Wednesday, April 18, 2001
Part II
Department of Justice Drug Enforcement Agency
Denial of Petition; Notice
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DEPARTMENT OF JUSTICE Congress may be amended by the Attorney DEA.2 Also attached is a document prepared General in rulemaking proceedings by DEA that specifies other data relevant to Drug Enforcement Administration prescribed by the Administrative Procedure your petition that DEA considered. Act. 21 U.S.C. 811(a). The Attorney General C. Basis for Denial of Your Petition: The Notice of Denial of Petition has delegated this authority to the Evidence Demonstrates That Marijuana Does Administrator of DEA. 28 CFR 0.100. Have A High Potential For Abuse By letter dated March 20, 2001, the As you have done, any interested party Your petition rests on your contention that Drug Enforcement Administration may petition the Administrator to initiate marijuana does not have a ‘‘high potential for rulemaking proceedings to reschedule a (DEA) denied a petition to initiate abuse’’ commensurate with schedule I or II rulemaking proceedings to reschedule controlled substance. 21 U.S.C. 811(a); 21 of the CSA. The Assistant Secretary has marijuana. Because DEA believes that CFR 1308.43(a). Before initiating such concluded, based on current scientific and this matter is of particular interest to proceedings, the Administrator must gather medical evidence, that marijuana does have members of the public, the agency is the necessary data and request from the a high potential for abuse commensurate publishing below the letter sent to the Secretary of HHS a scientific and medical with schedule I. The additional data gathered evaluation and recommendation as to by DEA likewise reveals that marijuana has petitioner (denying the petition), along whether the controlled substance should be with the supporting documentation that a high potential for abuse. Indeed, when the rescheduled as the petitioner proposes. 21 HHS evaluation is viewed in combination was attached to the letter. U.S.C. 811(b); 21 CFR 1308.43(d). The with the additional data gathered by DEA, Dated: March 28, 2001. Secretary has delegated this function to the the evidence overwhelmingly leads to the 1 Donnie R. Marshall, Assistant Secretary for Health. conclusion that marijuana has a high The recommendations of the Assistant Administrator. potential for abuse. Secretary are binding on the Administrator Accordingly, there is no statutory basis for U.S. Department of Justice, with respect to scientific and medical DEA to grant your petition to initiate Drug Enforcement Administration, matters. Id. If the Administrator determines rulemaking proceedings to reschedule Washington, D.C. 20537 that the evaluations and recommendations of marijuana. For this reason alone, your the Assistant Secretary and ‘‘all other petition must be denied. March 20, 2001. relevant data’’ constitute substantial evidence D. A Schedule I Drug With a High Potential Jon Gettman: that the drug that is the subject of the petition For Abuse and No Currently Accepted Dear Mr. Gettman: On July 10, 1995, you should be subject to lesser control or Medical Use or Safety for Use Must Remain petitioned the Drug Enforcement removed entirely from the schedules, he shall Classified In Schedule I Administration (DEA) to initiate rulemaking initiate rulemaking proceedings to proceedings under the rescheduling reschedule the drug or remove it from the DEA’s denial of your petition is based provisions of the Controlled Substances Act schedules as the evidence dictates. 21 U.S.C. exclusively on the scientific and medical (CSA). Specifically, you petitioned DEA to 811(b); 21 CFR 1308.43(e). In making such a findings of HHS, with which DEA concurs, propose rules, pursuant to 21 U.S.C. 811(a), determination, the Administrator must that lead to the conclusion that marijuana has that would amend the schedules of consider eight factors: a high potential for abuse. Nonetheless, controlled substances with respect to the (1) The drug’s actual or relative potential independent of this scientific and medical following controlled substances: marijuana; for abuse; basis for denying your petition, there is a tetrahydrocannabinols; dronabinol; and (2) Scientific evidence of its logical flaw in your proposal that should be nabilone. Although you grouped these pharmacological effect, if known; noted. substances together in your petition, the (3) The state of current scientific You do not assert in your petition that scheduling analysis differs for each. To avoid knowledge regarding the drug; marijuana has a currently accepted medical confusion, DEA is providing you with a (4) Its history and current pattern of abuse; use in treatment in the United States or that separate response for each of the controlled (5) The scope, duration, and significance of marijuana has an accepted safety for use substances that you proposed be abuse; under medical supervision. Indeed, the HHS rescheduled. This letter responds to your (6) What, if any, risk there is to the public scientific and medical evaluation reaffirms petition to reschedule marijuana. health; expressly that marijuana has no currently accepted medical use in treatment in the Summary (7) The drug’s psychic or physiological dependence liability; and United States and a lack of accepted safety You requested that DEA remove marijuana (8) Whether the drug is an immediate for use under medical supervision. from schedule I based on your assertion that precursor of a substance already controlled Nor do you dispute that marijuana is a drug of abuse. That is, you do not contend ‘‘there is no scientific evidence that [it has] under the CSA. sufficient abuse potential to warrant schedule that marijuana has no potential for abuse I or II status under the [CSA].’’ In accordance 21 USC 811(c). such that it should be removed entirely from with the CSA rescheduling provisions, DEA In this case, you submitted your petition by the CSA schedules. Rather, your contention gathered the necessary data and forwarded letter dated March 10, 1995. After gathering is that marijuana has less than a ‘‘high that information and your petition to the the necessary data, DEA referred the petition potential for abuse’’ commensurate with Department of Health and Human Services to HHS on December 17, 1997, and requested schedules I and II and, therefore, it cannot be (HHS) for a scientific and medical evaluation from HHS a scientific and medical evaluation classified in either of these two schedules. and scheduling recommendation. HHS and scheduling recommendation. HHS Congress established only one schedule— concluded that marijuana does have a high forwarded its scientific and medical schedule I—for drugs of abuse with ‘‘no potential for abuse and therefore evaluation and scheduling recommendation currently accepted medical use in treatment recommended that marijuana remain in to DEA on January 17, 2001. in the United States’’ and ‘‘lack of accepted schedule I. Based on the HHS evaluation and B. HHS Scientific and Medical Evaluation safety for use * * * under medical all other relevant data, DEA has concluded and Other Relevant Data Considered by DEA supervision.’’ 21 USC 812(b). To be classified that there is no substantial evidence that in schedules II through V, a drug of abuse Attached to this letter is the scientific and marijuana should be removed from schedule medical evaluation and scheduling I. Accordingly, your petition to initiate 2 recommendation that HHS submitted to To avoid confusion, those parts of the HHS rulemaking proceedings to reschedule document that are not relevant to your petition with marijuana is hereby denied. respect to marijuana (i.e., those parts that are 1 As set for in a memorandum of understanding relevant only to the scheduling of Detailed Explanation entered in to by HHS, the Food and Drug tetrahydrocannabinols, dronabinol, or nabilone) A. Statutory Requirements and Procedural Administration (FDA), and the National Institute on have been redacted from the attachment. The HHS History Drug Abuse (NIDA), FDA acts as the lead agency evaluation of these other substances will be within HHS in carrying out the Secretary’s addressed when DEA responds (in separate letters) The CSA provides that the schedules of scheduling responsibilities under the CAS, with the to your petitions with respect to these other controlled substances established by concurrence of NIDA. 50 FR 9518 (1985). substances.
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must have a ‘‘currently accepted medical use placement in schedules III through V since it CSA. In December 1997, the DEA in treatment in the United States.’’ 3 Id. This has no currently accepted medical use in Administrator requested that the is why the CSA allows practitioners to treatment in the United States—a Department of Health and Human prescribe only those controlled substances determination that is reaffirmed by HHS in that are listed in schedules II through V. 21 the attached medical and scientific Services (DHHS) develop scientific and USC 829. Drugs listed in schedule I, by evaluation. medical evaluations and contrast, may not be prescribed for patient For the foregoing reasons, your petition to recommendations as to the proper use; they may only be dispensed by reschedule marijuana cannot be granted scheduling of the substances at issue, practitioners who are conducting FDA- under the CSA and is, therefore, denied. pursuant to 21 U.S.C. 811(b). approved research and have obtained a Sincerely, schedule I research registration from DEA. 21 This document responds to the USC 823(f); 21 CFR 5.10(a)(9), 1301.18, Donnie R. Marshall, portion of the petition that concerns 1301.32. Administrator. marijuana * * *. Attachments. That schedule I controlled substances are In accordance with 21 U.S.C. 811(b), characterized by a lack of accepted medical Department of Health and Human Services, use was recently reiterated by Congress, the DEA has gathered information, and Office of the Secretary, Office of the Public when it declared, in a provision entitled, the Secretary of DHHS has considered Health and Science, Assistant Secretary for ‘‘NOT LEGALIZING MARIJUANA FOR eight factors in a scientific and medical Health, Surgeon General, Washington, D.C. MEDICINAL USE’’: 20201. evaluation, to determine how to It is the sense of the Congress that— schedule and control marijuana January 17, 2001. (1) certain drugs are listed on Schedule I (Cannabis sativa) under the CSA. The of the Controlled Substances Act if they have Mr. Donnie R. Marshall, a high potential for abuse, lack any currently Deputy Administrator, Drug Enforcement eight factors are: actual or relative accepted medical use in treatment, and are Administration, Washington, D.C. 20537. potential for abuse, scientific evidence unsafe, even under medical supervision; Dear Mr. Marshall: In response to your of pharmacological effects, scientific (2) the consequences of illegal use of request dated December 17, 1997, and knowledge about the drug or substance Schedule I drugs are well documented, pursuant to the Controlled Substances Act in general, history and current patterns particularly with regard to physical health, (CSA), 21 U.S.C. § 811 (b), (c), and (f), the of abuse, the scope and duration and highway safety, and criminal activity; Department of Health and Human Services significance of abuse, the risk (if any) to (3) pursuant to section 401 of the (DHHS) recommends that marijuana * * * Controlled Substances Act, it is illegal to public health, psychic or physiologic continue to be subject to control under dependence liability, and whether the manufacture, distribute, or dispense Schedule I. * * * Marijuana and the marijuana, heroin, LSD, and more than 100 tetrahydrocannabinols are currently substance is an immediate precursor of other Schedule I drugs; controlled under Schedule I of the CSA. a substance that is already controlled. If (4) pursuant to section 505 of the Federal Marijuana continues to meet the three criteria appropriate, the Secretary must also Food, Drug and Cosmetic Act, before any for placing a substance in Schedule I of the make three findings—related to a drug can be approved as a medication in the CSA under 21 U.S.C. 812(b)(1). As discussed substance’s abuse potential, legitimate United States, it must meet extensive in the attached analysis, marijuana has a high scientific and medical standards established medical use, and safety or dependence potential for abuse, has no currently accepted liability—and then a recommendation. by the Food and Drug Administration to medical use in treatment in the United ensure it is safe and effective; States, and has a lack of accepted safety for This evaluation presents scientific and (5) marijuana and other Schedule I drugs use under medical supervision. Accordingly, medical knowledge under the eight have not been approved by the Food and HHS recommends that marijuana * * * factors, findings in the three required Drug Administration to treat any disease or continue to be subject to control under areas, and a recommendation. condition. Schedule I of the CSA. Administrative responsibilities for * * * * * You will find enclosed two documents Pub. L. No. 105–277, Div. F., 112 Stat. 2681– prepared by FDA’s Controlled Substance evaluating a substance for control under 760 to 2681–761 (1998) (emphasis added). Staff that are the bases for the the CSA are performed by the Food and Thus, when it comes to a drug that is recommendations. Drug Administration (FDA), with the currently listed in schedule I, if it is Sincerely yours, concurrence of the National Institute on undisputed that such drug has no currently David Satcher, Drug Abuse (NIDA), as described in the accepted medical use in treatment in the Assistant Secretary for Health and Surgeon Memorandum of Understanding (MOU) United States and a lack of accepted safety General. of March 8, 1985 (50 FR 9518–20). for use under medical supervision, and it is Enclosure. further undisputed that the drug has at least Pursuant to 21 U.S.C. 811(c), the eight some potential for abuse sufficient to warrant Basis for the Recommendation for factors pertaining to the scheduling of control under the CSA, the drug must remain Maintaining Marijuana in Schedule I of marijuana are considered below. The in schedule I. In such circumstances, the Controlled Substances Act weight of the scientific and medical placement of the drug in schedules II through V would conflict with the CSA since such A. Background evidence considered under these factors supports the three findings that: (1) drug would not meet the criterion of ‘‘a On July 10, 1995, Mr. Jon Gettman Marijuana has a high potential for currently accepted medical use in treatment submitted a petition to the Drug in the United States.’’ 21 USC 812(b). abuse, (2) marijuana has no currently Enforcement Administration (DEA) Therefore, even if one were to assume, requesting that proceedings be initiated accepted medical use in treatment in the theoretically, that your assertions about United States, and (3) there is a lack of marijuana’s potential for abuse were correct to repeal the rules and regulations that place marijuana and the accepted evidence about the safety of (i.e., that marijuana had some potential for using marijuana under medical abuse but less than the ‘‘high potential for tetrahydrocannabinols in Schedule I of abuse’’ commensurate with schedules I and the Controlled Substances Act (CSA) supervision. II), marijuana would not meet the criteria for and dronabinol and nabilone in B. Evaluating Marijuana Under the Schedule II of the CSA. The petition Eight Factors 3 A controlled substance in schedule II must have contends that evidence of abuse either ‘‘a currently accepted medical use in This section presents scientific and treatment in the United States or a currently potential is insufficient for each accepted medical use with severe restrictions.’’ 21 substance or class of substances to be medical knowledge about marijuana USC 812(b)(2)(B). controlled in Schedule I or II of the under the eight required factors.
