The Regulate, Control and Tax Cannabis Act of 2010 (Proposition 19, to be voted on November 2, 2010 in California) falsely asserts in its “Findings” that “Cannabis is not physically addictive.”(1) While CSAM recognizes the public’s right to decide the issue of marijuana legalization through the legislative process, and while we strongly support the use of treatment for substance abuse rather than incarceration, we also believe that a well informed public is a prerequisite to making good policy. We are therefore eager to place before voters strong scientific evidence, collected over the past two decades, that proves marijuana has all the characteristics of an addictive drug.

Four lines of evidence all substantiate that marijuana is addictive: basic neuroscience, animal studies, clinical reports of human experience with marijuana, and epidemiology. Data from these four areas of scientific research corroborate each other and interweave fluidly to dispel the myth that marijuana is not addictive.

In order to place the following information in its proper perspective, medicine’s current understanding of how marijuana interacts with the brain needs to be outlined. Scientific research has discovered an extensive system of nerves within the brain that communicate with each other using the same basic chemistry found in marijuana. The THC (tetrahydrocannabinol) and similar molecules in marijuana are able to affect the brain by mimicking our natural neurotransmitters and flooding receptor sites with stimulation. All the cannabinoid-based areas of the brain are subsequently activated beyond normal physiological levels by using marijuana.

While we are only beginning to unravel the pervasive role the endocannabinoid (i.e., the brain’s naturally occurring THC-like molecules) system plays in overall brain function, Raphael Mechoulam, one of the most important pioneers in cannabinoid research, has declared that “The cannabinoid receptors are found in higher concentrations than any other receptor in the brain… and the endocannabinoid system acts essentially in just about every physiological system that people have looked into, so it appears to be a very central system.”(2)

I. Effect of marijuana on the Reward Center (Nucleus Accumbens)

The brain’s Reward Center (Nucleus Accumbens) is the final common pathway activated by all drugs of addiction.(3) Normally, the reward center experiences a rise in dopamine in response to behaviors that bear repeating (eating, exercising, sexual activity, novelty) to promote survival. By a wide variety of mechanisms, every drug known to cause addiction promotes an increase in dopamine in the Reward Center, often by a full order of magnitude (10X) higher than is normally found physiologically. While this increase in dopamine is not the whole story of addiction, it is the hallmark of addictive drugs (e.g., nicotine, caffeine, alcohol, benzodiazepines, opiates, stimulants, etc.)

As the attached references and abstracts demonstrate, the Reward Center contains cannabinoid receptors and the natural endocannabinoid chemistry to stimulate them.(4) Ingesting marijuana leads to a rise in dopamine and alters the rate of nerve cell firing in the Reward Center of a magnitude similar to that caused by others addictive drugs.(5) If a cannabinoid blocker is administered first, the THC contained in marijuana no longer causes a rise in dopamine, demonstrating the direct effect of marijuana on the Reward Center.(6) Chronic administration of THC eventually alters both the sensitivity and the structure of connections (synapses) within the Reward Center.(7-12)

II. Animal Studies

One of the gold standards for demonstrating the behaviors characteristic of addiction is to develop an animal (i.e., nonhuman) model; in other words, can it be demonstrated that animals will self-administer marijuana? This has been accomplished with squirrel monkeys that had never been exposed to psychoactive drugs previously. Both the THC found in marijuana and the brain’s natural endocannabinoid (anandamide) effectively reinforce a monkey’s pushing a level to self-administer an intravenous dose.(13-14) Similar results with mice and rats have been obtained.(15)

Animal models have also been developed for studying withdrawal from cannabinoid addiction. After being administered THC (or a variety of similar cannabinoid drugs) via injection on a daily or twice daily basis for a week, animals have been given a cannabinoid blocker (SR141716A), an antagonist that is capable of stopping all cannabinoid activity in the brain. The antagonist has little or no impact when given by itself. But, when the brain has been primed by a week of THC administration, SR141716A suddenly precipitates a recognizable pattern of withdrawal symptoms: diarrhea, vomiting, increased aggressiveness, and increases in restless behavior and trembling, head shaking and sleep disruption (with EEG disturbances). Similar signs of withdrawal have been demonstrated across a variety of species.(16-21) Although more exaggerated by having withdrawal precipitated, on the face of things these withdrawal symptoms appear to resemble spontaneous reports by humans in early abstinence from chronic marijuana use.

Although the focus of this article is on the addictive potential of marijuana, attention should also be paid to multiple other ways that the brain is altered by chronic use. For example, the number of cannabinoid receptor sites, and therefore the sensitivity of the brain to its own endocannabinoid chemistry, is reduced in areas outside the Reward Center by as much as 70%.(22)

III. Clinical Reports of Withdrawal in Humans

Human beings almost never ingest a cannabinoid blocker and so do not experience precipitous withdrawal from marijuana. The fact that THC is a fatty acid and is only gradually released from the body’s fat stores after an individual becomes abstinent also contributes to the lack of precipitous withdrawal. The question remains, however, whether any symptoms of withdrawal (and therefore of physical addiction) occur in humans, and what significance these symptoms would have if they are present.

Especially after improvements in the THC content of marijuana became widely available, controlled studies of heavy smoker’s in abstinence began to find significant increases in anxiety, irritability, physical tension, and decreases in mood and appetite during marijuana withdrawal. Chronic marijuana users display more aggressive behavior on days 3 and 7 of marijuana abstinence, continuing for as long as 28 days.(23-26) Adolescents voluntarily seeking treatment for cannabis dependence have reported restlessness, appetite change, and cravings, irritability, depression, twitches and shakes, and perspiring.(27)

Alan Budney has organized the symptoms of marijuana withdrawal into the following proposed formal diagnostic framework:

Proposed Cannabis Withdrawal Syndrome

Common symptoms (reported by > 70% of abstinent individuals)

• Anger or aggression
• Decreased appetite or weight loss
• Irritability
• Nervousness/anxiety
• Restlessness
• Sleep difficulties, including strange dreams

Less common symptoms/equivocal symptoms

• Chills
• Depressed mood
• Stomach pain
• Shakiness
• Sweating

A strong relationship exists between relapses from marijuana abstinence in response to intolerance of one or more of these withdrawal symptoms.(28)

