Federal Register Notices > Notices - 2001 > Denial of Petition

Notices - 2001

[Federal Register: April 18, 2001 (Volume 66, Number 75)]
[Notices]
[Page 20037-20076]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr18ap01-124]

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Part II

Department of Justice Drug Enforcement Agency

Denial of Petition; Notice

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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

Notice of Denial of Petition

By letter dated March 20, 2001, the Drug Enforcement Administration (DEA) denied a petition to initiate rulemaking proceedings to reschedule marijuana. Because DEA believes that this matter is of particular interest to members of the public, the agency is publishing below the letter sent to the petitioner (denying the petition), along with the supporting documentation that was attached to the letter.

Dated: March 28, 2001.

Donnie R. Marshall,
Administrator.

U.S. Department of Justice,

Drug Enforcement Administration, Washington, D.C. 20537

March 20, 2001.

Jon Gettman:

Dear Mr. Gettman: On July 10, 1995, you petitioned the Drug Enforcement Administration (DEA) to initiate rulemaking proceedings under the rescheduling provisions of the Controlled Substances Act (CSA). Specifically, you petitioned DEA to propose rules, pursuant to 21 U.S.C. 811(a), that would amend the schedules of controlled substances with respect to the following controlled substances: marijuana; tetrahydrocannabinols; dronabinol; and nabilone. Although you grouped these substances together in your petition, the scheduling analysis differs for each. To avoid confusion, DEA is providing you with a separate response for each of the controlled substances that you proposed be rescheduled. This letter responds to your petition to reschedule marijuana.

Summary

You requested that DEA remove marijuana from schedule I based on your assertion that "there is no scientific evidence that [it has] sufficient abuse potential to warrant schedule I or II status under the [CSA].'' In accordance with the CSA rescheduling provisions, DEA gathered the necessary data and forwarded that information and your petition to the Department of Health and Human Services (HHS) for a scientific and medical evaluation and scheduling recommendation. HHS concluded that marijuana does have a high potential for abuse and therefore recommended that marijuana remain in schedule I. Based on the HHS evaluation and all other relevant data, DEA has concluded that there is no substantial evidence that marijuana should be removed from schedule I. Accordingly, your petition to initiate rulemaking proceedings to reschedule marijuana is hereby denied.

Detailed Explanation

A. Statutory Requirements and Procedural History

The CSA provides that the schedules of controlled substances established by Congress may be amended by the Attorney General in rulemaking proceedings prescribed by the Administrative Procedure Act. 21 U.S.C. 811(a). The Attorney General has delegated this
authority to the Administrator of DEA. 28 CFR 0.100. 

As you have done, any interested party may petition the Administrator to initiate rulemaking proceedings to reschedule a controlled substance. 21 U.S.C. 811(a); 21 CFR 1308.43(a). Before initiating such proceedings, the Administrator must gather the necessary data and request from the Secretary of HHS a scientific and medical evaluation and recommendation as to whether the controlled substance should be rescheduled as the petitioner proposes. 21 U.S.C. 811(b); 21 CFR 1308.43(d). The Secretary has delegated this function to the Assistant Secretary for Health.¹ 

The recommendations of the Assistant Secretary are binding on the Administrator with respect to scientific and medical matters. Id. If the Administrator determines that the evaluations and recommendations of the Assistant Secretary and "all other relevant data'' constitute substantial evidence that the drug that is the subject of the petition should be subject to lesser control or removed entirely from the schedules, he shall initiate rulemaking proceedings to reschedule the drug or remove it from the schedules as the evidence dictates. 21 U.S.C. 811(b); 21 CFR 1308.43(e). In making such a determination, the Administrator must consider eight factors:

1. The drug's actual or relative potential for abuse;
    

2. Scientific evidence of its pharmacological effect, if known;
    

3. The state of current scientific knowledge regarding the drug;
    

4. Its history and current pattern of abuse;
    

5. The scope, duration, and significance of abuse;
    

6. What, if any, risk there is to the public health;
    

7. The drug's psychic or physiological dependence liability; and
    

8. Whether the drug is an immediate precursor of a substance already controlled under the CSA.

21 USC 811(c).

In this case, you submitted your petition by letter dated March 10, 1995. After gathering the necessary data, DEA referred the petition to HHS on December 17, 1997, and requested from HHS a scientific and medical evaluation and scheduling recommendation. HHS forwarded its scientific and medical evaluation and scheduling recommendation to DEA on January 17, 2001.