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1. Its Actual or Relative Potential for Abuse liability is a complex a particular substance, whether from Abuse determination with many dimensions. laboratory studies or epidemiological The CSA defines marijuana as the There is no single test or assessment data, are given greater weight than following: procedure that, by itself, provides a full animal studies suggesting the same and complete characterization. Thus, no compound has no abuse potential. All parts of the plant Cannabis Sativa L., single measure of abuse liability is ideal. Throughout his petition, Mr. Gettman whether growing or not; the seeds thereof; Scientifically, a comprehensive argues that while many people ‘‘use’’ the resin extracted from any part of such plant; and every compound, manufacture, evaluation of the relative abuse marijuana, few ‘‘abuse’’ it. He appears to salt, derivative, mixture, or preparation of potential of a drug substance can equate abuse with the level of physical such plant, its seeds or resin. Such term does include consideration of the drug’s dependence and toxicity resulting from not include the mature stalks of such plant, receptor binding affinity, preclinical marijuana use. Thus, he appears to be fiber produced from such stalks, oil or cake pharmacology, reinforcing effects, arguing that a substance that causes made from the seeds of such plant, any other discriminative stimulus effects, only low levels of physical dependence compound, manufacture, salt, derivative, dependence producing potential, and toxicity must be considered to have mixture, or preparation of such mature stalks pharmacokinetics and route of a low potential for abuse. The Secretary (except the resin extracted therefrom), fiber, administration, toxicity, assessment of does not agree with this argument. oil, or cake, or the sterilized seed of such Physical dependence and toxicity are plant which is incapable of germination. the clinical efficacy-safety database 21 U.S.C. 802(16). relative to actual abuse, clinical abuse not the only factors that are considered liability studies and the public health in determining a substance’s abuse The term ‘‘abuse’’ is not defined in risks following introduction of the potential. The actual use and frequency the CSA. However, the legislative substance to the general population. It is of use of a substance, especially when history of the CSA suggests the important to note that abuse may exist that use may result in harmful following in determining whether a independent of a state of physical consequences such as failure to fulfill particular drug or substance has a dependence, because drugs may be major obligations at work or school, potential for abuse: abused in doses or in patterns that do physical risk-taking, or even substance- a. Individuals are taking the substance not induce physical dependence. related legal problems, are indicative of in amounts sufficient to create a hazard Animal data and epidemiological data a substance’s abuse potential. to their health or to the safety of other are both used in determining a a. There is evidence that individuals individuals or to the community. substance’s abuse liability. While are taking the substance in amounts b. There is a significant diversion of animal data may help the Secretary sufficient to create a hazard to their the drug or substance from legitimate draw conclusions on the abuse liability health or to the safety of other drug channels. of a substance, data regarding human individuals or to the community. c. Individuals are taking the substance abuse, if available, is given greater Marijuana is a widely used substance. on their own initiative rather than on weight. For example, even if a The pharmacology of the psychoactive the basis of medical advice from a compound fails to display abuse constituents of marijuana (including practitioner licensed by law to liability in animal laboratory testing, delta9-THC, the primary psychoactive administer such substances. positive evidence of abuse liability in ingredient in marijuana) has been d. The substance is so related in its humans is given greater weight. studied extensively in animals and action to a substance already listed as Epidemiological data can also be an humans and is discussed in more detail having a potential for abuse to make it important indicator of actual abuse and below in Section 2, ‘‘Scientific Evidence likely that it will have the same may, in some circumstances, be given of its Pharmacological Effects, if potential for abuse as such substance, greater weight than laboratory data. Known.’’ Although it is difficult to thus making it reasonable to assume that Thus, in situations where the determine the full extent of marijuana there may be significant diversions from epidemiological data indicates that a abuse, extensive data from the National legitimate channels, significant use substance is abused, despite the lack of Institute on Drug Abuse (NIDA) and contrary to or without medical advice, positive abuse liability indications in from the Substance Abuse Mental or that it has a substantial capability of animal or human laboratory testing, the Health Services Administration creating hazards to the health of the user abuse liability determination may rest (SAMHSA) are available. These data are or to the safety of the community. more heavily on the epidemiological discussed in detail in Section 4 ‘‘Its Comprehensive Drug Abuse Prevention data. Finally, evidence of clandestine History and Current Pattern of Abuse;’’ and Control Act of 1970, H.R. Rep. No. production and illicit trafficking of a Section 5, ‘‘The Scope, Duration, and 91–1444, 91st Cong., Sess. 1 (1970) substance are also important factors to Significance of Abuse;’’ and Section 6, reprinted in U.S.C.C.A.N. 4566, 4603. consider as this evidence sheds light on ‘‘What, if any Risk There is to the Public In considering these concepts in a both the demand for a substance as well Health.’’ variety of scheduling analyses over the as the ease with which it can be According to the National Household last three decades, the Secretary has obtained. Survey on Drug Abuse (NHSDA), of the analyzed a range of factors when The Secretary disagrees with Mr. 14.8 million Americans who used illicit assessing the abuse liability of a Gettman’s assertion that ‘‘[t]he accepted drugs on a monthly basis in 1999, 11.2 substance. These factors have included contemporary legal convention for million used marijuana. In 1998, 1.6 the prevalence and frequency of use in evaluating the abuse potential of a drug million children between the ages of 12 the general public and in specific sub- or substance is the relative degree of and 17 used marijuana for the first time. populations, the amount of the material self-administration the drug induces in (See the discussion of the 1999 NHSDA that is available for illicit use, the ease animal subjects.’’ As discussed above, in Section 4). A 1999 survey of 8th, with which the substance may be self-administration tests that identify 10th, and 12th grade students indicates obtained or manufactured, the whether a substance is reinforcing in that marijuana is the most widely used reputation or status of the substance ‘‘on animals are but one component of the illicit drug in this age group. By 12th the street’’, as well as evidence relevant scientific assessment of the abuse grade, 37.8% of students report having to population groups that may be at potential of a substance. Positive used marijuana in the past year, and particular risk. indicators of human abuse liability for 23.1% report using it monthly. (See the
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discussion of the Monitoring the Future reinforcing properties for many 2. Scientific Evidence of Its Study in Section 4). Primary marijuana individuals. The FDA has not approved Pharmacological Effects, If Known abuse accounts for 13% of the a new drug application for marijuana, We concur with the petitioner that admissions to treatment facilities for although research under several INDs is there is abundant scientific data substance abuse, with 92% of those currently active. Based on the large available on the neurochemistry, admitted having used marijuana for the number of individuals who use toxicology, and pharmacology of first time by age 18. (See discussion of marijuana, it can be concluded that the marijuana. This section includes a the Treatment Episode Data Set in majority of individuals using cannabis scientific evaluation of marijuana’s Section 4). do so on their own initiative, not on the neurochemistry and pharmacology, The Drug Abuse Warning Network basis of medical advice from a central nervous system effects including (DAWN) is a national probability survey practitioner licensed to administer the human and animal behavior, of hospitals with emergency drug in the course of professional pharmacodynamics of central nervous departments (EDs). DAWN is designed practice. to obtain information on ED episodes d. The substance is so related in its system effects, cognitive effects, that are induced by or related to the use action to a substance already listed as cardiovascular and autonomic effects, of an illegal drug or the non-medical use having a potential for abuse to make it endocrine system effects and of a legal drug. DAWN recently reported likely that it will have the same immunological system effects. The 87,150 ED drug mentions for marijuana/ potential for abuse as such substance, overview presented below relies upon hashish in 1999, representing 16 % of thus making it reasonable to assume the most current research literature on all drug-related episodes in 1999. (See that there may be significant diversions cannabinoids. discussion of DAWN in Section 4). In from legitimate channels, significant use Neurochemistry and Pharmacology of 1999, DAWN data show that out of 664 contrary to or without medical advice, Marijuana medical examiner marijuana-related or that it has a substantial capability of To date, a total of 483 natural episodes, there were 187 deaths in creating hazards to the health of the constituents have been identified in persons who had used marijuana alone. user or to the safety of the community. marijuana of which approximately 66 While marijuana has a low level of Two drug products that contain toxicity when compared to other drugs cannabinoid compounds that are belong to the general group known as of abuse, there are a number of risks structurally related to the active cannabinoids (Ross and ElSohly, 1995). resulting from both acute and chronic components in marijuana are already The cannabinoids appear to be unique use of marijuana. These risks are regulated under the CSA. These are to marijuana, and most of those discussed in full in sections 2 and 6 Marinol (dronabinol, delta9-THC), occurring naturally have already been below. which is a Schedule III drug, and identified. Within the cannabinoids, 9 9 b. There is significant diversion of the nabilone, which is a Schedule II drug. delta -tetrahydrocannabinol (delta - substance from legitimate drug All other cannabinoid compounds that THC) is considered the major channels. are structurally related to the active psychoactive constituent of marijuana. Because cannabis is currently components in marijuana are listed as Since the elucidation of the structure available through legitimate channels Schedule I drugs under the CSA. and discovery of the function of delta9- for research purposes only, there is Cannabinoid compounds constitute a THC, in 1964 by Gaoni and Mechoulam, limited legitimate use of this substance distinct pharmacological class that is cannabis and cannabinoid research has and thus limited potential for diversion. unrelated to other drugs currently listed flourished. Substantial discoveries on The lack of significant diversion of in the CSA. The primary psychoactive the pharmacology, biochemistry and investigational supplies may also result compound in botanical marijuana is behavioral mechanisms of action of the from the ready availability of cannabis delta9-tetrahydrocannabinol (delta9- cannabinoids have been accomplished, of equal or greater potency through THC). Other cannabinoids also present and laid the scientific foundations for a illicit channels. in the marijuana plant likely contribute better understanding of the effects of The magnitude of the demand for to the psychoactive effects. Individuals marijuana. marijuana is, however, evidenced by the administer the constituents of marijuana There is conclusive evidence of the Drug Enforcement Administration by burning the material and inhaling existence of at least two cannabinoid (DEA) / Office of National Drug Control (smoking) many of its combustible and receptors, CB1 and CB2, and it is now Policy (ONDCP) statistics. Data on vaporized products. The route of known that some of the pharmacological marijuana seizures can often highlight administration of a drug is one effects of cannabinoids are mediated trends in the overall trafficking patterns. component of its abuse potential. Most through activation of these receptors. The DEA’s Federal-Wide Drug Seizure psychoactive drugs exert their The cannabinoid receptors belong to the System (FDSS) provides information on maximum subjective effects when blood G-protein-coupled receptors family and total federal drug seizures. FDSS reports levels of the drug are rapidly increased. present a typical seven transmembrane- total federal seizures of 699 metric tons Inhalation of drugs permits a rapid spanning domain structure. Many G- of marijuana in fiscal year 1997, 825 delivery and distribution of the drug to protein coupled receptors are linked to metric tons in fiscal year 1998 and 1,175 the brain. The intense psychoactive adenylate cyclase, and stimulation of metric tons in fiscal year 1999 (ONDCP, drug effect, which can be rapidly these receptors might result, either in 2000). achieved by smoking, is often called a inhibition or activation of adenylate c. Individuals are taking the ‘‘rush’’ and generally is considered to be cyclase, depending on the receptor substance on their own initiative rather the effect desired by the abuser. This system. Cannabinoid receptors are than on the basis of medical advice effect explains why marijuana abusers linked to an inhibitory G protein (Gi), from a practitioner licensed by law to prefer the inhalation, intravenous or meaning that when activated, inhibition administer such substances. intranasal routes rather than oral routes of the activity of adenylate cyclase The 1998 NHSDA suggests that 6.8 of administration. Such is also the case occurs, thus preventing the conversion million individuals use marijuana on a with cocaine, opium, heroin, of ATP to the second messenger cyclic weekly basis (SAMHSA, 1998), phencyclidine, and methamphetamine AMP (cAMP). Examples of inhibitory- confirming that marijuana has (Wesson & Washburn, 1990). coupled receptors include opioid,