IV. Epidemiology

Measurements of the frequency of substance abuse (high risk use) and substance dependence are usually based on the diagnostic criteria established in DSM-IV – the Diagnostic and Statistical Manual used to define psychiatric illnesses. These criteria can be summarized as follows:

• Tolerance/Withdrawal
• Loss of Control
• Preoccupation with the drug
• Continued Use in the Face of Adverse Consequences
• Cognitive Distortions/Denial

In 2007, 14.4 million Americans aged 12 or older used marijuana at least once in the month prior to being surveyed. Of those individuals who initiate marijuana use at 18 years or older, approximately 9% eventually satisfy DSM criteria for dependence.(24) Rates of cannabis dependence are estimated at 20% to 30% among those who have used at least five times, and even higher estimates (35%-40%) are reported among those who report near daily use.(29-30) For those who use marijuana before age 18, the rate of dependence can triple, depending on how early use begins. Marijuana dependence also develops more quickly in adolescents, with up to 17% becoming addicted within the first two years of use.(31)

Conclusion

The fact that marijuana is clearly addictive for a minority of people, and especially so for adolescents and children, does not mean that the public does not have a right to legalize its use. We currently permit the marketing, sale and consumption of multiple legal, though addictive, substances – e.g., caffeine, nicotine and alcohol. We also permit the prescription medical use of very powerfully addictive drugs – e.g., tranquilizers (benzodiazepines), sleep aids, amphetamine, opiate analgesics.

The California Society of Addiction Medicine contends that legalizing an additional addictive drug is a matter for public health debate and not merely political debate. Any effort, whether through ignorance, denial or deception, to obscure the fact that marijuana has all the characteristics of an addictive drug does a grave disservice to the voting public. Legalizing marijuana will have health consequences for some, and these consequences will have to be dealt with by us all. Incarcerating marijuana users has clearly not been an effective approach to dealing with the current health consequences created by this addictive substance. If the public decides to try legalization as an alternative strategy, it would be well advised to be aware of the addictive nature of marijuana and to be prepared to create an effective public health, prevention and treatment response to what will undoubtedly be an increase in marijuana use, to the detriment of a significant minority of users.

References

1. Text of Proposition 19
2. Brown, D.; The New Science of Cannabinoid-Based Medicine: An Interview with Dr. Raphael Mechoulam, www.mavericksofthemind.com, Copyright 2005-6, Smart Publications
3. Di Chiara, G., Imperato, A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats
   Proc Natl Acad Sci U S A, Vol 85, Issue 14, pp 5274-8, 1988

Abstract

The effect of various drugs on the extracellular concentration of dopamine in two terminal dopaminergic areas, the nucleus accumbens septi (a limbic area) and the dorsal caudate nucleus (a subcortical motor area), was studied in freely moving rats by using brain dialysis. Drugs abused by humans (e.g., opiates, ethanol, nicotine, amphetamine, and cocaine) increased extracellular dopamine concentrations in both areas, but especially in the accumbens, and elicited hypermotility at low doses. On the other hand, drugs with aversive properties (e.g., agonists of kappa opioid receptors, U-50,488, tifluadom, and bremazocine) reduced dopamine release in the accumbens and in the caudate and elicited hypomotility. Haloperidol, a neuroleptic drug, increased extracellular dopamine concentrations, but this effect was not preferential for the accumbens and was associated with hypomotility and sedation. Drugs not abused by humans [e.g., imipramine (an antidepressant), atropine (an antimuscarinic drug), and diphenhydramine (an antihistamine)] failed to modify synaptic dopamine concentrations. These results provide biochemical evidence for the hypothesis that stimulation of dopamine transmission in the limbic system might be a fundamental property of drugs that are abused.

4. Gardner, E. L. Addictive potential of cannabinoids: the underlying neurobiology
   Chem Phys Lipids. 2002 Dec 31;121(1-2):267-90.

Abstract

Drugs that are addictive in humans have a number of commonalities in animal model systems-(1). they enhance electrical brain-stimulation reward in the core meso-accumbens reward circuitry of the brain, a circuit encompassing that portion of the medial forebrain bundle (MFB) which links the ventral tegmental area (VTA) of the mesencephalic midbrain with the nucleus accumbens (Acb) of the ventral limbic forebrain; (2). they enhance neural firing of a core dopamine (DA) component of this meso-accumbens reward circuit; (3). they enhance DA tone in this reward-relevant meso-accumbens DA circuit, with resultant enhancement of extracellular Acb DA; (4). they produce conditioned place preference (CPP), a behavioral model of incentive motivation; (5). they are self-administered; and (6). they trigger reinstatement of drug-seeking behavior in animals behaviorally extinguished from intravenous drug self-administration behavior and, perforce, pharmacologically detoxified from their self-administered drug. Cannabinoids were long considered ‘anomalous’, in that they were believed to not interact with these brain reward processes or support drug-seeking and drug-taking behavior in these animal model systems. However, it is now clear-from the published data of several research groups over the last 15 years-that this view of cannabinoid action on brain reward processes and reward-related behaviors is untenable. This paper reviews those data, and concludes that cannabinoids act on brain reward processes and reward-related behaviors in strikingly similar fashion to other addictive drugs.

5. Pistis, M., Muntoni, A. L., Pillolla, G., Gessa, G. L. Cannabinoids inhibit excitatory inputs to neurons in the shell of the nucleus accumbens: an in vivo electrophysiological study
   Eur J Neurosci. 2002 Jun;15(11):1795-802.