B. HHS Scientific and Medical Evaluation and Other Relevant Data Considered by DEA

Attached to this letter is the scientific and medical evaluation and scheduling recommendation that HHS submitted to DEA.² Also attached is a document prepared by DEA that specifies other data relevant to your petition that DEA considered.

C. Basis for Denial of Your Petition: The Evidence Demonstrates That Marijuana Does Have A High Potential For Abuse

Your petition rests on your contention that marijuana does not have a "high potential for abuse'' commensurate with schedule I or II of the CSA. The Assistant Secretary has concluded, based on current scientific and medical evidence, that marijuana does have a high potential for abuse commensurate with schedule I. The additional data gathered by DEA likewise reveals that marijuana has a high potential for abuse. Indeed, when the HHS evaluation is viewed in combination with the additional data gathered by DEA, the evidence overwhelmingly leads to the conclusion that marijuana has a high potential for abuse.

Accordingly, there is no statutory basis for DEA to grant your petition to initiate rulemaking proceedings to reschedule marijuana. For this reason alone, your petition must be denied. 

D.  A Schedule I Drug With a High Potential For Abuse and No Currently Accepted Medical Use or Safety for Use Must Remain Classified In Schedule I

DEA's denial of your petition is based exclusively on the scientific and medical findings of HHS, with which DEA concurs, that lead to the conclusion that marijuana has a high potential for abuse. Nonetheless, independent of this scientific and medical basis for denying your petition, there is a logical flaw in your proposal that should be noted.

You do not assert in your petition that marijuana has a currently accepted medical use in treatment in the United States or that marijuana has an accepted safety for use under medical supervision. Indeed, the HHS scientific and medical evaluation reaffirms expressly that marijuana has no currently accepted medical use in treatment in the United States and a lack of accepted safety for use under medical supervision.

Nor do you dispute that marijuana is a drug of abuse. That is, you do not contend that marijuana has no potential for abuse such that it should be removed entirely from the CSA schedules. Rather, your contention is that marijuana has less than a "high potential for abuse'' commensurate with schedules I and II and, therefore, it cannot be classified in either of these two schedules.

Congress established only one schedule--schedule I--for drugs of abuse with "no currently accepted medical use in treatment in the United States'' and "lack of accepted safety for use * * * under medical supervision.'' 21 USC 812(b). To be classified in schedules II through V, a drug of abuse

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must have a "currently accepted medical use in treatment in the United States.'' ³ Id. This is why the CSA allows practitioners to prescribe only those controlled substances that are listed in schedules II through V. 21 USC 829. Drugs listed in schedule I, by contrast, may not be prescribed for patient use; they may only be dispensed by practitioners who are conducting FDA-approved research and have obtained a schedule I research registration from DEA. 21 USC 823(f); 21 CFR 5.10(a)(9), 1301.18, 1301.32.

That schedule I controlled substances are characterized by a lack of accepted medical use was recently reiterated by Congress, when it declared, in a provision entitled, "NOT LEGALIZING MARIJUANA FOR MEDICINAL USE'':

It is the sense of the Congress that--

1. certain drugs are listed on Schedule I of the Controlled Substances Act if they have a high potential for abuse, lack any currently accepted medical use in treatment, and are unsafe, even under medical supervision;
    

2. the consequences of illegal use of Schedule I drugs are well documented, particularly with regard to physical health, highway safety, and criminal activity; 
    

3. pursuant to section 401 of the Controlled Substances Act, it is illegal to manufacture, distribute, or dispense marijuana, heroin, LSD, and more than 100 other Schedule I drugs;
    

4. pursuant to section 505 of the Federal Food, Drug and Cosmetic Act, before any drug can be approved as a medication in the United States, it must meet extensive scientific and medical standards established by the Food and Drug Administration to ensure it is safe and effective;
    

5. marijuana and other Schedule I drugs have not been approved by the Food and Drug Administration to treat any disease or condition.

                               *              *           *           *          *

Pub. L. No. 105-277, Div. F., 112 Stat. 2681-760 to 2681-761 (1998) (emphasis added).

