moore P B, Marsh V R, Ferrier I N (2001)
Electrophysiological and cognitive function in young euthymic patients
with bipolar affective disorder. Bipolar Disord 3: 79–87
Estroff T W, Dackis C A, Golod M S, Pottash A L C (1985) Drug abuse and
bipolar disorders. Int J Psychiatry Med 15: 37–40

Ferrier I N, Thompson J M (2002) Cognitive impairment in bipolar affec-
tive disorder: implications for the bipolar diathesis. Br J Psychiatry 180:

293–295
Fabre L F, McLendon D (1981) The efficacy and safety of nabilone (a
synthetic cannabinoid) in the treatment of anxiety. J Pharmacol Sci 21:
377S–382S
Gardner E L (1999) Cannabinoid interaction with reward systems. In Nahas
G G, Sutin K M, Harvey D J, Agurell S (eds), Marihuana and Medicine.
Humana Press, Totowa, New Jersey, pp. 187–205

Geddes J R, Carney S M, Davies C (2003) Relapse prevention with anti-
depressant treatment in depressive disorders. Lancet 361: 643–651

Geddes J, Goodwin G (2001) Bipolar disorder: clinical uncertainty,
evidence-based medicine and large-scale randomised trials. Br J
Psychiatry 41 (Suppl): S191–S194
Gerth C W, Schultze-Lutter F, Mauss C, Ruhrmann S, Klosterkotter J,
Leweke F M (2002) B113: the natural cannabinoid cannabidiol in the
treatment of acute schizophrenia. Schizophr Res 53 (Suppl): 192
Gieringer D H (2003) The acceptance of medicinal marijuana in the US. J
Cannabis Ther 3: 53–65
Glass R M, Uhlenhuth E H, Hartel F W, Schuster C R, Fischman M W

(1980) A single dose study of nabilone, a synthetic cannabinoid.
Psychopharmacology 71: 137–142
Gold M S (1992) Marihuana and hashish. In Winger G, Hoffman F G, Woods
J H (eds). A Handbook of Drug and Alcohol Abuse. The Biological
Aspects. Chapter 7. Oxford University Press, Oxford, pp. 117–131

Goodwin G M (2003) Evidence-based guidelines for treating bipolar disor-
der: recommendations from the British Association of Psychopharma-
cology. J Psychopharmacol 17: 149–173

Goodwin G, Sachs G (2004) Definitions: Diagnosis and Comorbidity.
Bipolar Disorder – Fast Facts. Health Press, Oxford
Grinspoon L, Bakalar J B (1998) The use of cannabis as a mood stabilizer
in bipolar disorder: anecdotal evidence and the need for clinical
research. J Psychoactive Drugs 30: 171–177
Grotenhermen F (2003) Clinical pharmacokinetics. J Cannabis Ther 3: 3–51
Gruber A J, Pope H G, Brown M E (1996) Do patients use marijuana as an
antidepressant? Depression 4: 77–80
Guimaraes F S, Chiaretti T M, Graeff F G, Zuardi A W (1990) Antianxiety
effect of cannabidiol in the elevated plus-maze. Psychopharmacology
100: 558–559
Herkenham M (1995) Localisation of cannabinoid receptors in brain and
periphery. In Pertwee R G (ed.), Cannabinoid Receptors. Academic
Press, London, pp. 145–166
Hodges C (1993) I wish I could get it at the chemist’s. The Independent
23rd February 1993.
Howlett A C (1995) Cannabinoid compounds and signal transduction
mechanisms. In Pertwee R G (ed.), Cannabinoid Receptors. Academic
Press, London, pp. 167–204

Ilaria R L, Thornby J I, Fann W E (1981) Nabilone, a cannabinol deriva-
tive, in the treatment of anxiety neurosis. Curr Ther Res 29: 943–949

Johns A (2001) The psychiatric effects of cannabis. Br J Psychiatry 178:
116–122
Joy J E, Watson S J, Benson J A (eds) (1999) Marijuana and Medicine.
National Academy Press, Washington, DC

Lloyd A J, Harrison C L, Ferrier I N, Young A H (2003) The pharmacolog-
ical treatment of bipolar affective disorder: practice is improving but

could be better. J Psychopharmacol 17: 230–233
Macleod J, Oakes R, Copello A, Crome I, Egger M, Hickman M,
Oppenkowski T, Stokes-Lampard H, Smith G D (2004) Psychological
and social sequelae of cannabis and other illicit drug use by young
people: a systematic review of longitudinal, general population studies.
Lancet 363: 1579–1588
Marken P A, Stanislav S W, Lacombe S, Pierce C, Horstra R, Sommi R W

(1992) Profile of a sample of subjects admitted to an acute care psychi-
atric facility with manic symptoms. Psychopharmacol Bull 28: 201–205