Abstract

The nucleus accumbens (NAc) represents a critical site for the rewarding properties of diverse classes of drugs of abuse. Glutamatergic afferents to the NAc are involved in the actions of psychostimulants and opioids, while the potentiation of dopaminergic neurotransmission in the NAc is a common feature of abused drugs, including cannabinoids. Cannabinoid receptors (CB1) are densely expressed in regions that provide excitatory innervation to the NAc, such as the amygdala, the cortex and the hippocampus. Recent in vitro evidence suggests that indeed cannabinoids modulate glutamatergic synapses in the NAc. In this study we recorded extracellularly from neurons in the shell of the NAc which responded to the stimulation of the baso-lateral amygdala (BLA) or the medial prefrontal cortex (PFC) in urethane anaesthetized rats. BLA or PFC stimulation induced generation of action potentials in NAc neurons. This excitatory effect was strongly inhibited by the synthetic cannabinoid agonists WIN 55212,2 (0.062-0.25 mg/kg, i.v.) and HU-210 (0.125-0.25 mg/kg, i.v.) or the psychoactive principle of Cannabis delta(9)-tetrahydrocannabinol (1.0 mg/kg, i.v.). Neither the D1 or D2 dopamine receptor antagonists (SCH23390 0.5-1.0 mg/kg, sulpiride 5-10 mg/kg, i.v.) or the opioid antagonist naloxone (1.0 mg/kg, i.v.) were able to reverse the action of cannabinoids, while the selective CB1 receptor antagonist/reverse agonist SR141716A (0.5 mg/kg, i.v.) fully suppressed the action of cannabinoid agonists, whereas per se had no significant effect. These results provide evidence that cannabinoids, in common with other drugs of abuse, in vivo strongly inhibit the excitability of neurons in the shell of the NAc.

6. Tanda, G., Loddo, P., Di Chiara, G. Dependence of mesolimbic dopamine transmission on delta9-tetrahydrocannabinol
   Eur J Pharmacol. 1999 Jul 2;376(1-2):23-6.

Abstract

Rats were administered daily for 8 days with increasing doses (2-12 mg/kg/day) of delta9-tetrahydrocannabinol (delta9-THC) and than challenged with different doses of SR141716A, an antagonist of cannabinoid receptors. SR141716A dose dependently reduced dialysate dopamine (DA) in the nucleus accumbens shell and precipitated a physical withdrawal syndrome. No such effects were obtained after administration of SR141716A to saline controls.

7. Hoffman, A. F., Oz, M., Caulder, T., Lupica, C. R. Functional tolerance and blockade of long-term depression at synapses in the nucleus accumbens after chronic cannabinoid exposure
   J Neurosci. 2003 Jun 15;23(12):4815-20.

Abstract

The rewarding properties of the psychoactive constituents of marijuana, termed “cannabinoids,” may reflect actions on synaptic transmission in the nucleus accumbens (NAc). Furthermore, long-term changes in these synapses may support the addictive process. Excitatory and inhibitory synapses are acutely inhibited by cannabinoids in the NAc, and endogenous cannabinoids (endocannabinoids) play a critical role in the expression of long-term depression (LTD) of excitatory cortical afferents in this structure. Because humans often use marijuana for prolonged periods, we examined the impact of long-term cannabinoid exposure on synaptic processes in an animal model. Electrophysiological recordings in rat brain slices containing the NAc were performed after chronic exposure to vehicle solution, Delta9-tetrahydrocannabinol (THC), or the cannabinoid agonist R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl)methanone mesylate (WIN55,212-2). Extracellular glutamatergic postsynaptic potentials and whole-cell GABAergic IPSCs were concentration-dependently inhibited by WIN55,212-2 in slices from naive or vehicle-treated animals. However, the sensitivity to WIN55,212-2 was diminished in chronic agonist-treated animals. In addition, cross-tolerance to the inhibitory effect of the mu-opioid agonist Tyr-D-Ala2, N-CH3-Phe4,Gly-ol-enkephalin was observed. Endocannabinoid-mediated LTD was initiated via electrical stimulation (5 min, 10 Hz) of glutamatergic afferents to the NAc and was completely blocked by the cannabinoid receptor antagonist SR141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] in vehicle-treated animals. LTD was not observed in brain slices from rats chronically treated with Delta9-THC or WIN55,212-2. These data demonstrate that long-term exposure to the active ingredient of marijuana blocks synaptic plasticity in the NAc and reduces the sensitivity of GABAergic and glutamatergic synapses to both cannabinoids and opioids.

8. Kolb, B., Gorny, G., Limebeer, C. L., Parker, L. A. Chronic treatment with Delta-9-tetrahydrocannabinol alters the structure of neurons in the nucleus accumbens shell and medial prefrontal cortex of rats
   Synapse. 2006 Nov;60(6):429-36.

Abstract

The potential of repeated exposure to Delta(9)-tetrahydrocannabinol (Delta(9)-THC) to produce long-lasting changes in synaptic connections in a manner similar to other drugs of abuse was evaluated in Sprague-Dawley rats. For 12 days, rats received two i.p. injections per day (8 h apart) of vehicle, a low dose of Delta(9)-THC (0.5 mg/kg), or escalating doses of Delta(9)-THC (0.5-4.0 mg/kg). Thirty days later, they were evaluated for sensitized locomotor activity (during the night cycle) for 60 min on each of three trials. Using a within-groups design, rats were tested following an injection of vehicle, 0.5 mg/kg Delta(9)-THC or 2.0 mg/kg Delta(9)-THC. The rats showed no evidence of sensitized locomotor activity in any group. Twenty-four hours after the final sensitization test, their brains were removed and then processed for Golgi-Cox staining. Prior exposure to Delta(9)-THC (both the low dose and the escalating doses) increased the length of the dendrites as well as the number of dendritic branches in the shell of the nucleus accumbens and in the medial prefrontal cortex, but not in the hippocampus, striatum, orbital frontal cortex, parietal cortex, or occipital cortex. These results are similar to those evident in brains of rats sensitized to amphetamine, and support previous findings that cannabinoids promote DA activity in the mesolimbic DA system.

9. Pistis, M., Perra, S., Pillolla, G., Melis, M., Muntoni, A. L., Gessa, G. L. Adolescent exposure to cannabinoids induces long-lasting changes in the response to drugs of abuse of rat midbrain dopamine neurons
   Biol Psychiatry. 2004 Jul 15;56(2):86-94.