Thus, when it comes to a drug that is currently listed in schedule I, if it is undisputed that such drug has no currently accepted medical use in treatment in the United States and a lack of accepted safety for use under medical supervision, and it is further undisputed that the drug has at least some potential for abuse sufficient to warrant control under the CSA, the drug must remain in schedule I. In such circumstances, placement of the drug in schedules II through V would conflict with the CSA since such drug would not meet the criterion of "a currently accepted medical use in treatment in the United States.'' 21 USC 812(b).

Therefore, even if one were to assume, theoretically, that your assertions about marijuana's potential for abuse were correct (i.e., that marijuana had some potential for abuse but less than the "high potential for abuse'' commensurate with schedules I and II), marijuana would not meet the criteria for placement in schedules III through V since it has no currently accepted medical use in treatment in the United States--a determination that is reaffirmed by HHS in the attached medical and scientific evaluation.

For the foregoing reasons, your petition to reschedule marijuana cannot be granted under the CSA and is, therefore, denied.

Sincerely,

Donnie R. Marshall,
Administrator.
Attachments.

Department of Health and Human Services,

Office of the Secretary, Office of the Public Health and Science, Assistant Secretary for Health, Surgeon General, Washington, D.C. 20201.

January 17, 2001.

Mr. Donnie R. Marshall,
Deputy Administrator, Drug Enforcement Administration, Washington, D.C. 20537.

Dear Mr. Marshall:  In response to your request dated December 17, 1997, and pursuant to the Controlled Substances Act (CSA), 21 U.S.C. § 811 (b), (c), and (f), the Department of Health and Human Services (DHHS) recommends that marijuana * * * continue to be subject to control under Schedule I. * * * Marijuana and the tetrahydrocannabinols are currently controlled under Schedule I of the CSA. Marijuana continues to meet the three criteria for placing a substance in Schedule I of the CSA under 21 U.S.C. 812(b)(1). As discussed in the attached analysis, marijuana has a high potential for abuse, has no currently accepted medical use in treatment in the United States, and has a lack of accepted safety for use under medical supervision. Accordingly, HHS recommends that marijuana * * * continue to be subject to control under Schedule I of the CSA.

You will find enclosed two documents prepared by FDA's Controlled Substance Staff that are the bases for the recommendations.

Sincerely yours,

David Satcher,
Assistant Secretary for Health and Surgeon General.
Enclosure.

Basis for the Recommendation for Maintaining Marijuana in Schedule I of the Controlled Substances Act

A. Background

On July 10, 1995, Mr. Jon Gettman submitted a petition to the Drug Enforcement Administration (DEA) requesting that proceedings be initiated to repeal the rules and regulations that place marijuana and the tetrahydrocannabinols in Schedule I of the Controlled Substances Act (CSA) and dronabinol and nabilone in Schedule II of the CSA. The petition contends that evidence of abuse potential is insufficient for each substance or class of substances to be controlled in Schedule I or II of the CSA. In December 1997, the DEA Administrator requested that the Department of Health and Human Services (DHHS) develop scientific and medical evaluations and recommendations as to the proper scheduling of the substances at issue, pursuant to 21 U.S.C. 811(b).

This document responds to the portion of the petition that concerns marijuana *   *   *.

In accordance with 21 U.S.C. 811(b), the DEA has gathered information, and the Secretary of DHHS has considered eight factors in a scientific and medical evaluation, to determine how to schedule and control marijuana (Cannabis sativa) under the CSA. The eight factors are: actual or relative potential for abuse, scientific evidence of pharmacological effects, scientific knowledge about the drug or substance in general, history and current patterns of abuse, the scope and duration and significance of abuse, the risk (if any) to public health, psychic or physiologic dependence liability, and whether the substance is an immediate precursor of a substance that is already controlled. If appropriate, the Secretary must also make three findings--related to a substance's abuse potential, legitimate medical use, and safety or dependence liability--and then a recommendation. This evaluation presents scientific and medical knowledge under the eight factors, findings in the three required areas, and a recommendation.