Martin B R, Cone E J (1999) Chemistry and pharmacology of cannabis. In
Kalant H, Corrigal W A, Hall W, Smart R G (eds), The Health Effects
of Cannabis. Centre for Addiction and Mental Health, Toronto, pp.
21–68
Martyn C N, Illis L S, Thom J (1995) Nabilone in the treatment of multiple
sclerosis. Lancet 345: 579
Maykutt M O (1985) Health consequences of acute and chronic marihuana
use. Prog Neuropsychopharmacol Biol Psychiatry 9: 209–238
McPartland J M, Russo E B (2001) Cannabis and cannabis extracts: greater
than the sum of their parts? J Cannabis Ther 1: 103–32
Mechoulam R, Parker L A, Gallily R (2002) Cannabidiol: an overview of
some pharmacological aspects. Clin Pharmacol 42: 11S–19S
Mendelson J H, Mello N K (1999) Marihuana effects on pituitary and
gonadal hormones. In Nahas G G, Sutin K M, Harvey D, Agurell S (eds),
Marihuana and Medicine. Humana Press, Totowa, NJ, pp. 385–392
Miller F T, Busch F, Tanenbaum J H (1989) Drug abuse in schizophrenia
and bipolar disorder. Am J Drug Alcohol Abuse 15: 291–295
Cannabinoids in bipolar disorder 299

Mishra A, Moore P B, Hobbs R (2004) Does quetiapine have mood
altering properties? J Psychopharmacol 18: 281–284
Monti J M (1997) Hypnotic-like effects of cannabidiol in the rat.
Psychopharmacology 55: 263–265
Mueser K T, Yarnold P R, Bellack A S (1992) Diagnostic and demographic
correlates of substance abuse in schizophrenia and major affective
disorder. Acta Psychiatr Scand 85: 105–114
Musty R E, Reggio P, Consroe P (1995) A review of recent advances in
cannabinoid research and the 1994 international symsposium on
cannabis and the cannabinoids. Life Sci 56: 1933–1940
Negrete J C, Gill K (1999) Cannabis and schizophrenia: an overview of the
evidence to day. In Nahas G G, Sutin K M, Harvey D, Agurell S (eds),
Marihuana and Medicine. Humana Press, Totowa, NJ, pp. 671–682
Notcutt W, Price M, Chapman G (1997) Clinical experience with nabilone
for chronic pain. Pharmaceutical Sci 3: 551–555
Paton W D M, Pertwee R G (1973) The actions of cannabis in man. In
Nahas G G, Paton W D M (eds), Marijuana: Chemistry, Pharmacology,
Metabolism and Clinical Effects. Pergamon Press, Oxford, pp. 735–38
Pertwee R G (1997) Pharmacology of cannabinoid CB1 and CB2 receptors.
Pharmacol Ther 74: 129–180
Pertwee R G (1999a) Cannabinoid receptors and their ligands in brain and
other tissues. In Nahas G G, Sutin K M, Harvey D, Agurell S (eds),
Marihuana and Medicine. Humana Press, Totowa, NJ, pp. 177–185
Pertwee R G (1999b) Pharmacology of cannabinoid receptor ligands. Curr
Med Chem 6: 635–664
Pertwee R G (2001) Cannabinoid receptors and pain. Prog Neurobiol 63:
569–611
Phillips M L, Drevets W C, Rauch S L, Lane R (2003) Neurobiology of
emotion perception II: Implications for major psychiatric disorders.
Biol Psychiatry 54: 515–528

Piomelli D, Giuffrida A, Calignano A, de Fonseca F R (2000) The endo-
cannabinoid system as a target for therapeutic drugs. Trends Pharm Sci

21: 218–224
Porter R, Ferrier N, Ashton H (1999) Anticonvulsants as mood stabilisers.
Adv Psychiatr Treat 5: 96–103
Randall R (ed.) (1991) Muscle Spasm, Pain and Marijuana Therapy. Galen
Press, Washington, DC
Randall M D, Kendall D A (1998) Endocannabinoids: a new class of
vasoactive substances. Trends Pharm Sci. 19: 55–58
Ratey J J, Ciraulo D A, Shader R I (1981) Lithium and marijuana. J Clin
Psychopharmacol 1: 32–33
Regelson W, Butler J R, Schulz J, Kirk T, Peek L, Green M L, Zalis M O

(1976) Delta-9-THC as an effective antidepressant and appetite-
stimulating agent in advanced cancer patients. In Braude M C, Szara S

(eds), The Pharmacology of Marihuana. Raven Press, New York, NY,
pp. 763–776
Regier D A, Farmer M E, Rae D S, Locke B Z, Keith S J, Judd L L,
Goodwin F K (1990) Comorbidity of mental disorders with alcohol and
other drug abuse. J Am Med Assoc 264: 2511–2518

Rottanburg D, Robins A H, Ben-Arie O, Teggin A, Elk R (1982) Cannabis-
associated psychosis with hypomanic features. Lancet 2: 1364–1366