Abstract

BACKGROUND: Recent studies have raised concerns about subtle long-lasting neurobiological changes that might be triggered by exposure to Cannabis derivatives, especially in a critical phase of brain maturation, such as puberty. The mesolimbic dopamine (DA) system, involved in the processing of drug-induced reward, is a locus of action of cannabinoids and endocannabinoids. Thus, we compared the effects of repeated cannabinoid administration in adolescent and adult rats on DA neuronal functions and responses to drugs of abuse. METHODS: Single-unit extracellular recordings from antidromically identified mesoaccumbens DA neurons and from their target cells in the nucleus accumbens were carried out in urethane-anesthetized rats. Animals were pretreated during adolescence or adulthood, for 3 days, with the cannabinoid agonist WIN55212.2 (WIN) or vehicle and allowed a 2-week interval. RESULTS: In cannabinoid-administered rats, DA neurons were significantly less responsive to the stimulating action of WIN, regardless of the age of pretreatment; however, in the adolescent group, but not in the adult, long-lasting cross-tolerance developed to morphine, cocaine, and amphetamine. CONCLUSIONS: Our study suggests that an enduring form of neuronal adaptation occurs in DA neurons after subchronic cannabinoid intake at a young age, affecting subsequent responses to drugs of abuse.

10. Robbe, D., Alonso, G., Manzoni, O. J. Exogenous and endogenous cannabinoids control synaptic transmission in mice nucleus accumbens
    Ann N Y Acad Sci. 2003 Nov;1003:212-25.

Abstract

Addictive drugs are thought to alter normal brain function and cause the remodeling of synaptic functions in areas important to memory and reward. Excitatory transmission to the nucleus accumbens (NAc) is involved in the actions of most drugs of abuse, including cannabis. We have explored the functions of the endocannabinoid system at the prefrontal cortex-NAc synapses. Immunocytochemistry showed cannabinoid receptor (CB1) expression on axonal terminals making contacts with NAc neurons. In NAc slices, synthetic cannabinoids inhibit spontaneous and evoked glutamate-mediated transmission through presynaptic activation of presynaptic K+ channels and GABA-mediated transmission most likely via a direct presynaptic action on the vesicular release machinery. How does synaptic activity lead to the production of endogenous cannabinoids (eCBs) in the NAc? More generally, do eCBs participate in long-term synaptic plasticity in the brain? We found that tetanic stimulation (mimicking naturally occurring frequencies) of prelimbic glutamatergic afferents induced a presynaptic LTD dependent on eCB and CB1 receptors (eCB-LTD). Induction of eCB-LTD required postsynaptic activation of mGlu5 receptors and a rise in postsynaptic Ca2+ from ryanodine-sensitive intracellular Ca2+ stores. This retrograde signaling cascade involved postsynaptic eCB release and activation of presynaptic CB1 receptors. In the NAc, eCB-LTD might be part of a negative feedback loop, reducing glutamatergic synaptic strength during sustained cortical activity. The fact that this new form of LTD was occluded by an exogenous cannabinoid suggested that cannabis derivatives, such as marijuana, may alter normal eCB-mediated synaptic plasticity. These data suggest a major role of the eCB system in long-term synaptic plasticity and give insights into how cannabis derivatives, such as marijuana, alter normal eCB functions in the brain reward system.

11. Robbe, D., Kopf, M., Remaury, A., Bockaert, J., Manzoni, O. J. Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens
    Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8384-8.

Abstract

Do endocannabinoids (eCBs) participate in long-term synaptic plasticity in the brain? Using pharmacological approaches and genetically altered mice, we show that stimulation of prelimbic cortex afferents at naturally occurring frequencies causes a long-term depression of nucleus accumbens glutamatergic synapses mediated by eCB release and presynaptic CB1 receptors. Translation of glutamate synaptic transmission into eCB retrograde signaling involved metabotropic glutamate receptors and postsynaptic intracellular Ca(2+) stores. These findings unveil the role of the eCB system in activity-dependent long-term synaptic plasticity and identify a mechanism by which marijuana can alter synaptic functions in the endogenous brain reward system.

12. Whitlow, C. T., Freedland, C. S., Porrino, L. J. Functional consequences of the repeated administration of Delta9-tetrahydrocannabinol in the rat
    Drug Alcohol Depend. 2003 Aug 20;71(2):169-77.

Abstract

The repeated administration of Delta(9)-tetrahydrocannabinol (THC) results in tolerance to many of its behavioral and physiological effects. It also produces changes in the functionality of cannabinoid receptors. What is not completely understood is how these cellular events translate into the behavioral and physiological changes that are associated with repeated cannabinoid agonist treatment. The purpose of these studies was to determine the development of changes in the patterns of functional activity, as measured by the 2-[14C]deoxyglucose method (2DG), associated with repeated THC exposure. Male Sprague-Dawley rats (n=4-5) were administered THC (vehicle or 10 mg/kg, intraperitoneally), daily for 7 or 21 days. Fifteen minutes following the final THC treatment the 2DG procedure was initiated. In separate sets of rats similarly treated with THC, locomotor activity and core body temperature were measured at corresponding time points in order to establish the behavioral profile of repeated THC administration. The acute administration of THC following 7 or 21 days of drug exposure resulted in a significant attenuation of changes in rates of glucose utilization throughout the majority of brain regions analyzed when compared to the large global decreases observed following a single administration of THC. After 7 and 21 days of treatment, cerebral metabolic rates were no longer different from vehicle-treated controls in most cortical, thalamic and basal ganglia regions. This attenuation closely paralleled the development of tolerance to the effects of THC on locomotor activity and core body temperature. However, glucose utilization remained altered in the nucleus accumbens, mediodorsal thalamus, basolateral amygdala, portions of the hippocampus and median raphe. These data suggest that the development of tolerance to the cerebral metabolic effects of THC is regionally specific and temporally distinct. The persistence of effects in limbic areas as well as portions of the hippocampal complex, however, suggests that processes such as stress, reward, and aspects of memory mediated by these brain regions may continue to be affected by THC even after prolonged THC exposure.

13. Justinova, Z., Solinas, M., Tanda, G., Redhi, G. H., Goldberg, S. R. The endogenous cannabinoid anandamide and its synthetic analog R(+)-methanandamide are intravenously self-administered by squirrel monkeys
    J Neurosci. 2005 Jun 8;25(23):5645-50.