Administrative responsibilities for evaluating a substance for control under the CSA are performed by the Food and Drug Administration (FDA), with the concurrence of the National Institute on Drug Abuse (NIDA), as described in the Memorandum of Understanding (MOU) of March 8, 1985 (50 FR 9518-20).

Pursuant to 21 U.S.C. 811(c), the eight factors pertaining to the scheduling of marijuana are considered below. The weight of the scientific and medical evidence considered under these factors supports the three findings that: (1) Marijuana has a high potential for abuse, (2) marijuana has no currently accepted medical use in treatment in the United States, and (3) there is a lack of accepted evidence about the safety of using marijuana under medical supervision.

B. Evaluating Marijuana Under the Eight Factors

This section presents scientific and medical knowledge about marijuana under the eight required factors.

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1. Its Actual or Relative Potential for Abuse The CSA defines marijuana as the following:

All parts of the plant Cannabis Sativa L., whether growing or not; the seeds thereof; the resin extracted from any part of such plant; and every compound, manufacture, salt, derivative, mixture, or preparation of such plant, its seeds or resin. Such term does not include the mature stalks of such plant, fiber produced from such stalks, oil or cake made from the seeds of such plant, any other compound, manufacture, salt, derivative, mixture, or preparation of such mature stalks (except the resin extracted therefrom), fiber, oil, or cake, or the sterilized seed of such plant which is incapable of germination. 21 U.S.C. 802(16).

The term "abuse'' is not defined in the CSA. However, the legislative history of the CSA suggests the following in determining whether a particular drug or substance has a potential for abuse:

1. Individuals are taking the substance in amounts sufficient to create a hazard to their health or to the safety of other individuals or to the community.
    

2. There is a significant diversion of the drug or substance from legitimate drug channels.
    

3. Individuals are taking the substance on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such substances.
    

4. The substance is so related in its action to a substance already listed as having a potential for abuse to make it likely that it will have the same potential for abuse as such substance, thus making it reasonable to assume that there may be significant diversions from legitimate channels, significant use contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety of the community.

Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. No. 91-1444, 91st Cong., Sess. 1 (1970) reprinted in U.S.C.C.A.N. 4566, 4603.

In considering these concepts in a variety of scheduling analyses over the last three decades, the Secretary has analyzed a range of factors when assessing the abuse liability of a substance. These factors have included the prevalence and frequency of use in the general public and in specific sub-populations, the amount of the material that is available for illicit use, the ease with which the substance may be obtained or manufactured, the reputation or status of the substance "on the street'', as well as evidence relevant to population groups that may be at particular risk.

Abuse liability is a complex determination with many dimensions. There is no single test or assessment procedure that, by itself, provides a full and complete characterization. Thus, no single measure of abuse liability is ideal. Scientifically, a comprehensive evaluation of the relative abuse potential of a drug substance can include consideration of the drug's receptor binding affinity, preclinical pharmacology, reinforcing effects, discriminative stimulus effects, dependence producing potential, pharmacokinetics and route of administration, toxicity, assessment of the clinical efficacy-safety database relative to actual abuse, clinical abuse liability studies and the public health risks following introduction of the substance to the general population. It is important to note that abuse may exist independent of a state of physical dependence, because drugs may be abused in doses or in patterns that do not induce physical dependence.

Animal data and epidemiological data are both used in determining a substance's abuse liability. While animal data may help the Secretary draw conclusions on the abuse liability of a substance, data regarding human abuse, if available, is given greater weight. For example, even if a compound fails to display abuse liability in animal laboratory testing, positive evidence of abuse liability in humans is given greater weight. Epidemiological data can also be an important indicator of actual abuse and may, in some circumstances, be given greater weight than laboratory data. Thus, in situations where the epidemiological data indicates that a substance is abused, despite the lack of positive abuse liability indications in animal or human laboratory testing, the abuse liability determination may rest more heavily on the epidemiological data. Finally, evidence of clandestine production and illicit trafficking of a substance are also important factors to consider as this evidence sheds light on both the demand for a substance as well as the ease with which it can be obtained.

The Secretary disagrees with Mr. Gettman's assertion that "[t]he accepted contemporary legal convention for evaluating the abuse potential of a drug or substance is the relative degree of self-administration the drug induces in animal subjects.'' As discussed above, self-administration tests that identify whether a substance is reinforcing in animals are but one component of the scientific assessment of the abuse potential of a substance. Positive indicators of human abuse liability for a particular substance, whether from laboratory studies or epidemiological data, are given greater weight than animal studies suggesting the same compound has no abuse potential.

