Basic research on rewarding, tolerance and withdrawal
In recent years, scientists were able to show that animals
do self-administer THC under certain conditions. Basic animal
research also shows that cannabis produces tolerance and withdrawal.
This research helps explain abuse of cannabis and dependency
in humans. However, basic research cannot predict how pronounced
these effects will be in humans and whether they are stronger
or less strong compared to other drugs such as caffeine, nicotine
Tanda et al. (2000) demonstrated for the first time that
animals self-administer THC. They write in their abstract:
"Many attempts to obtain reliable self-administration
behavior by laboratory animals with delta-9-tetrahydrocannabinol
(THC), the psychoactive ingredient in marijuana, have been
unsuccessful. Because self-administration behavior has been
demonstrated in laboratory animals for almost all other psychoactive
drugs abused by humans, as well as for nicotine, the psychoactive
ingredient in tobacco, these studies would seem to indicate
that marijuana has less potential for abuse. Here we show
persistent intravenous self-administration behavior by monkeys
for doses of THC lower than doses used in previous studies,
but comparable to doses in marijuana smoke inhaled by humans"
(Tanda et al. 2000).
In this study Tanda, Munzar and Goldberg used a low but clinically
relevant dose of THC administered intravenously in a clear
solution. This solution rapidly distributed THC to the brain.
Previous attempts to show self-administration, using much
higher doses of THC held in a suspension, failed. One reason
for this may be that, although higher doses were used, the
suspension resulted in less brain penetration. In this study,
the monkeys had previously been trained to self-administer
cocaine by pressing a lever 10 times. When saline was substituted
for cocaine, self-administration stopped. When THC replaced
the saline, the monkeys quickly started to press the lever
again. The monkeys gave themselves about 30 injections during
an hour-long session, which equates roughly with the dose
received by a person smoking a marijuana joint.
The team went on to confirm that giving the monkeys a second
drug that directly blocks cannabinoid receptors in the brain
could prevent self-administration. Dr. Goldberg's team concludes
from its observations that THC "has as much potential
for abuse as other drugs of abuse, such as cocaine and heroin."
However, Martin Jarvis, professor of health psychology at
University College London (UK) said in an interview to the
British Medical Journal this would probably overstate the
case. He said that misuse is "a judgment best made by
looking at patterns of actual human use." He continued:
"We shouldn't assume that unreasonable behavior in society
follows from the observation of brain reward behavior in animals
alone" (Berger 2000).
Ian Stolerman, professor of behavioral pharmacology at the
Institute of Psychiatry in London, agreed with Jarvis and
states during the interview: "This is an important study
because for the first time it provides a method for studying
directly the intake of THC by a laboratory animal and thus
models a key behavioral feature of addictive states generally.
It will lead to studies of how and where THC works in the
brain to generate drug abuse. It does show that THC shares
properties with other drugs of abuse, but whether it is really
as potentially abusive as cocaine and heroin is not so clear"
Several studies in recent years have demonstrated that there
is an interaction between the endogenous cannabinoid system
and several other transmitter and modulator systems in the
brain, among them the opioid system.
Lichtmann et al. (2001) have shown that there seems to be
a reciprocal relationship between the cannabinoid and opioid
system relative to dependency. THC was able to block some
of the withdrawal symptoms in morphine dependent mice, and
morphine was able to reduce some of the withdrawal symptoms
in THC dependent mice. The mu-opioid receptor seems to be
involved in THC dependence. These findings are consistent
with the results of a study by Yamaguchi et al. (2001). Their
study in mice suggests that in morphine dependence, upregulation
of cannabinoid CB1 receptors occurs. Thus, CB1 receptor agonists
may have potential as therapeutic drugs for opiate withdrawal
symptoms. Successful treatment of withdrawal from opiates
has already been described by physicians of the 19th century
and also in contemporary case reports.
Valverde et al. (2001) support the concept of an interaction
between the cannabinoid and the opiate systems. They found
several effects of THC on the opiate system in mice including
facilitation of the antinociceptive and antidepressant-like
responses elicited by the endogenous enkephalins and increased
release of Met-enkephalin-like material in the nucleus accumbens.