Russo E (2003) Cannabis: from pariah to prescription. J Cannabis Ther 3:
1–29
Sachs G S, Printz D J, Kahn D A (2000) The Expert Consensus Guideline
Series: Medication treatment of bipolar disorder. Postgrad Med Spec.
No: 1–104
Shiloh R, Nutt D, Weizman A (1999) Atlas of Psychiatric Chemotherapy.
Martin Dunitz, London
Solowij N (1998) Cannabis and Cognitive Function. Cambridge University
Press, Cambridge
Sonne S C, Brady K T, Morton W A (1994) Substance abuse and bipolar
affective disorder. J Nerv Ment Dis 182: 349–352

Steffens M, Feuerstein T J (2004) Receptor-independent depression of DA
and 5-HT uptake by cannabinoids in rat neocortex – involvement of
Na(+)/K(+)-ATPase. Neurochem Int 44: 529–538
Stein E A, Fuller S A, Edgemond W S, Campbell W B (1996) Physiological

and behavioural effects of the endogenous cannabnoid, arachidonyl-
ethanolamine (anandamide), in the rat. Br J Pharmacol 119: 107–114

Strakowski S M, DelBello M P, Sax K W (1999) Brain magnetic resonance
imaging of structural abnormalities in bipolar disorder. Arch Gen
Psychiatry 56: 254–260
Strakowski S M, DelBello M P, Fleck D E, Arndt S (2000) The impact of
substance abuse on the course of bipolar disorder. Biol Psychiatry 48:
477–485
Sulcova E, Mechoulam R, Fride E (1998) Biphasic effects of anandamide.
Pharmacol Biochem Behav 59: 347–353
Surguladze S, Keedwell P, Phillips M (2003) Neural systems underlying
affective disorders. Adv Psychiatr Treat 9: 446–455

Svendsen K B, Jensen T S, Bach F W (2004) Does the cannabinoid dron-
abinol reduce central pain in multiple sclerosis? Randomised double

blind placebo controlled crossover trial. Br Med J 329: 253–258

Terranova J P, Michaud J D, Le Fur G, Soubrie P (1995) Inhibiting long-
term potentiation in rat hippocampal slice by anandamide and WIN55,

212-2: Reversal by SR1411716A, a selective antagonist of CB1 canna-
binoid receptors. Naunyn-Schmiedeberg’s Arch Pharmacol 352: 576–579

Terranova J P, Storme J J, Lafon N, Perio A, Rinaldi-Ca J, Le Fur G,
Soubrie P (1996) Improvement in memory in rodents by selective CB1
cannabinoid receptor antagonist, SR141716 A. Psychopharmacology
126: 165–172
Van der Stelt M, Di Marzo V (2003) The endocannabinoid system in the
basal ganglia and in the meslolimbic reward system: implications for
neurological and psychiatric disorders. Eur J Pharmacol 480: 133–150

Wade D, Robson P, House H, Makela P, Aram J (2003) A preliminary con-
trolled study to determine whether whole-plant cannabis extracts can

improve intractable neurogenic symptoms. Clin Rehab 17: 18–26
Whittle B A, Guy G W, Robson P (2001) Prospects for new cannabis-based
prescription medicines. J Cannabis Ther 1: 183–205

Williams C M, Kukham T C (1999) Anandamide induces overeating: medi-
ation by central cannabinoid (CB1) receptors. Psychopharmacology

143: 315–317
Williamson E M, Evans F J (2000) Cannabinoids in clinical practice. Drugs
60: 1303–1314
Wilson R I, Nicol R A (2001) Endogenous cannabinoids mediate retrograde
signalling at hippocampal synapses. Nature 410: 558–559
Winokur G, Turvey C, Skiskal H, Coryell W, Solomon D, Leon A, Mueller
T, Endicott J, Maser J, Keller M (1998) Alcoholism and drug abuse in
three groups – bipolar I, unipolars and their acquaintances. J Affect
Disord 50: 81–89
Wylie A S, Scott R T A, Burnett S J (1995) Psychosis due to ‘skunk’, Br
Med J 311: 125
Zuardi A W, Guimaraes F S (1997) Cannabidiol as an anxiolytic and
antipsychotic. In Mathre M L (ed.), Cannabis in Medical Practice.
McFarland & Company, Jefferson, NC, pp. 133–141
Zuardi A W, Shirakawa I, Finkelfarb E, Karmol I G (1982) Action of
cannabidiol on the anxiety and other effects produced by ∆9-THC in
normal subjects. Psychopharmacology 76: 245–259

Zuardi A W, Rodrigues J A, Cunha J M (1991) Effects of cannabidiol in ani-
mal models predictive of antipsychotic activity. Psychopharmacology

104: 260–264
Zuardi A W, Morais S L, Guimaraes F S, Mechoulam R (1995)
Antipsychotic effect of cannabidiol. J Clin Psychiatry 56: 485–486
Zullino D F, Delessert D, Eap C B, Preisij M, Baumann P (2002) Tobacco
and cannabis smoking cessation can lead to intoxication with clozapine
or olanzapine. Int Clin Psychopharmacol 17: 141–143