Abstract

Anandamide, an endogenous ligand for brain cannabinoid CB(1) receptors, produces many behavioral effects similar to those of Delta(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in marijuana. Reinforcing effects of THC have been demonstrated in experimental animals, but there is only indirect evidence that endogenous cannabinoids such as anandamide participate in brain reward processes. We now show that anandamide serves as an effective reinforcer of drug-taking behavior when self-administered intravenously by squirrel monkeys. We also show that methanandamide, a synthetic long-lasting anandamide analog, similarly serves as a reinforcer of drug-taking behavior. Finally, we show that the reinforcing effects of both anandamide and methanandamide are blocked by pretreatment with the cannabinoid CB(1) receptor antagonist rimonabant (SR141716). These findings strongly suggest that release of endogenous cannabinoids is involved in brain reward processes and that activation of cannabinoid CB(1) receptors by anandamide could be part of the signaling of natural rewarding events.

14. Justinova Z, Tanda G, Redhi GH, Goldberg SR Self-administration of delta9-tetrahydrocannabinol (THC) by drug naive squirrel monkeys
    Psychopharmacology (Berl).2003 Sep;169(2):135-40. Epub 2003 Jun 24.

Abstract

RATIONALE: Interest in therapeutic activities of cannabinoids has been restrained by the fact that they are most often mediated through activation of cannabinoid CB1 receptors, the same receptors that mediate the effects of delta9-tetrahydrocannabinol (THC) and are responsible for the abuse liability of marijuana. Persistent intravenous self-administration of THC by animals was first demonstrated in squirrel monkeys and shown to be mediated by CB1 receptors, but monkeys in the study had a history of cocaine self-administration, raising the possibility that persistent neurobiological adaptations might subsequently predispose animals to self-administer THC. OBJECTIVES: To demonstrate persistent intravenous self-administration of THC in drug-naive squirrel monkeys. METHODS: Monkeys with no history of exposure to other drugs learned to press a lever for intravenous injections (0.2 ml in 0.2 s) of THC under a 10-response, fixed-ratio schedule with a 60-s time-out after each injection. Acquisition of THC self-administration was rapid and the final schedule was reached in 11-34 sessions. Dose of THC was then varied from 1 to 16 microg/kg per injection with vehicle extinction following each dose of THC. RESULTS: THC maintained significantly higher numbers of self-administered injections per session and higher rates of responding than vehicle at doses of 2, 4 and 8 microg/kg per injection, with maximal rates of responding at 4 microg/kg per injection. Response rates, injections per session and total THC intake per session were two- to three-fold greater in monkeys with no history of exposure to other drugs compared to previous findings in monkeys with a history of cocaine self-administration. CONCLUSIONS: THC can act as an effective reinforcer of drug-taking behavior in monkeys with no history of exposure to other drugs, suggesting that self-administration of THC by monkeys provides a reliable animal model of human marijuana abuse.

15. Tanda, G., Goldberg, S. R. Cannabinoids: reward, dependence, and underlying neurochemical mechanisms–a review of recent preclinical data
    Psychopharmacology (Berl). 2003 Sep;169(2):115-34. Epub 2003 Jun 24

Abstract

BACKGROUND AND RATIONALE: Starting with the discovery of an endogenous brain cannabinoid system with specific receptors and endogenous ligands, research in the cannabinoid field has accelerated dramatically over the last 15 years. Cannabis is the most used illicit psychotropic substance in the world but only recently have reliable preclinical models become available for investigating the rewarding and dependence-producing actions of its psychoactive constituent, delta9-tetrahydrocannabinol (THC). OBJECTIVES: The goal of this review is to examine the various animal models currently available that are being used to facilitate our understanding of the rewarding and dependence-producing actions of cannabinoids, which are central to their abuse liability, and of the neurochemical mechanisms that may underlie these actions of cannabinoids. RESULTS AND CONCLUSIONS: Recent demonstrations that strong and persistent intravenous self-administration behavior can be obtained in squirrel monkeys using a range of THC doses that are in agreement with the total intake and the single doses of THC normally self-administered by humans smoking marijuana cigarettes provides a reliable and direct tool for assessing the reinforcing effects of THC that are central to its abuse liability. In addition, recent demonstrations of persistent intravenous self-administration of synthetic cannabinoid CB1 receptor agonists by rats and mice and the development of genetically modified mice lacking specific cannabinoid receptors provide convenient rodent models for exploring underlying neurochemical mechanisms. Repeated demonstrations in rats that THC and synthetic CB1 agonists can induce conditioned place preferences or aversions, depending on details of dose and spacing, can reduce the threshold for intracranial self-stimulation behavior under certain conditions, and can serve as effective discriminative stimuli for operant behavior provide less direct, but more rapidly established, measures for investigating the rewarding effects of cannabinoids. Finally, there have been numerous recent reports of major functional interactions between endogenous cannabinoid, opioid, and dopaminergic neurotransmitter systems in areas such as analgesia, physical dependence and tolerance development, and drug reinforcement or reward. This provides an opportunity to search for drugs with the beneficial therapeutic effects of currently available cannabinoids or opioids but without undesirable adverse effects such as abuse liability.

16. Aceto MD, Scates SM, Martin BB Spontaneous and precipitated withdrawal with a synthetic cannabinoid, WIN 55212-2
    Eur J Pharmacol. 2001 Mar 23;416(1-2):75-81.

Abstract

Physical dependence on the synthetic cannabinoid-receptor agonist R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate (WIN 55212-2) was demonstrated in rats by the use of a chronic continuous infusion. Spontaneous withdrawal, of moderate intensity, was shown for the first time with this class of drugs of abuse. Behavioral withdrawal signs were also elicited after challenge with (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide.HCl (SR141716A), a specific CB(1) cannabinoid-receptor antagonist. In both instances, the high-dose regimen (4, 8, 16 and 16 mg/kg/day, i.p. on days 1-4, respectively) was sufficient to evoke a typical withdrawal syndrome quantified by the signs wet-dog shakes and facial rubs. These results are discussed relative to those obtained with Delta(9)-tetrahydrocannabinol and anandamide. With Delta(9)-tetrahydrocannabinol, precipitated but not spontaneous or abrupt withdrawal was observed, and this was ascribed to pharmacokinetic properties. Anandamide, which showed little, if any, physical dependence potential, behaved atypically. Possible implications regarding pharmacotherapeutic and human abuse issues are discussed.