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muscarinic,″ 2-adrenoreceptors, physiological functions by the receptors, context of the abuse potential of dopamine (D2) and serotonin (5-HT1) through the blockade of their responses. marijuana is still unknown. among others. The pharmacological Delta9-THC displays similar affinity Central Nervous System Effects relevance of the adenylate cyclase for CB1 and CB2 receptors but behaves inhibition has been difficult to as a weak agonist for CB2 receptors as Human Behavioral Effects judged by inhibition of adenylate determine (Adams and Martin, 1996). As with other psychoactive drugs, the Advances in molecular biology cyclase. The identification of synthetic response that an individual has to allowed the cloning of a cannabinoid cannabinoid ligands deprived of the marijuana is dependent on the set receptor (Matsuda et al., 1990), first typical THC-like psychoactive (psychological and emotional from rat brain origin followed by the properties, that selectively bind to CB2 cloning of the human receptor (Gerard receptors, supports the idea that the orientation) and setting (circumstances) et al., 1991) therefore offering definitive psychotropic effects of cannabinoids are under which the individual takes the drug. Thus, if an individual uses evidence for a specific cannabinoid mediated through the activation of CB1- receptor. Autoradiographic studies have receptors (Hanus et al., 1999). marijuana while in a happy state of provided information on the Furthermore, cannabinoid agonists such mind among good friends, the responses distribution of cannabinoid receptors. as delta9-THC and the synthetic ones, are likely to be interpreted as more positive than if that individual uses the CB1 receptors are present in the brain WIN–55,212–2 and CP–55,940, produce and spinal cord and in certain hypothermia, analgesia, hypoactivity drug during a crisis while alone. peripheral tissues. The distribution and cataplexy. These effects are The mental and behavioral effects of marijuana can vary widely among pattern of these receptors within the reversed by the selective CB1 antagonist, central nervous system is SR–141716A, providing good evidence individuals, but common responses, described by Wills (1998) and others heterogeneous. It is believed that the for the involvement of a CB1 receptor localization of these receptors in various mediated mechanism. (Adams and Martin 1996; Hollister regions of the brain, such as basal In addition, the discovery of the 1986a, 1988a; Institute of Medicine ganglia, cerebellum, hippocampus and endogenous cannabinoid receptor 1982) are listed below: cerebral cortex, may explain agonists, anandamide and arachidonyl (1) Dizziness, nausea, tachycardia, cannabinoid interference with glycine (2–AG) confirmed the belief of facial flushing, dry mouth and tremor movement coordination and effects on a central cannabinoid neuromodulatory can occur initially memory and cognition. Concentration of system. Indeed, cannabinoid and their (2) Merriment, happiness and even CB1 receptors is considerably lower in endogenous ligands are present in exhilaration at high doses peripheral tissues than in the central central as well as peripheral tissues. (3) Disinhibition, relaxation, nervous system (Henkerham et al., 1990 Mechanisms for the synthesis and increased sociability, and talkativeness and 1992). CB2 receptors have been metabolism of anandamide have been (4) Enhanced sensory perception, detected only outside the central described. The physiological roles of giving rise to increased appreciation of nervous system. Their occurrence has endogenous cannabinoids are not yet music, art and touch been shown to be primarily in immune fully characterized, although it has been (5) Heightened imagination leading to tissues such as leukocytes, spleen and the target of large research efforts a subjective sense of increased creativity tonsils and it is believed that the CB2- (Martin et al., 1999). (6) Time distortions type receptor is responsible for In conclusion, progress in (7) Illusions, delusions and mediating the immunological effects of cannabinoid pharmacology, including hallucinations are rare except at high cannabinoids (Galiegui et al., 1995). the characterization of the cannabinoid doses Recently it has been shown that CB1 receptors, isolation of endogenous (8) Impaired judgement, reduced co- but not CB2 receptors inhibit N- and Q cannabinoid ligands, synthesis of ordination and ataxia, which can type calcium channels and activate agonists and antagonists with diverse impede driving ability or lead to an inwardly rectifying potassium channels. degree of affinity and selectivity for increase in risk-taking behavior Inhibition of the N-type calcium cannabinoid receptors, have provided (9) Emotional lability, incongruity of channels decreases neurotransmitter the foundation for the elucidation of the affect, dysphoria, disorganized thinking, release from several tissues and this specific effects mediated by inability to converse logically, agitation, may the mechanism by which cannabinoids and their roles in paranoia, confusion, restlessness, cannabinoids inhibit acetylcholine, psychomotor disorders, memory, anxiety, drowsiness and panic attacks noradrenaline and glutamate release cognitive functions, analgesia, may occur, especially in inexperienced from specific areas of the brain. These antiemesis, intraocular and systemic users or in those who have taken a large effects might represent a potential blood pressure modulation, dose cellular mechanism underlying the broncodilation, and inflammation. (10) Increased appetite and short-term antinociceptive and psychoactive effects The reinforcing properties of a memory impairment are common of cannabinoids (Ameri, 1999). number of commonly abused drugs such Humans demonstrate a preference for Several synthetic cannabinoid as amphetamine, cocaine, alcohol, higher doses of marijuana (1.95% delta9- agonists have been synthesized and morphine and nicotine, have been THC) over lower doses (0.63% delta9- characterized and selective antagonists explained by the effects of these drugs THC) (Chaitand Burke, 1994), similar to for both receptors have been identified. in the activation of dopaminergic the dose preference exhibited for many In 1994, SR–141716A, the first selective pathways in certain areas of the brain other drugs of abuse. antagonist with CB1 selectivity was and in particular the mesolimbic identified, and more recently the dopaminergic system (Koob, 1992). It Animal Behavioral Effects 9 selective CB2 receptor antagonist, SR- has been demonstrated that delta -THC • Predictors of Reinforcing Effects 144528, was described (Rinaldi- increases dopamine activity in reward (Self-Administration and Conditioned Carmona et al., 1994 and 1998). In relevant circuits in the brain (French, Place Preference) general, antagonists have proven to be 1997; Gessa, et al. 1998), but the One indicator of whether a drug will invaluable tools in pharmacology. They mechanism of these effects and the be reinforcing in humans is the self- allow the identification of key relevance of these findings in the administration test in animals. Self-
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administration of marijuana, LSD, sigma dose levels. However, cannabinoid tolerance and dependence and is not a receptor agonists, or cholinergic antagonists also induce CPP, suggesting phenomenon unique to drugs of abuse. antagonists is difficult to demonstrate in that occupation of the cannabinoid Down-regulation of cannabinoid animals. However, when it is known receptor itself, may be responsible. receptors has been suggested as the that humans voluntarily consume a • Drug Discrimination Studies mechanism underlying tolerance to the particular drug for its pleasurable Animals, including monkeys and rats effects of marijuana (Rodriguez de effects, the inability to establish self- (Gold et al., 1992) as well as humans Fonseca et al., 1994, Oviedo et al., administration with that drug in (Chait, 1988) can discriminate 1993). By pharmacological definition, animals has no practical importance. cannabinoids from other drugs or tolerance does not indicate the physical This is because the animal test is only placebo. Discriminative stimulus effects dependence liability of a drug. useful as a rough predictor of human of delta9-THC are pharmacologically Physical dependence is a condition behavioral response in the absence of specific for marijuana-containing resulting from the repeated naturalistic data. Thus, the petitioner is cannabinoids (Balster and Prescott, consumption of certain drugs. incorrect that the accepted legal 1992, Barrett et al., 1995, Browne and Discontinuation of the drug results in convention for abuse potential is self- Weissman, 1981, Wiley et al., 1993, withdrawal signs and symptoms known administration in animals and that Wiley et al., 1995). Additionally, the as withdrawal or abstinence syndrome. because marijuana does not induce self- major active metabolite of delta9-THC, It is believed that the withdrawal administration in animals, it has a lower 11-OH-delta9-THC, also generalized to syndrome probably reflects a rebound of abuse potential than drugs that easily the stimulus cue elicited by delta9-THC certain physiological effects that were induce self-administration in animals. (Browne and Weissman, 1981). Twenty- altered by the repeated administration Similarly, the petitioner is incorrect that two other cannabinoids found in of the drug. These pharmacological the difficulty in inducing self- marijuana also fully substituted for events of physical dependence and administration of marijuana in animals delta9-THC. The discriminative withdrawal are not associated uniquely is due to a lack of effect on dopamine stimulus effects of the cannabinoid with drugs of abuse. Many medications receptors. In fact, dopamine release can group appear to provide unique effects such as antidepressants, beta-blockers be stimulated indirectly by marijuana, because stimulants, hallucinogens, and centrally acting antihypertensive following direct action of the drug on opioids, benzodiazepines, barbiturates, drugs that are not associated with cannabinoid receptors. However, it is NMDA antagonists and antipsychotics addiction can produce these effects after important to note that while self- have not been shown to substitute for abrupt discontinuation. administration in animals has been delta9-THC. Some authors describe a marijuana withdrawal syndrome consisting of correlated with dopamine function, both Pharmacodynamics of CNS Effects pleasurable and painful stimuli can restlessness, irritability, mild agitation, evoke dopaminergic responses. Psychoactive effects occur within insomnia, sleep EEG disturbances, Dopamine functioning does not seconds after smoking marijuana, while nausea and cramping that resolves in determine scheduling under the CSA. the onset of effects after oral days (Haney et al., 1999). This Naı¨ve animals will not typically self- administration is 30–60 min. After a syndrome is mild compared to classical administer cannabinoids when they single moderate smoked dose, most alcohol and barbiturate withdrawal must choose between saline and a mental and behavioral effects are phenomena, which may include cannabinoid. However, a recent report measurable for approximately 4 to 6 agitation, paranoia, and seizures. shows that when squirrel monkeys are hours (Hollister 1986, 1988). Venous Marijuana withdrawal syndrome has first trained to self-administer blood levels of delta9-THC or other more frequently been reported in intravenous cocaine, they will continue cannabinoids correlate poorly with adolescents who were admitted for to bar-press at the same rate when THC intensity of effects and character of substance abuse treatment or under is substituted for cocaine, at doses that intoxication (Agurell et al. 1986; Barnett research conditions upon are comparable to those used by humans et al. 1985; Huestis et al. 1992a). There discontinuation of daily administration. who smoke marijuana (Tanda et al., does not appear to be a ‘‘hangover’’ According to the American 2000). This effect was blocked by the syndrome following acute Psychiatric Association, Diagnostic and cannabinoid receptor antagonist, SR administration of marijuana containing Statistical Manual (DSM–IV–TRTM, 141716. These data demonstrate that 2.1% delta9-THC (Chait, 1985). 2000), the distinction between under specific pretreatment conditions, We agree with the petitioner that occasional use of cannabis and an animal model of reinforcement by clinical studies do not demonstrate cannnabis dependence or abuse can be cannabinoids now exists for future tolerance to the ‘‘high’’ from marijuana. difficult to make because social, investigations. Additionally, mice have This may be related to recent behavioral, or psychological problems been reported to self-administer WIN electrophysiological data showing that may be difficult to attribute to the 55212, a CB1 receptor agonist with a the ability of THC to increase neuronal substance, especially in the context of non-cannabinoid structure (Martellotta firing in the ventral tegmental area (a use of other substances. Denial of heavy et al., 1998). There may be a critical region known to play a critical role in use is common, and people appear to dose-dependent effect, though, since drug reinforcement and reward) is not seek treatment for cannabis dependence aversive effects, rather than reinforcing reduced following chronic or abuse less often than for other types effects, have been described in rats with administration of the drug (Wu and of substance-related disorders. high doses of WIN 55212 (Chaperon et French, 2000). On the other hand, Although pronounced withdrawal al., 1998) as well as delta9-THC tolerance can develop in humans to symptoms can be provoked from the (Sanudo-Pena et al., 1997). The marijuana-induced cardiovascular and administration of a cannabinoid cannabinoid antagonist, SR 141716, autonomic changes, decreased antagonist in animals who had received counteracted these aversive effects. intraocular pressure, sleep and sleep chronic THC administration, there is no The conditioned place preference EEG, mood and certain behavioral overt withdrawal syndrome (CPP) test also functions as a predictor changes (Jones et al., 1981). behaviorally in animals under of reinforcing effects. Animals show Repeated use of many drugs leads to conditions of natural discontinuation CPP to cannabinoids, but only at mid- the normal physiological adaptations of following chronic THC administration.
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This may be the result of slow release However, the majority of early-onset (Capriotti et al., 1988, Benowitz and of cannabinoids from adipose storage, as marijuana users do not go on to become Jones, 1975). However, prolonged well as the presence of the major heavy users of marijuana, and those that delta9-THC ingestion produces metabolite, 11-OH-delta9-THC, which is do tend to associate with delinquent significant heart rate slowing and blood also psychoactive. social groups (Kandel and Chen, 2000). pressure lowering (Benowitz and Jones, An individual’s drug history may play 1975). Both plant-derived cannabinoids Cognitive Effects a role in the response that person has to and the endogenous ligands have been Acute administration of smoked marijuana. Frequent marijuana users shown to elicit hypotension and marijuana impairs performance on tests (greater than 100 times) were better able bradycardia via activation of of learning, associative processes, and to identify a drug effect from low dose peripherally located CB1 receptors psychomotor behavior (Block et al., delta9-THC than infrequent users (less (Wagner et al., 1998). The mechanism of 1992). These data demonstrate that the than 10 times) and were less likely to these effects were suggested in that short-term effects of marijuana can experience sedative effects from the study to include presynaptic CB1 interfere significantly with an drug (Kirk and deWit, 1999). This receptor mediated inhibition of individual’s ability to learn in the difference in experiential history may norepinephrine release from peripheral classroom or to operate motor vehicles. account for data showing that reaction sympathetic nerve terminals, with the Administration of 290 ug/kg delta9-THC times are not altered by acute possibility of additional direct in a smoked marijuana cigarette by administration of marijuana in long vasodilation via activation of vascular human volunteers impaired perceptual term marijuana users (Block and cannabinoid receptors. motor speed and accuracy, two skills Wittenborn, 1985), suggesting that Impaired circulatory responses to that are critical to driving ability behavioral adaptation or tolerance can standing, exercise, Valsalva maneuver, (Kurzthaler et al., 1999). Similarly, occur to the acute effects of the drug in and cold pressor testing following THC administration of 3.95% delta9-THC in the absence of evidence for dependence. administration suggest a state of a smoked marijuana cigarette increased The impact of in utero marijuana sympathetic insufficiency. Tolerance dysequilibrium measures as well as the exposure on a series of cognitive tasks developed to the orthostatic latency in a task of simulated vehicle had been studied in children at different hypotension, possibly related to plasma braking at a rate comparable to an stages of development. Differences in volume expansion, but did not develop increase in stopping distance of 5 feet at several cognitive domains distinguished to the supine hypotensive effects. 60 mph (Liguori et al., 1998). the 4-year-old children of heavy During chronic marijuana ingestion, The effects of marijuana may not marijuana users. In particular, memory nearly complete tolerance was shown to resolve fully until at least a day after the and verbal measures were negatively have developed to the tachycardia and acute psychoactive effects have associated with maternal marijuana use psychological effects when subjects subsided. A study at the National (Fried and Watkinson, 1987). Maternal were challenged with smoked Institute on Drug Abuse (NIDA) showed marijuana use was predictive of poorer marijuana. Electrocardiographic changes residual impairment on memory tasks performance on abstract/visual were minimal despite the large 24 hours after volunteer subjects had reasoning tasks, although it was not cumulative dose of THC. (Benowitz and smoked 0, 1, or 2 marijuana cigarettes associated with an overall lowered IQ in Jones, 1975) containing 2.57% delta9-THC on two 3-year old children (Griffith et al., Cardiovascular effects of smoked or occasions the previous day (Heishman 1994). At 6 years of age, prenatal oral marijuana have not been shown to et al., 1990). However, later studies at marijuana history was associated with result in any health problems in healthy NIDA showed that there were no an increase in omission errors on a and relatively young users. However, residual alterations in subjective or vigilance task, possibly reflecting a marijuana smoking by older patients, performance measures the day after deficit in sustained attention, was noted particularly those with some degree of subjects were exposed to 1.8%, or 3.6% (Fried et al., 1992). Recently, it had been coronary artery or cerebrovascular smoked delta9-THC, indicating that the speculated that prenatal exposure may disease, is postulated to pose greater residual effects of smoking a single affect certain behaviors and cognitive risks, because of the resulting increased marijuana cigarette are minimal (Fant et abilities that fall under the construct cardiac work, increased catecholamines, al., 1998). A John Hopkins study termed executive function, that is, not carboxyhemoglobin, and postural examined marijuana’s effects on associated with measures of global hypotension (Benowitz and Jones 1981; cognition on 1,318 participants over a intelligence. It was postulated that when Hollister 1988). 