Throughout his petition, Mr. Gettman argues that while many people "use'' marijuana, few "abuse'' it. He appears to equate abuse with the level of physical dependence and toxicity resulting from marijuana use. Thus, he appears to be arguing that a substance that causes only low levels of physical dependence and toxicity must be considered to have a low potential for abuse. The Secretary does not agree with this argument. Physical dependence and toxicity are not the only factors that are considered in determining a substance's abuse potential. The actual use and frequency of use of a substance, especially when that use may result in harmful consequences such as failure to fulfill major obligations at work or school, physical risk-taking, or even substance-related legal problems, are indicative of a substance's abuse potential.

a. There is evidence that individuals are taking the substance in amounts sufficient to create a hazard to their health or to the safety of other individuals or to the community.

Marijuana is a widely used substance. The pharmacology of the psychoactive constituents of marijuana (including delta⁹-THC, the primary psychoactive ingredient in marijuana) has been studied extensively in animals and humans and is discussed in more detail below in Section 2, "Scientific Evidence of its Pharmacological Effects, if Known.'' Although it is difficult to determine the full extent of marijuana abuse, extensive data from the National Institute on Drug Abuse (NIDA) and from the Substance Abuse Mental Health Services Administration (SAMHSA) are available. These data are discussed in detail in Section 4 "Its History and Current Pattern of Abuse;'' Section 5, "The Scope, Duration, and Significance of Abuse;'' and Section 6, "What, if any Risk There is to the Public Health.''

According to the National Household Survey on Drug Abuse (NHSDA), of the 14.8 million Americans who used illicit drugs on a monthly basis in 1999, 11.2 million used marijuana. In 1998, 1.6 million children between the ages of 12 and 17 used marijuana for the first time. (See the discussion of the 1999 NHSDA in Section 4). A 1999 survey of 8th, 10th, and 12th grade students indicates that marijuana is the most widely used illicit drug in this age group. By 12th grade, 37.8% of students report having used marijuana in the past year, and 23.1% report using it monthly. (See the

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discussion of the Monitoring the Future Study in Section 4). Primary marijuana abuse accounts for 13% of the admissions to treatment facilities for substance abuse, with 92% of those admitted having used marijuana for the first time by age 18. (See discussion of the Treatment Episode Data Set in Section 4).

The Drug Abuse Warning Network (DAWN) is a national probability survey of hospitals with emergency departments (EDs). DAWN is designed to obtain information on ED episodes that are induced by or related to the use of an illegal drug or the non-medical use of a legal drug. DAWN recently reported 87,150 ED drug mentions for marijuana/ hashish in 1999, representing 16 % of all drug-related episodes in 1999. (See discussion of DAWN in Section 4). In 1999, DAWN data show that out of 664 medical examiner marijuana-related episodes, there were 187 deaths in persons who had used marijuana alone. While marijuana has a low level of toxicity when compared to other drugs of abuse, there are a number of risks resulting from both acute and chronic use of marijuana. These risks are discussed in full in sections 2 and 6 below.

b. There is significant diversion of the substance from legitimate drug channels.

Because cannabis is currently available through legitimate channels for research purposes only, there is limited legitimate use of this substance and thus limited potential for diversion. The lack of significant diversion of investigational supplies may also result from the ready availability of cannabis of equal or greater potency through illicit channels.

The magnitude of the demand for marijuana is, however, evidenced by the Drug Enforcement Administration (DEA) / Office of National Drug Control Policy (ONDCP) statistics. Data on marijuana seizures can often highlight trends in the overall trafficking patterns. The DEA's Federal-Wide Drug Seizure System (FDSS) provides information on total federal drug seizures. FDSS reports total federal seizures of 699 metric tons of marijuana in fiscal year 1997, 825 metric tons in fiscal year 1998 and 1,175 metric tons in fiscal year 1999 (ONDCP, 2000).

c. Individuals are taking the substance on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such substances.