17. Cook SA, Lowe JA, Martin BR. CB1 receptor antagonist precipitates withdrawal in mice exposed to Delta9-tetrahydrocannabinol
    J Pharmacol Exp Ther. 1998 Jun;285(3):1150-6.

Abstract

Although tolerance to cannabinoids has been well established, the question of cannabinoid dependence had been very controversial until the discovery of a cannabinoid antagonist, SR141716A. The objective of this study was to develop and characterize a mouse model of precipitated withdrawal indicative of cannabinoid dependence. Using a dosing regimen known to produce pharmacological and behavioral tolerance, mice were treated with Delta9-tetrahydrocannabinol (Delta9-THC) twice a day for 1 wk. SR141716A administration after the last Delta9-THC injection promptly precipitated a profound withdrawal syndrome. Typical withdrawal behavior was an increase in paw tremors and head shakes that was accompanied with a decrease in normal behavior such as grooming and scratching. Of the three Delta9-THC regimens tested, daily Delta9-THC injections of 10 and 30 mg/kg produced the greatest number of paw tremors and head shakes and the least number of grooms after challenge with SR141716A. Precipitated withdrawal was apparent after 2, 3, 7 and 14 days of treatment based on an increase in paw tremors in Delta9-THC-treated mice as compared with vehicle-treated mice. These findings are consistent with SR141716A-precipitated withdrawal in rats. Moreover, these results suggest that mice are a viable model for investigating dependence to cannabinoids.

18. Kouri EM, Pope HG Jr. Abstinence symptoms during withdrawal from chronic marijuana use
    Exp Clin Psychopharmacol. 2000 Nov;8(4):483-92.

Abstract

Although marijuana is the most commonly used illicit drug in the United States, it is not established whether withdrawal from chronic use results in a clinically significant abstinence syndrome. The present study was conducted to characterize symptoms associated with marijuana withdrawal following chronic use during a supervised 28-day abstinence period. Three groups of participants were studied: (a) current chronic marijuana users, (b) former chronic marijuana users who had not used marijuana for at least 6 months prior to the study, and (c) marijuana nonusers. Current users experienced significant increases in anxiety, irritability, physical tension, and physical symptoms and decreases in mood and appetite during marijuana withdrawal. These symptoms were most pronounced during the initial 10 days of abstinence, but some were present for the entire 28-day withdrawal period. These findings support the notion of a marijuana withdrawal syndrome in humans.

19. Kouri EM, Pope HG Jr, Lukas SE. Changes in aggressive behavior during withdrawal from long-term marijuana use
    Psychopharmacology (Berl). 1999 Apr;143(3):302-8.

Abstract

RATIONALE: Even though marijuana is the most commonly abused illicit drug in the United States, it is still undetermined whether withdrawal after chronic use results in changes in aggressive behavior in humans. OBJECTIVE: The present study investigated the pattern and duration of changes in aggressive behavior in long-term marijuana users during a 28-day abstinence period verified by daily urines. METHOD: Chronic marijuana users who had smoked marijuana on at least 5000 occasions (the equivalent of smoking daily for approximately 14 years) and who were smoking regularly when recruited were studied on days 0 (when they were still smoking), 1 (during acute withdrawal), 3, 7 and 28 of a 28-day detoxification period. Aggressive behavior was measured using the Point Subtraction Aggression Paradigm. RESULTS: Compared to controls and to the pre-withdrawal data, chronic marijuana users displayed more aggressive behavior on days 3 and 7 of marijuana abstinence. These increases in aggressive responding returned to pre-withdrawal levels after 28 days and were paralleled by small, non-significant changes in depression and anxiety scores. CONCLUSIONS: Our findings confirm previous reports of an abstinence syndrome associated with chronic marijuana use and suggest that aggressive behavior should be an additional component of this syndrome.

20. Lichtman AH, Wiley JL, LaVecchia KL, Neviaser ST, Arthur DB, Wilson DM, Martin BR. Effects of SR 141716A after acute or chronic cannabinoid administration in dogs.
    Eur J Pharmacol. 1998 Sep 18;357(2-3):139-48.

Abstract

The effects of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-met hyl-1H-pyrazole-3-carboxamide HCl (SR 141716A), a specific cannabinoid receptor antagonist, were assessed in the dog static ataxia test after either acute treatment with two cannabinoid receptor agonists, delta9-tetrahydrocannabinol and arachidonylethanolamide (anandamide), or chronic treatment with delta9-tetrahydrocannabinol. As previously reported, acute intravenous (i.v.) injected delta9-tetrahydrocannabinol produced dose-dependent cannabinoid effects, including marked static ataxia, prancing, loss of muscle tone, and incoordination. The behavioral profile of anandamide was distinctly different in that it produced a loss of muscle tone and considerable sedation with little static ataxia, prancing, or incoordination. Despite these qualitative differences between the two agonists, SR 141716A blocked the acute behavioral effects of both drugs indicating a cannabinoid receptor mechanism of action. Interestingly, SR 141716A was able to precipitate a withdrawal syndrome in delta9-tetrahydrocannabinol-tolerant dogs, but failed to produce any observable effects in dogs receiving chronic vehicle injections. Acute toxicity caused by anandamide, which was not blocked by SR 141716A, precluded conducting dependence studies with this drug. The delta9-tetrahydrocannabinol precipitated withdrawal syndrome included diarrhea, vomiting, excessive salivation, decreases in social behavior, and increases in restless behavior and trembling. This is the first demonstration of a precipitated withdrawal syndrome in a non-rodent species.

21. Cutler MG, Mackintosh JH, Chance MR. Behavioural changes in laboratory mice during cannabis feeding and withdrawal.
    Psychopharmacologia. 1975 Oct 31;44(2):173-7.