15-year period and reported there were tests evaluate novel problem-solving As a comparison, the cardiovascular no significant differences in cognitive abilities as contrasted to knowledge, risks associated with use of cocaine are decline between heavy users, light there is an association between quite serious, including cardiac users, and nonusers of cannabis, nor any executive function and intelligence. In a arrhythmias, myocardial ischemia, male-female differences. The authors recent study (Fried et al., 1998), the myocarditis, aortic dissection, cerebral concluded that ‘‘these results * * * effect of prenatal exposure in 9–12 year ischemia, stroke and seizures. seem to provide strong evidence of the old children was analyzed, and Respiratory Effects absence of a long-term residual effect of similarly to what was shown in other cannabis use on cognition.’’ (Lyketsos et age groups, in utero marijuana exposure Transient bronchodilation is the most al., 1999). was negatively associated with typical effect following acute exposure Age of first use may be a critical factor executive function tasks that require to marijuana. The petitioner is correct in persistent impairment resulting from impulse control, visual analysis and that marijuana does not suppress chronic marijuana use. Individuals with hypothesis testing and it was not respiration in a manner that leads to a history of marijuana-only use that associated with global intelligence. death. With long-term use of marijuana, began before the age of 16 were found there can be an increased frequency of to perform more poorly on a visual Cardiovascular and Autonomic Effects pulmonary illness from chronic scanning task measuring attention than Single smoked or oral doses of delta9- bronchitis and pharyngitis. Large-airway individuals who started using marijuana THC ingestion produce tachycardia and obstruction, as evident on pulmonary after that age (Ehrenreich et al., 1999). unchanged or increased blood pressure function tests, can also occur with
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chronic marijuana smoking, as can effects of endogenous cannabinoids on cannabidiol (CBD) and cannabinol cellular inflammatory histopathological the immune system are not yet known. (CBN), has been characterized. CBD is abnormalities in bronchial epithelium The concentrations of THC that are not considered to have cannabinol-like (Adams and Martin 1996; Hollister necessary for psychoactivity are lower psychoactivity, but is thought to have 1986). than those that alter immune responses. significant anticonvulsant, sedative, and The low incidence of carcinogenicity A study presented by Abrams and anxiolytic activity (Adams and Martin, may be related to the fact that coworkers at the University of 1996; Agurell et al., 1984, 1986; intoxication from marijuana does not California, San Francisco at the XIII Hollister, 1986). require large amounts of smoked International AIDS Conference Marijuana is a mixture of the dried material. This may be especially true investigated the effect of marijuana on flowering tops and leaves from the plant today since marijuana has been reported immunological functioning in 62 AIDS (Agurell et al. 1984; Graham 1976; to be more potent now than a generation patients who were taking protease Mechoulam 1973) and is variable in ago and individuals typically titrate inhibitors. Subjects received one of content and potency (Agurell et al. their drug consumption to consistent three treatments, three times a day: 1986; Graham 1976; Mechoulam 1973). levels of intoxication. Several cases of Smoked marijuana cigarette containing Marijuana is usually smoked in the form lung cancer in young marijuana users 3.95% THC; oral tablet containing THC of rolled cigarettes. The other cannabis with no history of tobacco smoking or (2.5 mg oral dronabinol); or oral forms are also smoked. Potency of other significant risk factors have been placebo. There were no changes in HIV marijuana, as indicated by cannabinoid reported (Fung et al. 1999). However, a RNA levels between groups, content, has been reported to average recent study (Zhang et al., 1999) has demonstrating no short-term adverse from as low as one to two percent to as suggested that marijuana use may dose- virologic effects from using high as 17 percent. dependently interact with mutagenic cannabinoids. Additionally, those Delta9-THC is an optically active sensitivity, cigarette smoking and individuals in the cannabinoid groups resinous substance, insoluble in water alcohol use to increase the risk of head gained more weight than those in the and extremely lipid soluble. Chemically and neck cancer. The association of placebo group (3.51 kg from smoked is known as (6aR-trans)-6a,7,8,10a- marijuana use with carcinomas remains marijuana, 3.18 kg from dronabinol, tetrahydro-6,6,9-trimethyl-3-pentyl-6H- controversial. 1.30 kg from placebo) (7/13/00, Durban, dibenzo-[b,d]pyran-1-ol or (-)-delta9- South Africa). (trans)-tetrahydrocannabinol. The Endocrine System Effects pharmacological activity of delta9-THC In male human volunteers, neither 3. The State of Current Scientific is stereospecific; the (-)-trans isomer is smoked THC (18 mg/marijuana Knowledge Regarding the Drug or Other 6–100 times more potent than the (+)- cigarette) nor oral THC (10 mg t.i.d. for Substance trans isomer (Dewey et al., 1984). 3 days and on the morning of the fourth This section discusses the chemistry, The concentration of delta9-THC and day) altered plasma prolactin, ACTH, human pharmacokinetics, and medical other cannabinoids in marijuana varies cortisol, luteinizing hormone or uses of marijuana. greatly depending on growing conditions, parts of the plant collected testosterone levels (Dax et al., 1989). Chemistry Reductions in male fertility by (flowers, leaves stems, etc), plant marijuana are reversible and only seen According to the DEA, three forms of genetics, and processing after harvest in animals at concentrations higher than cannabis (that is, Cannabis sativa L. and (Adams and Martin , 1996; Agurell et those found in chronic marijuana users. other species) are currently marketed al., 1984; Mechoulam, 1973). Thus, Relatively little research has been illicitly in the U.S.A. These cannabis there are many variables that can performed on the effects of derivatives include marijuana, hashish influence the strength, quality and experimentally administered marijuana and hashish oil. purity of marijuana as a botanical on human female endocrine and Each of these forms contains a substance. In the usual mixture of leaves reproductive system function. Although complex mixture of chemicals. Among and stems distributed as marijuana, the suppressed ovulation and other these components the twenty-one concentration of delta9-THC ranges from ovulatory cycle changes occur in carbon terpenes found in the plant as 0.3 to 4.0 percent by weight. However, nonhuman primates, a study of human well as their carboxylic acids, specially grown and selected marijuana females smoking marijuana in a research analogues, and transformation products can contain 15 percent or even more hospital setting did not find hormone or are known as cannabinoids (Agurell et delta9-THC. Thus, a one-gram marijuana menstrual cycle changes like those in al., 1984, 1986; Mechoulam, 1973). The cigarette might contain as little as 3 monkeys that had been given delta9- cannabinoids appear to be unique to milligrams or as much as 150 milligrams THC (Mendelson et al., 1984a). marijuana and most of the naturally- or more of delta9-THC among several THC reduces binding of the occurring have been identified. Among other cannabinoids. As a consequence, corticosteroid dexamethasone in the cannabinoids, delta9- the clinical pharmacology of pure hippocampal tissue from tetrahydrocannabinol (delta9-THC, delta9-THC may not always be expected adrenalectomized rats, suggesting a alternate name delta1-THC) and delta-8- to have the same clinical pharmacology direct interaction with the tetrahydrocannabinol (delta8-THC, of smoked marijuana containing the glucocorticoid receptor. Chronic THC alternate name delta6-THC) are the only same amount of delta9-THC (Harvey, administration also reduced the number compounds in the plant, which show all 1985). Also, the lack of consistency of of glucocorticoid receptors. Acute THC of the psychoactive effects of marijuana. concentration of delta9-THC in botanical releases corti-costerone, but tolerance Because delta9-THC is more abundant marijuana from diverse sources makes developed with chronic THC than delta8-THC, the activity of the interpretation of clinical data very administration. (Eldridge et al., 1991) marijuana is largely attributed to the difficult. If marijuana is to be former, which is considered the main investigated more widely for medical Immune System Effects psychoactive cannabinoid in cannabis. use, information and data regarding the Immune functions can be enhanced or Delta8-THC is found only in few chemistry, manufacturing and diminished by cannabinoids, dependent varieties of the plant (Hively et al., specifications of marijuana must be on experimental conditions, but the 1966). Other cannabinoids, such as developed. 21 CFR 314.50(d)(1)
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describes the data and information that blood levels of delta9-THC or other to delta9-THC in producing marijuana- should be included in the chemistry, cannabinoids correlate poorly with like subjective effects (Agurell et al., manufacturing and controls section of a intensity of effects and character of 1986, Lemberger and Rubin, 1975). new drug application (NDA) to be intoxication (Agurell et al. 1986; Barnett Following oral administration of reviewed by FDA. et al. 1985; Huestis et al. 1992a). radioactive-labeled delta9-THC, it has Hashish consists of the cannabinoid- After smoking, venous levels of been confirmed that delta9-THC plasma rich resinous material of the cannabis delta9-THC decline precipitously within levels attained by the oral route are low plant, which is dried and compressed minutes, and within an hour are about relative to those levels after smoking or into a variety of forms (balls, cakes etc.). 5 to 10 percent of the peak level intravenous administration. The half- Pieces are then broken off, placed into (Agurell et al., 1986, Huestis et al., life of delta9-THC has been determined pipes and smoked. Cannabinoid content 1992a, 1992b). Plasma clearance of to be 23–28 hours in heavy marijuana in hashish has recently been reported by delta9-THC is approximately 950 mL/ users, but 60–70 hours in naive users DEA to average 6 percent. min or greater, thus approximating (Lemberger et al., 1970). Hash oil is produced by extracting the hepatic blood flow. The rapid Characterization of the cannabinoids from plant material with a disappearance of delta9-THC from blood pharmacokinetics of delta9-THC and solvent. Color and odor of the extract is largely due to redistribution to other other cannabinoids from smoked vary, depending on the type of solvent tissues in the body, rather than to marijuana is difficult (Agurell et al., used. Hash oil is a viscous brown or metabolism (Agurell et al., 1984, 1986). 1986, Herning et al., 1986, Heustis et al., amber-colored liquid that contains Metabolism in most tissues is relatively 1992a) in part because a subject’s approximately 15 percent cannabinoids. slow or absent. Slow release of delta9- smoking behavior during an experiment One or two drops of the liquid placed THC and other cannabinoids from cannot be easily controlled or quantified on a cigarette purportedly produce the tissues and subsequent metabolism by the researcher. An experienced equivalent of a single marijuana results in a long elimination half-life. marijuana smoker can titrate and cigarette. The terminal half-life of delta9-THC is regulate the dose to obtain the desired Human Pharmacokinetics estimated to range from approximately acute psychological effects and to avoid 20 hours to as long as 10 to 13 days, overdose and/or minimize undesired Marijuana is generally smoked as a though reported estimates vary as effects. Each puff delivers a discrete cigarette (weighing between 0.5 and 1.0 expected with any slowly cleared dose of delta9-THC to the body. Puff and gram), or in a pipe. It can also be taken substance and the use of assays of inhalation volume changes with phase orally in foods or as extracts of plant variable sensitivities. of smoking, tending to be highest at the material in ethanol or other solvents. In contrast, following an oral dose of beginning and lowest at the end of Pure preparations of delta9-THC and delta9-THC or marijuana, maximum smoking a cigarette. Some studies found other cannabinoids can be administered delta9-THC and other cannabinoid blood frequent users to have higher puff by mouth, rectal suppository, levels are attained after 2 to 3 hours volumes than less frequent marijuana intravenous injection, or smoked. (Adams and Martin 1996; Agurell et al. users. During smoking, as the cigarette The absorption, metabolism, and 1984, 1986). Oral bioavailability of length shortens, the concentration of 9 pharmacokinetic profile of delta -THC delta9-THC, whether pure or in delta9-THC in the remaining marijuana (and other cannabinoids) in marijuana marijuana, is low and extremely increases; thus, each successive puff or other drug products containing variable, ranging between 5 and 20 contains an increasing concentration of 9 delta -THC are determined by route of percent (Agurell et al. 1984, 1986). delta9-THC. administration and formulation (Adams There is inter-and intra-subject Cannabinoid metabolism is extensive. and Martin 1996; Agurell et al. 1984, variability, even when repeatedly dosed There are at least 80 probable 1986). When marijuana is administered under controlled and ideal conditions. biologically inactive, but not completely by smoking, delta9-THC in the form of The low and variable oral bioavailability studied, metabolites formed from delta9- an aerosol in the inhaled smoke is of delta9-THC is a consequence of its THC (Agurell et al., 1986; Hollister, absorbed within seconds. The delta9- first-pass hepatic elimination from 1988a). In addition to the primary active THC is delivered to the brain rapidly blood and erratic absorption from metabolite, 11-hydroxy-delta9-THC, and efficiently as would be expected of stomach and bowel. Because peak some inactive carboxy metabolites have a very lipid-soluble drug. The delta9- effects are slow in onset, typically one terminal half-lives of 50 hours to 6 days THC bioavailability from smoked or two hours after an oral dose, and or more. The latter substances serve as marijuana, i.e., the actual absorbed dose variable in intensity, it is more difficult long term markers of earlier marijuana as measured in blood, varies greatly for a user to titrate the oral delta9-THC use in urine tests. Most of the absorbed among individuals. Bioavailability can dose than with marijuana smoking. delta9-THC dose is eliminated in feces, range from one percent to 24 percent When smoked, the active metabolite, 11- and about 33 percent in urine. Delta9- with the fraction absorbed rarely hydroxy-delta9-THC, probably THC enters enterohepatic circulation exceeding 10 to 20 percent of the delta9- contributes little to the effects since and undergoes hydroxylation and THC in a marijuana cigarette or pipe relatively little is formed, but after oral oxidation to 11-nor-9-carboxy-delta9- (Agurell et al. 1986; Hollister 1988a). administration, metabolite levels THC. The glucuronide is excreted as the This relatively low and quite variable produced may exceed that of delta9-THC major urine metabolite along with about bioavailability results from significant and thus contribute greatly to the 18 nonconjugated metabolites. Frequent loss of delta9-THC in side-stream smoke, pharmacological effects of oral delta9- and infrequent marijuana users are from variation in individual smoking THC or marijuana. Delta9-THC is similar in the way they metabolize behaviors, from cannabinoid pyrolysis, metabolized via microsomal delta9-THC (Agurell et al., 1986). from incomplete absorption of inhaled hydroxylation to more than 80, active smoke, and from metabolism in the and inactive, metabolites (Lemberger et Medical Uses for Marijuana lungs. A smoker’s experience is likely al., 1970, Lemberger et al., 1972a, FDA has not approved a new drug an important determinant of the dose 1972b) of which the primary active application for marijuana, although that is actually absorbed (Herning et al. metabolite was 11-OH-delta9-THC. This there are several INDs currently active. 1986; Johansson et al. 1989). Venous metabolite is approximately equipotent There is suggestive evidence that