The 1998 NHSDA suggests that 6.8 million individuals use marijuana on a weekly basis (SAMHSA, 1998), confirming that marijuana has reinforcing properties for many individuals. The FDA has not approved a new drug application for marijuana, although research under several INDs is currently active. Based on the large number of individuals who use marijuana, it can be concluded that the majority of individuals using cannabis do so on their own initiative, not on the basis of medical advice from a practitioner licensed to administer the drug in the course of professional practice.

d. The substance is so related in its action to a substance already listed as having a potential for abuse to make it likely that it will have the same potential for abuse as such substance, thus making it reasonable to assume that there may be significant diversions from legitimate channels, significant use contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety of the community.

Two drug products that contain cannabinoid compounds that are structurally related to the active components in marijuana are already regulated under the CSA. These are Marinol (dronabinol, delta⁹-THC), which is a Schedule III drug, and nabilone, which is a Schedule II
drug. All other cannabinoid compounds that are structurally related to the active components in marijuana are listed as Schedule I drugs under the CSA. Cannabinoid compounds constitute a distinct pharmacological class that is unrelated to other drugs currently listed in the CSA. The primary psychoactive compound in botanical marijuana is delta⁹-tetrahydrocannabinol (delta⁹-THC). Other cannabinoids also present in the marijuana plant likely contribute to the psychoactive effects. Individuals administer the constituents of marijuana by burning the material and inhaling (smoking) many of its combustible and vaporized products. The route of administration of a drug is one component of its abuse potential. Most psychoactive drugs exert their maximum subjective effects when blood levels of the drug are rapidly increased. Inhalation of drugs permits a rapid delivery and distribution of the drug to the brain. The intense psychoactive drug effect, which can be rapidly achieved by smoking, is often called a "rush'' and generally is considered to be the effect desired by the abuser. This effect explains why marijuana abusers prefer the inhalation, intravenous or intranasal routes rather than oral routes of administration. Such is also the case with cocaine, opium, heroin, phencyclidine, and methamphetamine (Wesson & Washburn, 1990).

2. Scientific Evidence of Its Pharmacological Effects, If Known

We concur with the petitioner that there is abundant scientific data available on the neurochemistry, toxicology, and pharmacology of marijuana. This section includes a scientific evaluation of marijuana's neurochemistry and pharmacology, central nervous system effects including human and animal behavior, pharmacodynamics of central nervous system effects, cognitive effects, cardiovascular and autonomic effects, endocrine system effects and immunological system effects. The overview presented below relies upon the most current research literature on cannabinoids.

Neurochemistry and Pharmacology of Marijuana

To date, a total of 483 natural constituents have been identified in marijuana of which approximately 66 belong to the general group known as cannabinoids (Ross and ElSohly, 1995). The cannabinoids appear to be unique to marijuana, and most of those occurring naturally have already been identified. Within the cannabinoids, delta⁹- tetrahydrocannabinol (delta⁹-THC) is considered the major psychoactive constituent of marijuana. Since the elucidation of the structure and discovery of the function of delta⁹-THC, in 1964 by Gaoni and Mechoulam, cannabis and cannabinoid research has flourished. Substantial discoveries on the pharmacology, biochemistry and behavioral mechanisms of action of the cannabinoids have been accomplished, and laid the scientific foundations for a better understanding of the effects of marijuana.

There is conclusive evidence of the existence of at least two cannabinoid receptors, CB₁ and CB₂, and it is now known that some of the pharmacological effects of cannabinoids are mediated through activation of these receptors. The cannabinoid receptors belong to the G-protein-coupled receptors family and present a typical seven transmembrane-spanning domain structure. Many G-protein coupled receptors are linked to adenylate cyclase, and stimulation of these receptors might result, either in inhibition or activation of adenylate cyclase, depending on the receptor system. Cannabinoid receptors are linked to an inhibitory G protein (Gi), meaning that when activated, inhibition of the activity of adenylate cyclase occurs, thus preventing the conversion of ATP to the second messenger cyclic AMP (cAMP). Examples of inhibitory-coupled receptors include opioid,

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muscarinic," ₂-adrenoreceptors, dopamine (D₂) and serotonin (5-HT₁) among others. The pharmacological relevance of the adenylate cyclase inhibition has been difficult to determine (Adams and Martin, 1996).

