Dependence Liability: Basic Research On Rewarding Tolerance And Withdrawl


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 and heroin.

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” (Berger 2000).

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 of THC.

“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 these conditions.”

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 levels.

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.


Berger A. Marijuana has potential for misuse. BMJ 2000;321:979.
Brody S, Preut R. Cannabis, tobacco, and caffeine use modify the blood pressure reactivityprotection of ascorbic acid. Pharmacol Biochem Behav 2002;72(4):811-6.
Giuffrida A, Parsons LH, Kerr TM, Rodriguez de Fonseca F, Navarro M, Piomelli D. Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nat Neurosci 1999;2(4):358-63.
Leweke FM, Giuffrida A, Wurster U, Emrich HM, Piomelli D. Elevated endogenous cannabinoids in schizophrenia. Neuroreport 1999;10(8):1665-9.
Lichtman AH, Sheikh SM, Loh HH, Martin BR. Opioid and cannabinoid modulation of precipitated withdrawal in delta(9)-tetrahydrocannabinol and morphine-dependent mice. J Pharmacol Exp Ther 2001p;298(3):1007-14.
Stanley-Cary CC, Harris C, Martin-Iverson MT. Differing effects of the cannabinoid agonist, CP 55,940, in an alcohol or Tween 80 solvent, on prepulse inhibition of the acoustic startle reflex in the rat. Behav Pharmacol 2002;13(1):15-28.
Tanda G, Munzar P, Goldberg SR Self-administration behavior is maintained by the psychoactive ingredient of marijuana in squirrel monkeys. Nat Neurosci 2000;3(11):1073-4.
Valverde O, Noble F, Beslot F, Dauge V, Fournie-Zaluski MC, Roques BP. Delta9-tetrahydrocannabinol releases and facilitates the effects of endogenous enkephalins: reduction in morphine withdrawal syndrome without change in rewarding effect. Eur J Neurosci 2001;13(9):1816-24.
Yamaguchi T, Hagiwara Y, Tanaka H, Sugiura T, Waku K, Shoyama Y, Watanabe S, Yamamoto T. Endogenous cannabinoid, 2-arachidonoylglycerol, attenuates naloxone-precipitated withdrawal signs in morphine-dependent mice. Brain Res 2001;909(1-2):121-6.