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marijuana may have beneficial investigations and well-controlled An estimated 2.3 million persons of therapeutic effects in relieving spasticity clinical trials (DHHS, 1999). This action all ages used marijuana for the first time associated with multiple sclerosis, as an was prompted by the increasing interest in 1998, of whom 1.6 million were analgesic, as an antiemetic, as an in determining through scientifically between the ages of 12–17. (Information appetite stimulant and as a valid investigations whether on when people first used a substance bronchodilator, but there is no data from cannabinoids have medical use. is collected on a retrospective basis, so controlled clinical trials to support a this information is always one year new drug application for any of these 4. Its History and Current Pattern of behind information on current use.) indications. Data of the risks and Abuse This represents a slight reduction in potential benefits of using marijuana for To assess drug abuse patterns and new marijuana users from 1997, when these various indications must be trends, data from different sources such the rate was 2.6 million people of all developed to determine whether as National Household Survey on Drug ages and 1.8 million for those 12–17 botanical marijuana, or any cannabinoid Abuse (NHSDA), Monitoring the Future years old. Trends for marijuana use in particular, has a therapeutic role. (MTF), Drug Abuse Warning Network were similar to the trends for any illicit In February 1997, a NIH-sponsored (DAWN), and Treatment Episode Data use. There were no significant changes workshop analyzed available scientific Set (TEDS) have been analyzed. These between 1998 and 1999 for any of the information and concluded that ‘‘in indicators of marijuana use in the four age groups, but an increasing trend order to evaluate various hypotheses United States are described below: since 1997 among young adults age 18– concerning the potential utility of 25 years (12.8 % in 1997, 13.8 % in marijuana in various therapeutic areas, National Household Survey on Drug 1998, and 16.4 % in 1999) and a more and better studies would be Abuse decreasing trend since 1997 for youths needed’’ (NIH, 1997). In addition, in The National Household Survey on age 12–17 years (9.4 % in 1997, 8.3 % March 1999, the Institute of Medicine Drug Abuse (NHSDA, 1999) is in 1998, and 7.0 % in 1999). (IOM) issued a detailed report that conducted by the Department of Health Monitoring the Future supports the absolute need for evidence- and Human Service’s Substance Abuse Monitoring the Future (MTF, 1999) is based research into the effects of and Mental Health Services a national survey that tracks drug use marijuana and cannabinoid components Administration (SAMHSA) annually. trends among American adolescents. of marijuana, for patients with specific This survey has been the primary source The MTF has surveyed 8th, 10th and disease conditions. The IOM report also of estimates of the prevalence and 12th graders every spring in randomly emphasized that smoked marijuana is a incidence of alcohol, tobacco and illicit crude drug delivery system that exposes selected U.S. schools since 1975 for drug use in the US. It is important to 12th graders and since 1991 for 8th and patients to a significant number of note that this survey identifies whether harmful substances and that ‘‘if there is 10th graders. This survey is conducted an individual used a drug during a any future for marijuana as a medicine, by the Institute for Social Research at certain period, but not the amount of the it lies in its isolated components, the the University of Michigan under a drug used on each occasion. The survey cannabinoids and their synthetic grant from NIDA. The 1999 sample sizes is based on a nationally representative derivatives.’’ As such, the IOM were 17,300, 13,900, and 14,100 in 8th, sample of the civilian, non- recommended that clinical trials should 10th, and 12th grades, respectively. In institutionalized population 12 years of be conducted with the goal of all, about 45,000 students in 433 schools age and older. Persons excluded from developing safe delivery systems participated. Because multiple the survey include homeless people (Institute of Medicine, 1999). questionnaire forms are administered at who do not use shelters, active military Additionally, State-level public each grade level, and because not all initiatives, including referenda in personnel, and residents of institutional questions are contained in all forms, the support of the medical use of marijuana group quarters, such as jails and numbers of cases upon which a have generated interest in the medical hospitals. In 1999, 66,706 individuals particular statistic are based can be less community for high quality clinical were interviewed. than the total sample. investigation and comprehensive safety According to the 1999 NHSDA, illicit Comparisons between the MTF and and effectiveness data. drug use involved approximately 14.8 students sampled in the NHSDA The Department of Health and Human million Americans (6.7% of the US (described above) have generally shown Services (DHHS) is committed to population) on a monthly basis. The NHSDA prevalence to be lower than providing ‘‘research-grade marijuana for most frequently used illicit drug was MFT estimates, in which the largest studies that are the most likely to yield marijuana, with 11.2 million Americans difference occurred with 8th graders. usable, essential data’’ (DHHS, 1999). (5.1% of the US population) using it The MTF survey showed the use of The opportunity for scientists to monthly. The 1999 NHSDA no longer illegal drugs by adolescents leveled off conduct clinical research with botanical provides data on the weekly or daily use in 1997 and then declined somewhat for marijuana has increased due to changes of any drug, so these statistics are most drugs in 1998. Also, the 1998-year in the process for obtaining botanical unavailable for marijuana. The NHSDA survey showed that for the first time marijuana from the National Institute on estimated that 76.4 million Americans since 1991 an increase in the percentage Drug Abuse, the only legal source of the (34.6% of the population) have tried of 8th graders who said marijuana is a drug for research. Studies published in marijuana at least once during their risk to their health. the current medical literature lifetime. Thus, 14.7% of those who try Illicit drug use among teens remained demonstrate that clinical research with marijuana go on to use it monthly. steady in 1999 in all three grades, as did marijuana is being conducted in the US NHSDA data from 1999 show that 57% the use of a number of important under FDA-authorized Investigational of illicit drug users only use marijuana specific drugs such as marijuana, New Drug applications. In May 1999, on a monthly basis, which corresponds amphetamines, hallucinogens taken as a DHHS provided guidance on the to 8.44 million persons (3.8% of the US class, tranquilizers, heroin, and alcohol. procedures for providing research-grade population). However, there are no data Marijuana is the most widely used illicit marijuana to scientists who intend to available on marijuana-only use as a drug. For 1999, the annual prevalence study marijuana in scientifically valid percent of use of any drug. rates in grades 8, 10, and 12,
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respectively, are 17%, 32%, and 38%. changed in the remaining 8th and 10th from 1998 to 1999. Marijuana/hashish Current monthly prevalence rates are grade forms. mentions represented 16% of all drug- 9.7%, 19.4% and 23.1%. (See Table 1), related episodes in 1999. For adolescent Drug Abuse Warning Network (DAWN) whereas current daily prevalence rates patients age 12–17, there was no (defined as the proportion using it on 20 The Drug Abuse Warning Network statistical change from 1998 to 1999 in or more occasions in the prior thirty (DAWN, 1998) is a national probability drug use for any drug category (Table 2). days) are 1.4%, 3.8%, and 6.0%. survey of hospitals with emergency There was no a statistically significant departments (EDs) designed to obtain change in the number of marijuana/ TABLE 1.—TRENDS IN ANNUAL AND information on ED episodes that are hashish mentions, heroin/morphine of MONTHLY PREVALENCE OF USE OF induced by or related to the use of an cocaine from 1998 to 1999. illegal drug or the non-medical use of a VARIOUS DRUGS FOR EIGHTH, legal drug. The DAWN system provides TENTH, AND TWELFTH GRADERS TABLE 2.—ESTIMATED NUMBER OF information on the health consequences EMERGENCY DEPARTMENT DRUG [Entries are precentages] of drug use in the United States as EPISODES, DRUG MENTIONS AND manifested by drug-related visits to Annual 30-Day emergency departments (ED episodes). MENTIONS FOR SELECTED DRUGS Grade FOR TOTAL COTERMINOUS US BY 1997 1998 1999 1997 1998 1999 DAWN captures the non-medical use of a substance either for psychological YEAR FOR 1997–1999 Any illicit drug (a) effects, dependence, or suicide attempt. The ED data come from a representative 1997 1998 1999 8th ...... 22.1 21.0 20.5 12.9 12.1 12.2 sample of hospital emergency Drug epi- 10th ...... 38.5 35.0 35.9 23.0 21.5 22.1 department’s which are weighted to 12th ...... 42.4 41.4 42.1 26.2 25.6 25.9 sodes ...... 527,058 542,544 554,932 produce national estimates. As stated in Drug men- DAWN methodology, ‘‘the terms ’ED Any illicit drug other than cannabis (a) tions ...... 943,937 982,856 1,015,206 drug abuse episode’ or ’ED episode’ Cocaine ...... 161,087 172,014 168,763 8th ...... 11.8 11.0 10.5 6.0 5.5 5.5 refer to any ED visit that was induced Heroin/Mor- 10th ...... 18.2 16.6 16.7 8.8 8.6 8.6 by or related to drug abuse. Similarly, phine ...... 72,010 77,645 84,409 12th ...... 20.7 20.2 20.7 10.7 10.7 10.4 the terms ’ED drug mention’ or ’ED Marijuana/ mention’ refer to a substance that was Hashish .... 64,744 76,870 87,150 Marijuana/hashish mentioned in a drug abuse episode. Up Source: Office of applied studies, SAMHSA, to 4 substances can be reported for each Drug Abuse Warning Network, 1999 (03/2000 8th ...... 17.7 16.9 16.5 10.2 9.7 9.7 ED episode. Thus, the number of ED update). Note: These estimates are based on 10th ...... 34.8 31.1 32.1 20.5 18.7 19.4 mentions will always equal or exceed a representative sample of non-federal, short- 12th ...... 38.5 37.5 37.8 23.7 22.8 23.1 stay hospitals with 24-hour emergency depart- the number of ED episodes.’’ ments in the U.S. Cocaine Many factors can influence the estimates of ED visits, including trends There were no statistically significant 8th ...... 2.8 3.1 2.7 1.1 1.4 1.3 in the ED usage in general. Some drug increases in marijuana/hashish 10th ...... 4.7 4.7 4.9 2.0 2.1 1.8 users may have visited EDs for a variety mentions on the basis of age, gender, or 12th ...... 5.5 5.7 6.2 2.3 2.4 2.6 of reasons, some of which may have race/ethnicity subgroups between 1998 been life threatening, whereas others and 1999, although a 19% increase in Heroin (b) may have sought care at the ED for marijuana/hashish mentions (from detoxification because they needed 22,907 to 27,272) among young adults 8th ...... 1.3 1.3 1.4 0.6 0.6 0.6 certification before entering treatment. It age 18 to 25 was observed. 10th ...... 1.4 1.4 1.4 0.6 0.7 0.7 Approximately 15 percent of the 12th ...... 1.2 1.0 1.1 0.5 0.5 0.5 is important to note that the variable ‘‘Motive’’ applies to the entire episode emergency department marijuana/ Source. The Monitoring the Future Study, and since more than one drug can be hashish mentions involved patients in the University of Michigan. mentioned per episode, it may not apply the 6–17 years of age, whereas this age to the specific drug for which the tables group only accounts for less than 1 a. For 12th graders only: Use of ‘‘any have been created. DAWN data do not percent of the emergency department illicit drug’’ includes any use of distinguish the drug responsible for the heroin/morphine and approximately 2 marijuana, LSD, other hallucinogens, ED visit from others used percent of the cocaine emergency crack, other cocaine, or heroin, or any concomitantly. The DAWN report itself department mentions. Most of the use of other opiates, stimulants, states, ‘‘Since marijuana/hashish is emergency department heroin/morphine barbiturates, or tranquilizers not under frequently present in combination with and cocaine mentions involved subjects a doctor’s orders. For 8th and 10th other drugs, the reason for the ED in the 26–44 years of age range. graders: The use of other opiates and contact may be more relevant to the Marijuana/hashish is likely to be barbiturates has been excluded, because other drug(s) involved in the episode.’’ mentioned in combination with other these younger respondents appear to In 1999, there were an estimated substances, particularly with alcohol over-report use (perhaps because they 554,932 drug-related ED episodes and and cocaine. Marijuana use as a single include the use of nonprescription 1,015,206 ED drug mentions from these drug accounted for approximately 22% drugs in their answers). drug-related episodes. Nationally, the of the marijuana episodes. Single use of b. In 1995, the heroin question was number of ED episodes and mentions cocaine and heroin accounted for 29% changed in three of six forms for 12th remained relatively stable from 1998 to and 47% of the cocaine and heroine graders and in two forms for 8th and 1999. The 4 drugs mentioned most episodes respectively. 10th graders. Separate questions were frequently in ED reports—alcohol-in- The petitioner asserts that ‘‘common asked for use with injection and without combination (196,277 mentions), household painkillers’’ and injection. Data presented here cocaine (168,763), marijuana/hashish benzodiazepines produce more ED visits represents the combined data from all (87,150), and heroin/morphine than marijuana and that marijuana users forms. In 1996, the heroin question was (84,409)—were statistically unchanged are no more likely to be seen in EDs
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than other chronic drug users. DAWN Treatment Episode Data Set was reported by 4% of admissions for data do not confirm the petitioner’s The Treatment Episode Data Set primary marijuana abuse. The assertions. For 1999, the estimated rate (TEDS, 1998) system is part of combination marijuana/alcohol/cocaine of mentions of selected drugs per SAMHSA’s Drug and Alcohol Services accounts for 8.5% of marijuana primary 100,000 population is 69.4 for cocaine, Information System (Office of Applied admissions and 1.1% of all admissions. 35.8 for marijuana/hashish, 34.7 for Science, SAMHSA). TEDS comprises The TEDS Report concludes that, heroin/morphine, 17.5 for alprazolam/ data on treatment admissions that are ‘‘Overall, TEDS admissions data confirm diazepam/lorazepam, and 16.9 for routinely collected by States in that those admitted to substance abuse aspirin/acetaminophen. The estimated monitoring their substance abuse treatment have problems beyond their rate of mentions of marijuana/hashish treatment systems. The TEDS report dependence on drugs and alcohol, being per 100,000 population is similar to that provides information on the disadvantaged in education and of heroin/morphine, but approximately demographic and substance use employment when compared to the twice that of aspirin/acetaminophen and characteristics of the 1.5 million annual general population after adjusting for that of alprazolam/diazepam/ admissions to treatment for abuse of age, gender, and race/ethnicity lorazepam. However, marijuana alcohol and drugs in facilities that distribution differences between the estimated rate of mentions/100,000 report to individual State administrative general population and the TEDS. It is population is approximately half that of data systems. It is important to note that not possible to conclude cause and cocaine. TEDS is an admission-based system, effect from TEDS data—whether These drugs are easily distinguished and TEDS admissions do not represent substance abuse precedes or follows the by the motivation for their use. In 1999, individuals, because a given individual appearance of other life problems—but marijuana/hashish mentions were admitted to treatment twice within a the association between problems seems related to episodes in which the motive given year would be counted as two clear.’’ for drug intake was primarily admissions. TEDS includes facilities NIDA’s Community Epidemiology Work dependence (34.2%) followed by that are licensed or certified by the State Group (CEWG, 1999) recreational use (28%), suicide (11.5%) substance abuse agency to provide and other psychic effects (8.1%). DAWN substance abuse treatment and that are The CEWG is a network composed of defines ‘‘psychic effects’’ as a conscious required by the States to provide TEDS epidemiologic and ethnographic action to use a drug to improve or client-level data. Facilities that report researchers from major metropolitan enhance any physical, emotional, or TEDS data are those that receive State areas of the United States and selected social situation or condition. The use of alcohol and/or drug agency funds for countries from abroad that meets a drug for experimentation or to the provision of alcohol and/or drug semiannually to discuss the current enhance a social situation, as well as the treatment services. The primary goal for epidemiology of drug abuse. Large-scale use of drugs to enhance or improve any TEDS is to monitor the characteristics of databases used in analyses include mental, emotional, or physical state, is treatment episodes for substance TEDS; DAWN; the Arrestee Drug Abuse Monitoring (ADAM) program funded by reported to DAWN under this category. abusers. the National Institute of Justice; Examples of the latter include anxiety, Primary marijuana abuse accounted information on drug seizures, price, and stay awake, help to study, weight for 13% of TEDS admissions in 1998, purity from the Drug Enforcement control, reduce pain and to induce the latest year for which data are Administration; Uniform Crime Reports sleep. A different pattern is observed for available. In general, most of the maintained by the Federal Bureau of tranquilizers (alprazolam/diazepam/ individuals admitted for marijuana were white young males. Marijuana use began Investigation and Poison Control lorazepam) and aspirin/ at an early age among primary Centers. These data are enhanced with acetamipnophen. Alprazolam/ marijuana admissions and more than qualitative information obtained from diazepam/lorazepam mentions were half of the admitted patients had first ethnographic research, focus groups, primarily related to episodes where the used marijuana by the age of 14 and and other community-based sources. motive for drug intake was primarily 92% by the age of 18. More than half of Although data from TEDS and DAWN suicide (approximately 58%), followed marijuana treatment admissions were have been previously discussed this by dependence (approximately 17%), referred through the criminal justice document, the analysis offered by the other psychic effects (approximately system. CEWG gives a more descriptive 11%), and recreational use Approximately one-third of those who overview of individual geographical (approximately 5%). For the use of were admitted for primary marijuana areas. In 1999, marijuana indicators aspirin/acetaminophen the primary abuse use the drug daily. Between 1992 were stable in 17 of the 21 CEWG areas. motive of the episode was suicide and 1998, the proportion of admissions Indicators were mixed in two areas (80%), other psychic effects (9%) and for primary marijuana use increased (Atlanta and Baltimore) and increased recreational use (2%). from 6% to 13%, whereas the in two (Los Angeles and St. Louis). DAWN also collects information on proportion of admissions for primary Despite the stability of certain drug-related deaths from selected cocaine use declined from 18% in 1992 indicators, marijuana abuse remains a medical examiner offices from more to 15% in 1998. The proportion of serious problem in CEWG areas. In than 40 metropolitan areas. In 1997 and opiate admissions increased from 12% Atlanta, marijuana is the second most 1998, there were 678 and 595 in 1992 to 15% in 1998 and alcohol prevalent drug on the market and is marijuana-related death mentions, accounted for about half (47%) of all increasingly used by a wide variety of representing 7.1 and 5.9 percent of the TEDS admissions in 1998. Marijuana people mostly white males and young total drug abuse deaths for each year has not been associated with other drugs adolescents. In St. Louis, marijuana respectively. Medical examiner data in 30.8% of the primary marijuana indicators are increasing and DAWN also showed that in the majority of the admissions that corresponds to 4.1% of marijuana ED mentions rose 33.3% from mentions, marijuana was used all admissions. Secondary use of alcohol the last half of 1998 to the first half of concomitantly with cocaine, heroin and was reported by 38.2% of the marijuana 1999. Treatment admissions rose 40.1% alcohol. admissions and secondary cocaine use from the second half of 1998 to the first
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half of 1999, and another 9.6% in the episodes marijuana was associated with the most vulnerable to developing second half of 1999. alcohol, cocaine, and morphine. dependence on marijuana. Dysphoria is In recent years, the proportion of Data from the Treatment Episode Data a potential response in a minority of primary marijuana abusers entering Set confirm that 69% of admissions to individuals who use marijuana. drug treatment programs for primary drug abuse treatment programs has been Risks from chronic use of marijuana: increasing in many CEWG cities. For marijuana abuse also had concurrent example, between 1998 and the first use of alcohol and other drugs. The Marijuana smoke is considered to be semester of 1999, drug treatment TEDS report also emphasizes that comparable to tobacco smoke in respect admissions for primary marijuana abuse individuals who are admitted for drug to increased risk of cancer, lung damage, increased from 15.2% to 20.3% in treatment have multiple disadvantages and poor pregnancy outcome. An Atlanta. In the first half of 1999, primary in education and employment compared additional concern includes the marijuana abusers represented 18.8% of to the general population. Individuals potential for dependence on marijuana, drug treatment admissions in New York most likely to develop dependence on which has been assessed to be rare City compared with 16.6% in the first marijuana have a higher rate of among the general population but more half of 1998. In the first half of 1999, associated psychiatric disorders or are common among adolescents with primary marijuana abuse represented socializing with a delinquent crowd. conduct disorder and individuals with psychiatric disorders. Although a 41.2% of all drug treatment admissions 6. What, if Any, Risk There is to the distinctive marijuana withdrawal in Denver and totaled 3,179. The Public Health number of primary marijuana syndrome has been identified, it is mild The risk to the public health as admissions in St. Louis increased and short-lived. measured by quantifiers such as dramatically in the first half of 1999, emergency room episodes, marijuana- The Diagnostic and Statistical Manual representing 40.8% of treatment related deaths, and drug treatment (DSM–IV–SR, 2000) of American admissions. admissions is discussed in full in Psychiatric Association states that the The CEWG reports an increase in sections 1, 4, and 5 above. Accordingly, consequences of cannabis abuse are as problems associated with marijuana that this section focuses on the health risks follows: they attribute to the drug’s greater to the individual user. All drugs, both [P]eriodic cannabis use and intoxication availability/potency, its relative low medicinal and illicit, have a broad range can interfere with performance at work or cost, and a public attitude that use of of effects on the individual user that are school and may be physically hazardous in marijuana is less risky than use of other dependent on dose and duration of situations such as driving a car. Legal drugs. usage. It is not uncommon for a FDA problems may occur as a consequence of 5. The Scope, Duration, and approved drug product to produce arrests for cannabis possession. There may be Significance of Abuse adverse effects even at doses in the arguments with spouses or parents over the therapeutic range. Such adverse possession of cannabis in the home or its use According to the National Household responses are known as ‘‘side effects’’. in the presence of children. When Survey on Drug Abuse and the When determining whether a drug psychological or physical problems are Monitoring the Future study, marijuana product is safe and effective for any associated with cannabis in the context of remains the most extensively used indication, FDA performs a thorough compulsive use, a diagnosis of Cannabis illegal drug in the US, with 34.6% of risk-benefit analysis to determine Dependence, rather than Cannabis Abuse, individuals over age 12 (76.4 million) whether the risks posed by the drug should be considered. and 49.7% of 12th graders having tried product’s potential or actual side effects it at least once in their lifetime. While are outweighed by the drug product’s Individuals with Cannabis Dependence the majority of individuals (85.3%) who potential benefits. As marijuana is not have compulsive use and associated have tried marijuana do not use the drug approved for any use, any potential problems. Tolerance to most of the monthly, 11.2 million individuals benefits attributed to marijuana use effects of cannabis has been reported in (14.7%) report that they used marijuana have not been found to be outweighed individuals who use cannabis within the past 30 days. An examination by the risks. However, cannabinoids chronically. There have also been some of use among various age cohorts have a remarkably low acute lethal reports of withdrawal symptoms, but demonstrates that monthly use occurs toxicity despite potent psychoactivity their clinical significance is uncertain. primarily among college age and pharmacologic actions on multiple There is some evidence that a majority individuals, with use dropping off organ systems. of chronic users of cannabinoids report sharply after age 25. The consequences of marijuana use histories of tolerance or withdrawal and The Drug Abuse Warning Network and abuse are discussed below in terms that these individuals evidence more data show that among 18–25 year olds, of the risk from acute and chronic use severe drug-related problems overall. there was a 19% increase in 1999 for of the drug to the individual user (IOM, Individuals with Cannabis Dependence marijuana emergency department 1999) (see also the discussion of the may use very potent cannabis mentions. The fact that this age cohort central nervous system effects, cognitive throughout the day over a period of had the greatest degree of acute adverse effects, cardiovascular and autonomic months or years, and they may spend reactions to marijuana might be effects, respiratory effects, and the effect several hours a day acquiring and using expected given that this group has the on the immune system in Section 2): the substance. This often interferes with largest prevalence of marijuana use. Risks from acute use of marijuana: family, school, work, or recreational Marijuana was commonly associated Acute use of marijuana causes an activities. Individuals with Cannabis with alcohol and cocaine. impairment of psychomotor Dependence may also persist in their According to 1999 DAWN data, there performance, including performance of use despite knowledge of physical were 187 deaths mentions where complex tasks, which makes it problems (e.g., chronic cough related to marijuana was the only drug reported, inadvisable to operate motor vehicles or smoking) or psychological problems out of the total 664 medical examiners heavy equipment after using marijuana. (e.g., excessive sedation and a decrease episodes involving marijuana in 1999. People who have or are at risk of in goal-oriented activities resulting from In the majority of the medical examiners developing psychiatric disorders may be repeated use of high doses).
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7. Its Psychic or Physiologic According to the NHSDA, data Data show that humans prefer higher Dependence Liability discussed above in Section 1, 6.8 doses of marijuana to lower doses, million Americans used marijuana demonstrating that marijuana has dose- Tolerance can develop to marijuana- weekly in 1998. In addition, the DAWN dependent reinforcing effects. Marijuana induced cardiovascular and autonomic data discussed in Section 4 indicates has relatively low levels of toxicity and changes, decreased intraocular pressure, that 34.2% of the 87,150 ED marijuana physical dependence as compared to sleep and sleep EEG, mood and mentions in 1999 were related to other illicit drugs. However, as behavioral changes (Jones et al., 1981). episodes in which the motive for drug discussed above, physical dependence Down-regulation of cannabinoid intake was primarily dependence. It and toxicity are not the only factors to receptors has been suggested as the should be emphasized that the patient- consider in determining a substance’s mechanism underlying tolerance to the reported ‘‘motive’’ for the drug intake abuse potential. The large number of effects of marijuana (Rodriguez de applies to the entire episode and since individuals using marijuana on a regular Fonseca et al., 1994). Pharmacological more than one drug can be mentioned basis and the vast amount of marijuana tolerance does not indicate the physical per episode, it may not apply to one that is available for illicit use are dependence liability of a drug. specific drug. DAWN data do not indicative of widespread use. In In order for physical dependence to distinguish the drug responsible for the addition, there is evidence that exist, there must be evidence for a ED visit from others used marijuana use can result in withdrawal syndrome. Although concomitantly. Finally, the CEWG data psychological dependence in a certain pronounced withdrawal symptoms can discussed in Section 4 above reports an proportion of the population. be provoked from the administration of increase in the proportion of primary 2. Marijuana Has No Currently Accepted a cannabinoid antagonist in animals marijuana users entering drug abuse Medical Use in Treatment in the United who had received chronic THC treatment programs. Thus, there is States administration, there is no overt evidence among a certain proportion of withdrawal syndrome behaviorally in marijuana users for a true psychological The FDA has not approved a new animals under conditions of natural dependence syndrome. drug application for marijuana. The discontinuation following chronic THC opportunity for scientists to conduct administration. The marijuana 8. Whether the Substance is an clinical research with marijuana has withdrawal syndrome is distinct but Immediate Precursor of a Substance increased recently due to the mild compared to the withdrawal Already Controlled Under This Article implementation of DHHS policy syndromes associated with alcohol and Marijuana is not an immediate supporting clinical research with heroin use, consisting of symptoms such precursor of another controlled botanical marijuana. While there are as restlessness, mild agitation, substance. INDs for marijuana active at the FDA, insomnia, nausea and cramping that marijuana does not have a currently resolve after 4 days (Budney et al., 1999; C. Findings and Recommendation accepted medical use for treatment in the United States nor does it have an Haney et al., 1999). These symptoms are After considering the scientific and accepted medical use with severe comparable to the decreased vigor, medical evidence presented under the restrictions. increased fatigue, sleepiness, headache, eight factors above, FDA finds that and reduced ability to work seen with A drug has a ‘‘currently accepted marijuana meets the three criteria for medical use’’ if all of the following five caffeine withdrawal (Lane et al., 1998). placing a substance in Schedule I of the However, marijuana withdrawal elements have been satisfied: CSA under 21 U.S.C. 812(b)(1). a. The drug’s chemistry is known and syndrome has only been reported in Specifically: reproducible; adolescents who were inpatients for b. There are adequate safety studies; substance abuse treatment or in 1. Marijuana Has a High Potential for Abuse c. There are adequate and well- individuals who had been given controlled studies proving efficacy; marijuana on a daily basis during 11.2 million Americans used d. The drug is accepted by qualified research conditions. Physical marijuana monthly in 1999 and 1998 experts; and dependence on marijuana is a rare data indicate that 6.8 million Americans e. The scientific evidence is widely phenomenon compared to other used marijuana weekly. A 1999 study available. psychoactive drugs and if it develops, it indicates that by 12th grade, 37.8% of Alliance for Cannabis Therapeutics v. is milder when marijuana is the only students report having used marijuana DEA, 15 F.3d 1131, 1135 (D.C. Cir. drug instead of being used in in the past year, and 23.1 % report using 1994). combination with other drugs. it monthly. In 1999, 87,150 emergency Although the chemistry of many TEDS data for 1998 show that 37.9% department episodes were induced by cannabinoids found in marijuana have of admissions for treatment for primary or related to the use of marijuana/ been characterized, a complete scientific marijuana use met DSM IV criteria for hashish, representing 16% of all drug- analysis of all the chemical components cannabis dependence, whereas 27.7% related episodes. The primary motive found in marijuana has not been met DSM IV criteria for cannabis abuse. for drug intake in 34.2 % of those conducted. Safety studies for acute or Taken in the context of the total number episodes was reported to be subchronic administration of marijuana of admissions, a DSM IV diagnosis for dependence. DAWN data from that have been carried out through a limited cannabis dependence represented 6.6%, same year show that out of 664 medical number of Phase 1 clinical and a diagnosis for cannabis abuse examiner episodes involving marijuana, investigations approved by the FDA, but represented 4.9%, of all subjects marijuana was the only drug reported in there have been no studies that have admitted to treatment. In contrast, 187 deaths. In recent years, the scientifically assessed the efficacy of opioid and cocaine dependence was the proportion of primary marijuana abusers marijuana for any medical condition. A DSM diagnosis of 12.2% and 12.6% of entering drug abuse treatment programs material conflict of opinion among all admissions, respectively. (See has been increasing in major U.S. cities, experts precludes a finding that Section 6 regarding marijuana abuse and ranging from 19% in New York City to marijuana has been accepted by dependence). 41% in St. Louis and Denver. qualified experts. At this time, it is clear