Abstract

The effects of feeding cannabis at a level of 0.4% in the diet has been studied by an ethological analysis of encounters between male mice. Administration of cannabis to dominant males resulted in a reduction of non-social activity and an increase in flight and in social and sexual investigation when compared with untreated controls, but the behaviour of subordinate males was not significantly altered by cannabis. One week after withdrawal of cannabis, the behaviour of diminant males showed a rebound effect with increase in aggression. Nevertheless, by a preference feeding test it was demonstrated that the treated mice were not dependent on the cannabis-containing diet but consumed the control diet in preference.

22. Breivogel CS, Scates SM, Beletskaya IO, Lowery OB, Aceto MD, Martin BR. The effects of delta9-tetrahydrocannabinol physical dependence on brain cannabinoid receptors
    Eur J Pharmacol. 2003 Jan 17;459(2-3):139-50.

Abstract

The effects of chronic Delta(9)-tetrahydrocannabinol on cannabinoid receptor levels and receptor-G-protein coupling were investigated. Male Sprague-Dawley rats were infused continuously with low or high dose regimens of Delta(9)-tetrahydrocannabinol or vehicle for 4 days. Following treatment, rats were sacrificed for cannabinoid CB(1) receptor binding analysis or challenged with the cannabinoid CB(1) receptor antagonist, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A). The rats receiving Delta(9)-tetrahydrocannabinol exhibited antagonist-precipitated withdrawal signs. Each brain region (cerebellum, cortex, hippocampus and basal ganglia) from high-dose rats showed 30-70% decreases in 3H-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxyphenyl)cyclohexanol (WIN55212-2) B(max) values, indicating receptor down-regulation. Most regions showed decreased WIN55212-2-stimulated [35S]guanosine-5′-O-3-thiotriphosphate (GTPgammaS) binding, indicating desensitization of cannabinoid CB(1) receptors. Additional receptor binding assays in cerebellar membranes showed a significantly greater decrease in agonist than in antagonist B(max) values, indicating a lower fraction of coupled receptors after treatment. Concentration-effect analysis of five agonists revealed that the treatment resulted in greater decreases in the efficacy of low-efficacy agonists.

23. Budney, A. J., Hughes, J. R. The cannabis withdrawal syndrome
    Curr Opin Psychiatry, Vol 19, Issue 3, pp 233-8, 2006

Abstract

PURPOSE OF REVIEW: The demand for treatment for cannabis dependence has grown dramatically. The majority of the people who enter the treatment have difficulty in achieving and maintaining abstinence from cannabis. Understanding the impact of cannabis withdrawal syndrome on quit attempts is of obvious importance. Cannabis, however, has long been considered a ‘soft’ drug, and many continue to question whether one can truly become dependent on cannabis. Skepticism is typically focused on whether cannabis use can result in ‘physiological’ dependence or withdrawal, and whether withdrawal is of clinical importance. RECENT FINDINGS: The neurobiological basis for cannabis withdrawal has been established via discovery of an endogenous cannabinoid system, identification of cannabinoid receptors, and demonstrations of precipitated withdrawal with cannabinoid receptor antagonists. Laboratory studies have established the reliability, validity, and time course of a cannabis withdrawal syndrome and have begun to explore the effect of various medications on such withdrawal. Reports from clinical samples indicate that the syndrome is common among treatment seekers. SUMMARY: A clinically important withdrawal syndrome associated with cannabis dependence has been established. Additional research must determine how cannabis withdrawal affects cessation attempts and the best way to treat its symptoms.

24. Budney, A. J., Roffman, R., Stephens, R. S., Walker, D. Marijuana dependence and its treatment
    Addict Sci Clin Pract, Vol 4, Issue 1, pp 4-10

Abstract

The prevalence of marijuana abuse and dependence disorders has been increasing among adults and adolescents in the United States. This paper reviews the problems associated with marijuana use, including unique characteristics of marijuana dependence, and the results of laboratory research and treatment trials to date. It also discusses limitations of current knowledge and potential areas for advancing research and clinical intervention.

25. Budney AJ, Hughes JR, Moore BA, Novy PL. Marijuana abstinence effects in marijuana smokers maintained in their home environment
    Arch Gen Psychiatry. 2001 Oct;58(10):917-24.

Abstract

BACKGROUND: Although withdrawal symptoms are commonly reported by persons seeking treatment for marijuana dependence, the validity and clinical significance of a marijuana withdrawal syndrome has not been established. This controlled outpatient study examined the reliability and specificity of the abstinence effects that occur when daily marijuana users abruptly stop smoking marijuana. METHODS: Twelve daily marijuana smokers were assessed on 16 consecutive days during which they smoked marijuana as usual (days 1-5), abstained from smoking marijuana (days 6-8), returned to smoking marijuana (days 9-13), and again abstained from smoking marijuana (days 14-16). RESULTS: An overall measure of withdrawal discomfort increased significantly during the abstinence phases and returned to baseline when marijuana smoking resumed. Craving for marijuana, decreased appetite, sleep difficulty, and weight loss reliably changed across the smoking and abstinence phases. Aggression, anger, irritability, restlessness, and strange dreams increased significantly during one abstinence phase, but not the other. Collateral observers confirmed participant reports of these symptoms. CONCLUSIONS: This study validated several specific effects of marijuana abstinence in heavy marijuana users, and showed they were reliable and clinically significant. These withdrawal effects appear similar in type and magnitude to those observed in studies of nicotine withdrawal.

26. Budney, A. J., Hughes, J. R., Moore, B. A., Vandrey, R. Review of the validity and significance of cannabis withdrawal
    Am J Psychiatry, Vol 161, Issue 11, pp 1967-77, 2004

Abstract

The authors review the literature examining the validity and significance of cannabis withdrawal syndrome. Findings from animal laboratory research are briefly reviewed, and human laboratory and clinical studies are surveyed in more detail. Converging evidence from basic laboratory and clinical studies indicates that a withdrawal syndrome reliably follows discontinuation of chronic heavy use of cannabis or tetrahydrocannabinol. Common symptoms are primarily emotional and behavioral, although appetite change, weight loss, and physical discomfort are also frequently reported. The onset and time course of these symptoms appear similar to those of other substance withdrawal syndromes. The magnitude and severity of these symptoms appear substantial, and these findings suggest that the syndrome has clinical importance. Diagnostic criteria for cannabis withdrawal syndrome are proposed.