However, there was no modification of the rewarding responses
produced by morphine from the acute or chronic administration
"Recent studies have suggested that cannabinoids might
initiate the consumption of other highly addictive substances,
such as opiates. In this work, we show that acute administration
of Delta9-tetrahydrocannabinol in mice facilitates the antinociceptive
and antidepressant-like responses elicited by the endogenous
enkephalins protected from their degradation by RB 101, a
complete inhibitor of enkephalin catabolism. This emphasizes
the existence of a physiological interaction between endogenous
opioid and cannabinoid systems. Accordingly, Delta9-tetrahydrocannabinol
increased the release of Met-enkephalin-like material in the
nucleus accumbens of awake and freely moving rats measured
by microdialysis. In addition, this cannabinoid agonist displaced
the in vivo [3H]diprenorphine binding to opioid receptors
in total mouse brain. The repetitive pretreatment during 3
weeks of Delta9-tetrahydrocannabinol in mice treated chronically
with morphine significantly reduces the naloxone-induced withdrawal
syndrome. However, this repetitive administration of Delta9-tetrahydrocannabinol
did not modify or even decrease the rewarding responses produced
by morphine in the place preference paradigm. Taken together,
these behavioral and biochemical results demonstrate the existence
of a direct link between endogenous opioid and cannabinoid
systems. However, chronic use of high doses of cannabinoids
does not seem to potentiate the psychic dependence to opioids"
(Valverde et al. 2001).
The neurotransmitter dopamine seems to play a major role
in rewarding by drugs and physical activities, such as sex
and sports. It has been suggested that the use of cannabis,
like that of caffeine, tobacco and other drugs, is associated
with increased mesolimbic dopamine activity (Brody & Preut
2002). "However, evidence for such an effect is inconsistent"
(Stanley-Cary et al. 2002). E.g. Stanley-Cary et al. (2002)
investigated whether or not the cannabinoid agonist CP 55,940,
which binds to the CB1 receptor, mimicked the effects of amphetamine,
a drug which increases dopamine release, on prepulse inhibition
(PPI) of the acoustic startle reflex. They write:
"The first experiment measured the PPI of 16 male Wistar
rats injected (i.p.) with different doses of CP 55,940 in
a Latin-square design. A second experiment replicated the
effects of the first experiment in a between-subjects design,
and also examined the effects of using a 5% alcohol solution
as a solvent for cannabinoid agonists, in comparison to the
more inert detergent, Tween 80. In both experiments, CP 55,940
in Tween 80 significantly reduced basal activity, increased
startle onset latencies and increased PPI, effects opposite
to those of amphetamine. These results suggest that the net
behavioral effects of cannabinoids are opposite to those of
amphetamine. In addition, it was found that 1 ml/kg of a 5%
alcohol solution has significant behavioral effects on its
own, and reverses the effects of CP 55,940 on PPI" (Stanley-Cary
et al. 2002).
Effects of cannabis use on dopamine may be complex and are
not fully understood today. Studies showed that activation
of dopamine receptors with a dopamine-2(D2)-like receptor
ligand in the striatum (a region that controls planning and
execution of motor behaviors) led to a strong stimulation
of anandamide (an endocannabinoid) outflow (Giuffrida et al.
1999). The researchers concluded that the physiological role
of anandamide may be
"...to counter dopamine stimulation of motor activity.
(...) Thus, our findings may have implications for neuropsychiatric
disorders such as schizophrenia, Tourette's syndrome and Parkinson's
disease and may point to novel therapeutic approaches for
In another study of this group, elevated endocannabinoid
levels were found in the cerebrospinal fluid of people with
schizophrenia. One explanation for the higher levels in schizophrenics
is that the brain is attempting to compensate for a hyperactive
dopamine system. "It's the brain's response to bring
this dopamine activity down," said Daniele Piomelli,
professor at the University of California at Irvine in the
New Scientist of May 29, 1999. But, he added, the brain cannot
keep the amount of anandamide high enough to lower dopamine
In summary, animal studies show that THC and other ligands
to the CB1 receptor are rewarding, that they are self-administered
by animals under certain conditions, and that CB1 receptor
ligands exert complex interactions with the opiate and the
dopamine system. However, determining the relevance and implications
of these findings to humans requires clinical studies.
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