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Behavioral pharmacokinetics of Galiegui, S.; Mary, S.; Marchand, J.; Huestis, M.A.; Henningfield, J.E.; and Cone,
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E.J. Blood Cannabinoids. 1. Absorption National Drug Control Strategy: 2000 Mr. Gettman proposed that DEA of THC and formation of 11-OH-THC and Annual Report. Superintendent of promulgate a rule stating that ‘‘there is THC COOH during and after smoking Documents, Mail Stop: SSOP, no scientific evidence that [marijuana marijuana. J Anal Toxicol 1992b, 16(5), Washington, DC. has] sufficient abuse potential to 276–282. Oviedo, A., Glowa, J., Herkenham, M. Johansson, E.; Halldin, M.M.; Agurell, S.; Chronic cannabinoid administration warrant schedule I or II status under the Hollister, L.E.; and Gillespie, H.K. alters cannabinoid receptor binding in [CSA].’’ Terminal elimination plasma half-life of rat brain: a quantitative autoradiographic In accordance with the CSA, DEA delta 1-tetrahydrocannabinol (delta 1- study. Brain Res. 1993, 616, 293–302. gathered the necessary data and, on THC) in heavy users of marijuana. Eur J Rinaldi-Carmona, M., Barth F., Heaulme, M., December 17, 1997, forwarded that Clin Pharmacol 1989, 37(3), 273–277. Shire, D., Calandra, B., Congy, C., information along with Mr. Gettman’s Jones, R.T.; Benowitz, N.L.; and Herning, R.I. Martinez, S., Maruani, J., Neliat, G., petition to the Department of Health and Clinical relevance of cannabis tolerance Caput, D., et al. SR141716A, a potent and Human Services (HHS) for a scientific and dependence. J Clin Pharmacol 1981, selective antagonist of the brain and medical evaluation and scheduling 21,143S–152S. cannabinoid receptor. FEBS Letters 1994, recommendation. On January 17, 2001, Koob, G.F. Neural mechanisms of drug 350, 240–244. reinforcement. Ann. N Y Acad Sci 1992, Rinaldi-Carmona M, Barth F, Millan J, Derocq HHS forwarded to DEA its scientific and 654, 171–191. JM, Casellas P, Congy C, Oustric D, medical evaluation and scheduling Lane JD, Phillips-Bute BG. Caffeine Sarran M, Bouaboula M, Calandra B, recommendation. The CSA requires deprivation affects vigilance Portier M, Shire D, Breliere JC, Le Fur GL, DEA to determine whether the HHS performance and mood. Physiol Behav SR 144528, the first potent and selective scientific and medical evaluation and 1998 65, 171–5. antagonist of the CB2 cannabinoid scheduling recommendation and ‘‘all Lemberger L., Rubin A. The physiologic receptor. J Pharmacol Exp Ther. 1998 , other relevant data’’ constitute disposition of marihuana in man, Life 284(2), 644–50. substantial evidence that the drug Sci. 1975,17, 1637–42. Rodriguez de Fonseca F, Gorriti, M.A., should be rescheduled as proposed in Lemberger L., Silberstein, S.D., Axelrod, J., Fernandez-Ruiz, J.J., Palomo, T., Ramos, Kopin, I.J. Marihuana: studies on the J.A. Downregulation of rat brain the petition. 21 U.S.C. 811(b). This disposition and metabolism of delta-9- cannabinoid binding sites after chronic document contains an explanation of tetrahydrocannabinol in man. Science delta 9-tetrahydrocannabinoil treatment. the ‘‘other relevant data’’ that DEA 1970, 170, 1320–1322. Phamacol. Biochem. Behav. 1994, 47 (1), considered. Lemberger L., Weiss, J.L., Watanabe, A.M., 33–40. In deciding whether to grant a Galanter, I.M., Wyatt, R.J., Cardon, P. V. Ross, S.A. and ElSohlyy, M.A. Constituents petition to initiate rulemaking Delta-9-tetrahydrocannabinol: temporal of Cannabis Sativa L. XXVIII. A review proceedings, DEA must consider eight correlation of the psychological effects of the natural constituents:1980–1994. factors specified in 21 U.S.C. 811(c). and blood levels after various routes of Zagazig J. Pharm. Sci. 1995, 4 (2), 1–10. The information contained in this administration. New Eng. J. Med. 1972a, Sanudo-Pena M.C., Tsou, K., Delay, E.R., document is organized according to 286(13), 685–688. Hohman, A.G., Force, M., Walker, J.M. these eight factors. Lemberger, L., Crabtree, R.E., Rowe, H.M. 11- Endogenous cannabinoids as an aversive Hydroxy-)9-tetrahydrocannabinol: or counter-rewarding system in the rat. (1) Its Actual or Relative Potential for pharmacology, disposition and Neurosci. Lett., 223, 125–128, 1997. Abuse metabolism of a major metabolite of Treatment Episode Data Set (TEDS): 1993– marihuana in man. Science 1972b, 177, 1998. National Admissions to Substance Evaluation of the abuse potential of a 62–63. Abuse Treatment Services. Department drug is obtained, in part, from studies in Martin, B.R.; Mechoulam, R., Razdan, R.K. of Health and Human services. the scientific and medical literature. Discovery and characterization of Substance Abuse and Mental Health There are many preclinical indicators of endogenous cannabinoids. Life Sci. Services Administration. National a drug’s behavioral and psychological 1999, 65, 573–595. Clearinghouse for Alcohol and Drug effects that, when taken together, Matsuda, L.A., Lolait, S.J., Brownstein, M.J., information. Rockville, MD. provide an accurate prediction of the Young, A.C., Bonner, T.I. Structure of a Wesson, D.R.; Washburn, P. Current patterns human abuse liability. Specifically, cannabinoid receptor and functional of drug abuse that involve smoking. In expression of the cloned cDNA. Nature Research Findings on Smoking of these include assessments of the 1990, 346, 561–564. Abused Substances, Chiang, C.N.; discriminative stimulus effects, Mechoulam, R. Cannabinoid chemistry. In Hawks, R.L. (ED.) NIDA Research reinforcing effects, conditioned stimulus Mechoulam, R. (ED.) Marijuana, pp.2–88 Monograph, 99:5–11, 1990. effect, effects on operant response rates, (New York, NY, Academic Press, Inc.), locomotor activity, effects on food 1973. Additional Scientific Data Considered intake and other behaviors, and the Monitoring the Future. National Results on by the Drug Enforcement development of tolerance and Adolescent Drug Use. Overview of 1999 Administration in Evaluating Jon dependence (cf., Brady et al., 1990; Key findings, 1999. Department of Gettman’s Petition To Initiate Preston et al., 1997). Clinical studies of Health and Human services. National Rulemaking Proceedings To Reschedule the subjective and reinforcing effects in Institute on Drug Abuse. Rockville, MD. Marijuana (http://monitoringthefuture.org) substance abusers, interviews with National Institutes of Health (NIH). Drug and Chemical Evaluation Section, substance abusers, clinical interviews Workshop on the medical Utility of Office of Diversion Control, Drug with medical professionals, and Marijuana, February 19–20, 1997. Enforcement Administration, March epidemiological studies provide (www.nih.gov/news/medmarijuana/ 2001 quantitative data on abuse liability in MedicalMarijuana.htm) humans and some indication of actual NHSDA. Summary of Findings from the 1999 Introduction abuse trends (cf., deWit and Griffiths, National Household Survey on Drug On July 10, 1995, Jon Gettman 1991). Abuse. Office of Applied Studies. petitioned the Drug Enforcement Evidence of actual abuse and patterns Department of Health and Human services. Substance Abuse and Mental Administration (DEA) to initiate of abuse are obtained from a number of Health Services Administration. National rulemaking proceedings to reschedule substance abuse databases, and reports Clearinghouse for Alcohol and Drug marijuana. Marijuana is currently listed of diversion and trafficking. information. Rockville, MD. in schedule I of the Controlled Specifically, data from Drug Abuse Office of National Drug Control Policy. The Substances Act (CSA). Warning Network (DAWN), Poison
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Control Centers, System To Retrieve is the case for other drugs (cf. the stimulus effects of ∆9-THC increased Investigational Drug Evidence (STRIDE), Henningfield, 1984). 40-fold when supplemental doses of up seizures and declarations from U.S. In other behavioral and to 120 mg/kg/day ∆9-THC were Customs, DEA Drug Theft Reports and pharmacological tests used to assess administered under conditions of other diversion and trafficking data reinforcing efficacy, ∆9-THC produced suspended training (Wiley et al., 1993a). bases are indicators of the pattern, significant effects. Specifically, ∆9-THC The discriminative stimulus effects of scope, duration and significance of augments responding for intracranial ∆9-THC appear to be pharmacologically abuse. self-stimulation by decreasing the specific as non-cannabinoid drugs reinforcing threshold for brain typically do not elicit cannabimimetic Reinforcing Effects in Animals stimulation reward. It also dose- effects in drug discrimination studies As described by the petitioner, the dependently enhances dopamine efflux (Browne and Weissman, 1981; Balster preponderance of preclinical studies in forebrain nuclei associated with and Prescott, 1992, Gold et al., 1992; using animal models had, to recently, reward and this enhanced efflux occurs Barrett et al., 1995; Wiley et al., 1995a). shown that ∆9-THC had minimal locally in the terminal fields within Furthermore, these studies show that activity in behavioral paradigms brain reward pathways (Gardner and high doses of ∆9-THC produce marked predictive of reinforcing efficacy (i.e., Lowinson, 1991; Gardner, 1992; Chen et response rate disruption, immobility, self-administration paradigms; Harris et al., 1993, 1994). In conditioned place ataxia, sedation and ptosis in rhesus al., 1974; Pickens et al., 1973; Deneau preference procedures, ∆9-THC (2.0 and monkeys and rats (Wiley et al., 1993b; and Kaymakcalan, 1971). In general, ∆9- 4.0 mg/kg, i.p.) produced significant Gold et al., 1992; Martin et al., 1995). THC had been shown to be relatively dose-dependent increases in preference Clinical Abuse Potential ineffective in maintaining self- for the drug paired chamber, the administration behavior by either the magnitude of which was similar to that Both marijuana and THC can serve as intravenous or oral routes seen with 5.0 mg/kg cocaine and 4.0 positive reinforcers in humans. (Kaymakcalan, 1973; Harris et al., 1974; mg/kg morphine (Leprore et al., 1995). Marijuana and ∆9-THC produced Carney et al., 1977; Mansbach et al., However, ∆9-THC also produced a profiles of behavioral and subjective 1994). Under limited experimental conditioned place aversion and effects that were similar regardless of parameters, ∆9-THC self-administration conditioned taste aversion (Leprore et whether the marijuana was smoked or was demonstrated after animals were al., 1995; Parker and Gillies, 1995). The taken orally, as marijuana in brownies, either first trained to self-administer development of taste aversions with or orally as THC-containing capsules, PCP, after a chronic cannabinoid history drug administrations that also produce although the time course of effects was established or when maintained at place preferences have been described differed substantially. There is a large 80% reduced body weight (Pickens et as somewhat of a ‘‘drug paradox’’ by clinical literature documenting the al., 1973; Deneau and Kaymakcalan, Goudie; however, this has been found to subjective, reinforcing, discriminative 1971; Takahashi and Singer, 1979). occur within the ‘‘therapeutic window’’ stimulus, and physiological effects of However, Tanda, Munzar and Goldberg of all known drugs of abuse (cf Goudie, marijuana and THC and relating these of the Intramural Preclinical 1987). Goudie has concluded that drugs effects to the abuse potential of Pharmacology Section of the NIDA can possess both reinforcing and marijuana and THC (e.g., Chait et al., (2000) have clearly demonstrated that aversive properties at the same doses. 1988; Lukas et al., 1995; Kamien et al., THC can act as a strong reinforcer of This fact may underlie the reciprocal 1994; Chait and Burke, 1994; Chait and drug-taking behavior in an experimental relationship between the behavioral Pierri, 1992; Foltin et al., 1990; Azorlosa animal model, the squirrel monkey, as effects of THC, CBD, and THC+CBD et al., 1992; Kelly et al., 1993, 1994; it does in humans. The self- combinations, discussed below. Chait and Zacny, 1992; Cone et al., administration behavior was 1988; Mendelson and Mello, 1984). comparable in intensity to that Drug Discrimination in Animals These listed studies represent a maintained by cocaine under identical Preclinical drug discrimination fraction of the studies performed to conditions and was obtained using a studies with ∆9-THC are predictive of evaluate the abuse potential of range of doses similar to those self- the subjective effects of cannabinoid marijuana and THC. In general, these administered by humans smoking a drugs in humans and serve as animal studies demonstrate that marijuana and single marijuana cigarette. models of marijuana and THC THC dose-dependently increases heart Although the neuropharmacological intoxication in humans (Balster and rate and ratings of ‘‘high’’ and ‘‘drug actions of ∆9-THC suggest a powerful Prescott, 1992; Wiley et al., 1993b, liking’’, and alters behavioral brain substrate underlying its rewarding 1995). In a variety of species it has been performance measures (e.g., Azorlosa et and euphorigenic effects, behavioral found that ∆9-THC shares discriminative al., 1992; Kelly et al., 1993, 1994; Chait studies of ∆9-THC’s rewarding effects stimulus effects with cannabinoids that and Zacny, 1992; Kamien et al., 1994; had been inconclusive. Several reasons bind to CNS cannabinoid receptors with Chait and Burke, 1994; Chait and Pierri, for the previous inability by a number high affinity (Compton et al., 1993; Ja¨rbe 1992; Foltin et al., 1990; Cone et al., of laboratories to demonstrate self- et al., 1989; Gold et al., 1992; Wiley et 1988; Mendelson and Mello, 1984). administration of ∆9-THC in animals al., 1993b, 1995b; Ja¨rbe and Mathis, Marijuana also serves as a may be its relatively slow-onset, its 1992) and that are psychoactive in discriminative stimulus in humans and long-lasting behavioral effects and its humans (Balster and Prescott, 1992). produces euphoria and alterations in insolubility in physiological saline or Furthermore, recent studies show that mood. These subjective changes were water for injection (Mansbach et al., the discriminative stimulus effects of used by the subjects as the basis for the 9 1994). Similar findings have been found ∆ -THC are mediated via the CB1 discrimination from placebo (Chait et in the animal literature with nicotine— receptor subtype (Pe´rio et al., 1996). al., 1988). an avid reinforcer in humans. The Chronic ∆9-THC administration to rats In addition, smoked marijuana strength of THC, like nicotine, as a produced tolerance to the administration resulted in multiple brief reinforcer in animals may be more discriminative stimulus effects of ∆9- episodes of euphoria that were dependent on supplementary THC, but not to its response rate paralleled by rapid transient increases strengthening by ancillary stimuli than disruptions. Specifically, tolerance to in EEG alpha power (Lukas et al., 1995);