27. Milin R, Manion I, Dare G, Walker S. Prospective assessment of cannabis withdrawal in adolescents with cannabis dependence: a pilot study
    J Am Acad Child Adolesc Psychiatry. 2008 Feb;47(2):174-8.

Abstract

OBJECTIVE: To prospectively identify and assess withdrawal symptoms in adolescents with cannabis dependence. METHOD: Twenty-one adolescents ages 13 to 19 years voluntarily entering residential and day/outpatient substance abuse programs, with cannabis dependence as their only current substance of dependence, were assessed using the Teen-Addiction Severity Index, Substance Use Survey, Cannabis Withdrawal Scale, and the Structured Clinical Interview for DSM-IV Childhood Diagnoses Substance Use Disorders Module. Weekly assessments continued for 4 weeks. Thirteen youths attained a minimum of 2 weeks of abstinence. RESULTS: Cannabis withdrawal symptoms were present in adolescents. Cannabis withdrawal was greatest in the first 2 weeks of abstinence with evidence that it continued well into week 3. Most withdrawal symptoms were endorsed with a high degree of frequency. Those symptoms endorsed with the greatest severity were restlessness, appetite change, and thoughts of and cravings for cannabis, with the highest ratings occurring in week 1. Over the course of the study, participants reported fewer symptoms with decreasing levels of severity. Youth ratings of overall severity of withdrawal were significantly and positively correlated with withdrawal symptoms of irritability (r = 0.56), depression (r = 0.56), twitches and shakes (r = 0.57), perspiring (r = 0.57), thoughts of (r = 0.86), and cravings for (r = 0.69) cannabis. CONCLUSIONS: Findings support the presence of clinically significant cannabis withdrawal symptoms in adolescents with cannabis dependence seeking substance abuse treatment. This study also provides supporting evidence suggesting a vulnerability of adolescents to physiological cannabis dependence. The study supports the addition of cannabis withdrawal as a distinct entity for inclusion in DSM-V.

28. Hasin, D. S., Keyes, K. M., Alderson, D., Wang, S., Aharonovich, E., Grant, B. F. Cannabis withdrawal in the United States: results from NESARC
    J Clin Psychiatry, Vol 69, Issue 9, pp 1354-63.

Abstract

OBJECTIVE: Although cannabis is the most widely abused illicit drug, little is known about the prevalence of cannabis withdrawal and its factor structure, clinical validity, and psychiatric correlates in the general population. METHOD: National Epidemiologic Survey on Alcohol and Related Conditions participants were assessed, in 2001-2002, with structured in-person interviews covering substance history, DSM-IV Axis I and II disorders, and withdrawal symptoms after cessation of use. Of these, 2613 had been frequent cannabis users (> or = 3 times/week), and a “cannabis-only” subset (N = 1119) never binge-drank or used other drugs > or = 3 times/week. RESULTS: In the full sample and subset, 44.3% (SE = 1.19) and 44.2% (SE = 1.75), respectively, experienced > or = 2 cannabis withdrawal symptoms, while 34.4% (SE = 1.21) and 34.1% (SE = 1.76), respectively, experienced > or = 3 symptoms. The symptoms formed 2 factors, one characterized by weakness, hypersomnia, and psychomotor retardation and the second by anxiety, restlessness, depression, and insomnia. Both symptom types were associated with significant distress/impairment (p < .01), substance use to relieve/avoid cannabis withdrawal symptoms (p <.01), and quantity of cannabis use (among the cannabis-only users p < .05). Panic (p < .01) and personality (p > .01) disorders were associated with anxiety symptoms in both samples, family history of drug problems was associated with weakness symptoms in the subset (p = .01), and depression was associated with both sets of symptoms in the subset (p < or = .05). CONCLUSION: Cannabis withdrawal was prevalent and clinically significant among a representative sample of frequent cannabis users. Similar results in the subset without polysubstance abuse confirmed the specificity of symptoms to cannabis. Cannabis withdrawal should be added to DSM-V, and the etiology and treatment implications of cannabis withdrawal symptoms should be investigated.

29. Hall, W, Solowij,N, Lemon, J: The Health and Psychological Consequences of CannabisUse.National Drug Strategy Monograph No. 25
    Canberra: Australian Government Publication Services, 1994

30. Kandel DB, Davis M: Progression to regular marijuana involvement: phenomenology and risk factors of near daily use, in:GlantzM, Pickens R (eds.), Vulnerability to Drug Abuse. Washington, DC: American Psychological Association, 1992;221-253.
    
31. Winters, K. C., Lee, C. Y. Likelihood of developing an alcohol and cannabis use disorder during youth: association with recent use and age
    Drug Alcohol Depend, Vol 92, Issue 1-3, pp 239-47.

Abstract

AIM: We extend the literature on the association of early onset of drug use and estimated risk for developing a substance use disorder (SUD) by investigating the risk that recent onset of alcohol and cannabis use confers for developing a substance use disorder at each chronological age of adolescence and young adulthood (12-21-years-old). DESIGN: Using 2003 data from the National Survey on Drug Use and Health [Substance Abuse Mental Health Service Administration (SAMHSA), 2004. Overview of Findings from the 2003 National Survey on Drug Use and Health. Office of Applied Studies, NSDUH Series H-24, DHHS Publication No. SMA-04-3963, Rockville, MD], we computed separate risk indices for developing an alcohol and cannabis use disorder for recent (prior 2 years) alcohol and cannabis users, respectively, at each age from 12 to 21 years of age, and compared estimated risk to recent onsets users among respondents aged 22-26. FINDINGS: The results indicated that the teenage years were strongly linked to an elevated risk status. The odds ratio (OR) of having a prior year alcohol use disorder (AUD) among recent onset alcohol users was significantly elevated for youth at ages 14, 16, 17 and 18 (range of ORs=2.0-2.1) compared to the estimated risk for AUD among recent onset users aged 22-26. For cannabis, we obtained significantly elevated ORs for a cannabis use disorder (CUD) at each of teenage years (ages 12-18; range of ORs=3.9-7.2), when compared to older recent onset users (aged 22-26). CONCLUSIONS: These data provide further epidemiological support that adolescence is a particularly vulnerable period for developing a SUD.