Advances in molecular biology allowed the cloning of a cannabinoid receptor (Matsuda et al., 1990), first from rat brain origin followed by the cloning of the human receptor (Gerard et al., 1991) therefore offering definitive evidence for a specific cannabinoid receptor. Autoradiographic studies have provided information on the distribution of cannabinoid receptors. CB₁ receptors are present in the brain and spinal cord and in certain peripheral tissues. The distribution pattern of these receptors within the central nervous system is heterogeneous. It is believed that the localization of these receptors in various regions of the brain, such as basal ganglia, cerebellum, hippocampus and cerebral cortex, may explain cannabinoid interference with movement coordination and effects on memory and cognition. Concentration of CB₁ receptors is considerably lower in peripheral tissues than in the central nervous system (Henkerham et al., 1990 and 1992). CB₂ receptors have been detected only outside the central nervous system. Their occurrence has been shown to be primarily in immune tissues such as leukocytes, spleen and tonsils and it is believed that the CB₂-type receptor is responsible for mediating the immunological effects of cannabinoids (Galiegui et al., 1995).

Recently it has been shown that CB₁ but not CB₂ receptors inhibit N- and Q type calcium channels and activate inwardly rectifying potassium channels. Inhibition of the N-type calcium channels decreases neurotransmitter release from several tissues and this may the mechanism by which cannabinoids inhibit acetylcholine, noradrenaline and glutamate release from specific areas of the brain. These effects might represent a potential cellular mechanism underlying the antinociceptive and psychoactive effects of cannabinoids (Ameri, 1999). 

Several synthetic cannabinoid agonists have been synthesized and characterized and selective antagonists for both receptors have been identified. In 1994, SR-141716A, the first selective antagonist with CB₁ selectivity was identified, and more recently the selective CB₂ receptor antagonist, SR-144528, was described (Rinaldi-Carmona et al., 1994 and 1998). In general, antagonists have proven to be invaluable tools in pharmacology. They allow the identification of key physiological functions by the receptors, through the blockade of their responses. 

Delta⁹-THC displays similar affinity for CB₁ and CB₂ receptors but behaves as a weak agonist for CB₂ receptors as judged by inhibition of adenylate cyclase. The identification of synthetic cannabinoid ligands deprived of the typical THC-like psychoactive properties, that selectively bind to CB₂ receptors, supports the idea that the psychotropic effects of cannabinoids are mediated through the activation of CB₁-receptors (Hanus et al., 1999). Furthermore, cannabinoid agonists such as delta⁹-THC and the synthetic ones, WIN-55,212-2 and CP-55,940, produce hypothermia, analgesia, hypoactivity and cataplexy. These effects are reversed by the selective CB₁ antagonist, SR-141716A, providing good evidence for the involvement of a CB₁ receptor mediated mechanism.

In addition, the discovery of the endogenous cannabinoid receptor agonists, anandamide and arachidonyl glycine (2-AG) confirmed the belief of a central cannabinoid neuromodulatory system. Indeed, cannabinoid and their endogenous ligands are present in central as well as peripheral tissues. Mechanisms for the synthesis and metabolism of anandamide have been described. The physiological roles of endogenous cannabinoids are not yet fully characterized, although it has been the target of large research efforts (Martin et al., 1999).

In conclusion, progress in cannabinoid pharmacology, including the characterization of the cannabinoid receptors, isolation of endogenous cannabinoid ligands, synthesis of agonists and antagonists with diverse degree of affinity and selectivity for cannabinoid receptors, have provided the foundation for the elucidation of the specific effects mediated by cannabinoids and their roles in psychomotor disorders, memory, cognitive functions, analgesia, antiemesis, intraocular and systemic blood pressure modulation, broncodilation, and inflammation.

The reinforcing properties of a number of commonly abused drugs such as amphetamine, cocaine, alcohol, morphine and nicotine, have been explained by the effects of these drugs in the activation of dopaminergic pathways in certain areas of the brain and in particular the mesolimbic dopaminergic system (Koob, 1992). It has been demonstrated that delta⁹-THC increases dopamine activity in reward relevant circuits in the brain (French, 1997; Gessa, et al. 1998), but the mechanism of these effects and the relevance of these findings in the context of the abuse potential of marijuana is still unknown.