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these EEG changes are thought to be activity and grooming in rats, decreased continued abuse (Gauvin, Cheng & related to CNS processes of seizure threshold in mice, increased Holloway, 1993). reinforcement (Mello, 1983). aggressiveness, irritability and altered Crowley et al. (1998) screened To help elucidate the relationship operant performance in rhesus monkeys marijuana users for DSM–IIIR between the rise and fall of plasma THC (cf., Pertwee, 1991). The failure to dependence criteria. Of the 165 males and the self-reported psychotropic observe profound withdrawal signs and 64 female patients that met the effects, Harder & Rietbrock (1997) following abrupt discontinuation of the criteria, 82.1% were found to have co- measured both the plasma levels of THC drug may be due to ∆9-THC’s long half- morbid conduct disorders; 17.5% had and the psychological ‘‘high’’ obtained life in plasma and slowly waning levels major depression; and 14.8% had a from smoking a marijuana cigarette of drug that continue to permit receptor diagnosis of attention-deficit/ containing 1% THC. As can be seen adaptation. hyperactivity disorder. These results from these data, a rise in plasma THC Recently the discovery of a also showed that most patients claimed concentrations results in a cannabinoid receptor antagonist to have ‘‘serious problems’’ from corresponding increase in the demonstrates that a profound cannabis use. The data also indicated subjectively reported feelings of being precipitated withdrawal syndrome can that for adolescents with conduct ‘‘high’’. However, as THC levels drop be produced in ∆9-THC tolerant animals problems, cannabis use was not benign, the subjectively reported feelings of after twice daily injections (Tsou et al., and that the drug served as a potent ‘‘high’’ remain elevated. The subjective 1995) or continuous infusion (Aceto et reinforcer for further cannabis usage, effects seem to lag behind plasma THC al., 1995, 1996). producing dependence and withdrawal. levels. Similarly, Harder and Rietbrock Kelly & Jones (1992) quantified Physical Dependence in Humans compared lower doses of 0.3% THC- concentrations of THC and its containing and 0.1% THC-containing Signs of withdrawal in humans have metabolites in both plasma and urine cigarettes in human subjects. been demonstrated after studies with after a 5 mg intravenous dose of THC As can be clearly seen by these data, marijuana and ∆9-THC. Although the was administered to frequent and even low doses of marijuana, containing intensity of the withdrawal syndrome is infrequent marijuana smokers. The 1%, 0.3% and even 0.1% THC, typically related to the daily dose and frequency frequent smokers were users who referred to as ‘‘non-active’’, are capable of administration, in general, the signs smoked marijuana almost daily for at of producing subjective reports and of ∆9-THC withdrawal have been least two years. The infrequent smokers physiological markers of being ‘‘high’. relatively mild (cf., Pertwee, 1991). This were users who smoked marijuana no THC and its major metabolite, 11-OH- withdrawal syndrome has been more than two to three times per month THC, have similar psychoactive and compared to that of short-term, low dose but had done so for at least two years. pharmacokinetic profiles in man ( Wall treatment with opioids, sedatives, or Pharmacokinetic parameters after et al., 1976; DiMarzo et al., 1998; ethanol, and includes changes in mood, intravenously administered THC Lemberger et al., 1972). Perez-Reyes et sleep, heart rate, body temperature, and revealed no significant differences al. (1972) reported that THC and 11-OH- appetite. Other signs such as irritability, between frequent and infrequent THC were equipotent in generating a restlessness, tremor, mild nausea, hot marijuana users on area under the time- ‘‘high’’ in human volunteers. However, flashes and sweating have also been effect curve (AUC), volume of the metabolite, 11-OH-THC, crosses the noted (cf., Jones, 1980, 1983). distribution, elimination half-lives of blood-brain barrier faster than the Chait, Fischman, & Schuster (1985) parent THC and metabolites in plasma parent THC compound (Ho et al., 1973; have demonstrated an acute withdrawal and urine. There were also no group Perez-Reyes et al., 1976). Therefore, the syndrome or ‘‘hangover’’ occurring differences in metabolic or renal changes in THC plasma concentrations approximately 9 hours after a single clearances. The authors concluded that in humans may not be the best marijuana smoking episode. Significant there was no evidence for metabolic or predictive marker for the subjective and changes occurred on two subjective dispositional tolerance between the two physiological effects of marijuana in measures and on a time production task. groups of subjects. Kelly and Jones also humans. Cocchetto et al. (1981) have In 1973, Cousens & DiMascio reported a reported that tolerance was not evident used hysteresis plots to clearly similar ‘‘hangover’’ effect from acute in heart rate, diastolic blood pressure, ∆9 demonstrate that plasma THC administrations of -THC. The skin temperature, and the degree of concentration is a poor predictor of hangover phenomenon or continued psychological ‘‘high’’ from the i.v. simultaneous occurring physiological ‘‘high’’, in the Cousens & DiMascio administration of THC. (heart rate) and psychological (‘‘high’’) study, occurred 9 hrs after drug In two separate reports, Haney et al. pharmacological effects. Cocchetto et al. administration and was associated with have recently described abstinence demonstrated that the time course of some residual temporal disorganization, symptoms of an acute withdrawal tachycardia and psychological as well. These residual or hangover syndrome following high (30 mg q.i.d.) responses lagged behind the plasma effects may mimic the withdrawal and low (20 mg q.i.d) dose THC concentration-time profile. As syndrome, both qualitatively and administrations of oral THC (Haney et recently summarized by Martin & Hall quantitatively, which is expressed after al., 1999a) and following 5 puffs of high (1997, 1998) chronic marijuana exposure. This acute (3.1%) and low (1.8%) THC-containing hangover may reflect a true acute smoked marijuana cigarettes (Haney et There is no linear relationship between withdrawal syndrome similar to that al., 1999b). Abstinence from oral THC blood [THC] levels and pharmacological experienced from high acute alcohol increased ratings of ‘‘anxious’’, effects with respect to time, a situation that hampers the prediction of cannabis-induced intake. The presence of an acute ‘‘depressed’’, and ‘‘irritable’’, and impairment based on THC blood levels (p90). withdrawal syndrome after drug decreased the reported quantity and administration has been suggested to quality of sleep and decreased food Physical Dependence in Animals represent a physiological compensatory intake by 20–30% compared to baseline. There are reports that abrupt rebound by which chronic Abstinence from as low as 5 controlled withdrawal from ∆9-THC can produce a administration of the drug will puffs of active marijuana smoking mild spontaneous withdrawal syndrome eventually potentiate and produce increased ratings of ‘‘anxious’’, in animals, including increased motor dependence and the potential for ‘‘irritable’’ and ‘‘stomach pain’’, and
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significantly decreased food intake. The Results of THC Dose Comparison In order to determine marijuana dose- 5 controlled puffs of 5 second duration Studies effects on subjective and performance each were drawn from 2 separate There are reports in the scientific measures over a wide dose range, marijuana cigarettes (3 puffs from one, literature that evaluated dose-related Azorlosa et al. (1992) evaluated the 2 puffs from the other. The smoke was subjective and reinforcing effects of effects of 4, 10, or 25 puffs from held for 40 seconds and then exhaled. Cannabis sativa in humans. These marijuana cigarettes containing 1.75 or All subjects reported significant studies have assessed the subjective and 3.55% THC in seven male moderate increases on subjective measures of reinforcing effects of cannabis cigarettes users of marijuana. Orderly dose- ‘‘high’’, ‘‘good drug effect’’, and containing different potencies of THC response curves were produced for ‘‘stimulated’’, as well as ‘‘mellow’’, and/or which have manipulated the subjective drug effects, heart rate, and plasma concentration, as a function of ‘‘content’’, and ‘‘friendly’’ as a result of THC dose by varying the volume of THC THC content and number of puffs. After this limited and controlled draw of smoke inhaled (Azorlosa et al., 1992; smoking the 1.75% THC cigarette, THC. Both of these studies have Lukas et al., 1995; Chait et al., 1988; maximal plasma THC levels were 57 ng/ delineated a withdrawal syndrome from Chait and Burke, 1994; Kelly et al., ml immediately after smoking, 18.3 ng/ concentrations of THC significantly 1993). ml 15 minutes after smoking, 10.3 ng/ lower than those reported in any other Chait et al. (1988) studied the ml 30 minutes after smoking, and 7.7 previous study and, for the first time, discriminative stimulus effects of ng/ml 45 minutes after smoking. clearly identified a marijuana smoked marijuana cigarettes containing The study also showed that subjects withdrawal syndrome detected at low THC contents of 0%, 0.9%, 1.4%, 2.7%. could smoke more of the low THC levels of THC exposure that do not Marijuana smokers were trained to cigarette to produce effects that were produce tolerance. The abstinence discriminate smoked marijuana from similar to the high THC dose cigarette syndrome was not limited to subjective placebo using 4 puffs of a 2.7%-THC (Azorlosa et al., 1992). There were state changes but was also quantified cigarettes. Subjective ratings of ‘‘high’’, nearly identical THC levels produced by using a cognitive/memory test battery. and physiological measures (i.e., heart 10-puff low-THC cigarette (98.6 ng/ml) rate) were significantly and dose- In a related study, Khouri et al (1999) and 4-puff high THC cigarette (89.4 ng/ dependently increased after smoking the found that long-term heavy marijuana ml). Similarly, the subjective effects 0.9%, 1.4%, 2.7%. ratings, including high, stoned, users became more aggressive during Marijuana cigarettes containing 1.4% abstinence from marijuana than did impaired, confused, clear-headed and THC completely substituted for 2.7%- sluggish, produced under the 10 puff former or infrequent users. Previous THC on drug identification tasks, dependence studies have relied largely low- and high-THC and 25 puff low- however, 0.9%-THC did not. The THC conditions did not differ on patients’ subjective reports of a range authors found that the onset of of symptoms. Khouri et al. examined a significantly from each other. discriminative stimulus effects was As with most drugs of abuse, higher single symptom—aggression. The within 90 seconds after smoking began authors concluded that marijuana doses of marijuana are preferred over (after the first two puffs). Since the lower dose. Although not preferred, abstinence is associated with unpleasant 1.4%-THC cigarette substituted for 2- these lower doses still produce behavioral symptoms that may puffs of the 2.7%-THC cigarette, the cannabimimetic effects. Twelve regular contribute to continued marijuana use. authors estimate that an inhaled dose of marijuana smokers participated in a Kouri & Pope (2000) examined three THC as low as 3 mg can produce study designed to determine the groups of marijuana users during a 28- discriminable subjective effects. preference of a low potency (0.64%- day supervised abstinence period. Similarly, Lukas et al. (1995) reported THC) vs. a high potency (1.95%-THC) Current marijuana users experienced that marijuana cigarettes containing marijuana cigarette (Chait and Burke, significant increases in anxiety, either 1.26% or 2.53% THC produced 1994). The subjects first sampled the irritability, physical tension, and significant and dose-dependent marijuana of two different potencies in physical symptoms and decreases in increases in level of intoxication and one session, then chose which potency mood and appetite during marijuana euphoria in male occasional marijuana and how much to smoke. During withdrawal. These symptoms were most smokers. Four of the six subjects that sampling sessions, there were pronounced during the initial 10 days of smoked the 1.26%-THC cigarette significant dose-dependent increases in abstinence, bust some were present for reported marijuana effects and 75% of heart rate and subjective effects, the entire 28-day withdrawal period. these subjects reported euphoria. All six including ratings of peak ‘‘high’’, The findings from this study reveal that of the subjects that smoked 2.53% THC strength of drug effects, stimulated, and chronic heavy users of marijuana reported marijuana effects and euphoria. drug liking. During choice sessions, the experience a number of withdrawal Peak levels of self-reported intoxication higher dose marijuana was chosen over symptoms during abstinence and clearly occurred at 15 and 30 minutes after the lower dose marijuana on 87.5% of smoking and returned to control levels demonstrate a ‘‘marijuana dependence occasions. Not surprising, there was a by 90–105 minutes. There was no syndrome’’ in humans. significant positive correlation between difference between latency to or the total number of cigarettes smoked These data suggest that dependence duration of euphoria after smoking and the ratings of subjective effects, on THC may in fact be an important either the 1.26% or 2.53% THC strength of drug effect, drug ‘‘liking’’, consequence of repeated, daily exposure cigarettes. The higher dose-marijuana expired air carbon monoxide, and heart to cannabinoids and that daily cigarette produced a more rapid onset rate increases. The authors state it is not marijuana use may be maintained, at and longer duration of action than the necessary valid to assume that the least in part, by the alleviation of lower dose marijuana cigarette (1.26% preference observed in the present study abstinence symptoms. Relevant to the THC). Plasma THC levels peaked 5–10 for the high-potency marijuana was due present petition, the Haney et al. study minutes after smoking began; the to greater CNS effects from its higher is the first report demonstrating this average peak level attained after the THC content. The present study found syndrome with extremely low low- and high-dose marijuana cigarette that the low- and high-potency concentrations of THC. was 36 and 69 ng/ml respectively. marijuana cigarettes also differ on
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several sensory dimensions; the high- results in a functional potentiation of Other studies have reported that potency THC was found to be reported THC’s behavioral and subjective effects. cannabidiol has cannabinoid properties, as ‘‘fresher’’ and ‘‘hotter’’. Other studies This potentiation can be in both the including anticonvulsant effects in found that marijuana cigarettes intensity and/or duration of the high animal and human models (Consroe et containing different THC contents induced by marijuana. According to al., 1981; Carlini & Cunha, 1981; Doyle varied in sensory dimensions (cf., Chait Paris & Nahas (1984) the CBD:THC ratio and Spence, 1995), hypnotic effects et al., 1988; Nemeth-Coslett et al., 1986). in industrial or fiber type hemp is 2:1. (Monti, 1977), anxiolytic effects (Musty, As summarized by Martin & Hall for Relevant to the current petition, the 1984; Onaivi, Geen, & Martin, 1990; the United Nations only a small amount CBD:THC ratio producing the greatest Guimara˜res et al., 1990; 1994) and rate- of cannabis (e.g. 2–3 mg of available increase in euphoria in the Karniol, et decreasing effects on operant behavior THC) is required to produce a brief al. studies was 2:1 (60:30 mg). (Hiltunen et al., 1988). pleasurable high for the occasional user Jones & Pertwee (1972) were first to Experiments with cannabidiol in and a single joint may be sufficient for report that the presence of cannabidiol combination with THC have found that two or three individuals. Using these inhibited the metabolism of THC and its certain behavioral responses induced by data and those of Harder & Reitbroch active metabolite. These data were soon THC (i.e., operant, schedule-controlled (1997, above), a one gram cigarette replicated by Nilsson et al., (1973). responding) were attenuated by containing 1% THC containing Bronheim et al., (1995) examined the cannabidiol (Borgen and Davis, 1974; cannabis, would contain 10 mg of effects of CBD on the pharmacokinetic Brady and Balster, 1980; Consroe et al., THC—a dose well capable of producing profile of THC content in both blood 1977; Dalton et al., 1976; Kraniol and a social high. and brains of mice. CBD pretreatments Carlini, 1973; Karniol et al., 1974; Carlini et al. (1974) examined 33 produced a modest elevation in THC- Welburn et al., 1976; Zuardi and subjects who smoked marijuana blood levels; area under the kinetics Karniol, 1983; Zuardi et al., 1981, 1982; cigarettes with different ratios of curve of THC was increased by 50% as Hiltunen et al., 1988). However, other constituent cannabinoids. The plant a function of decreased clearance. CBD affects produced by THC are augmented containing 0.82% THC produced larger pretreatments also modestly increased or prolonged by the combined than expected results based on the the C , AUC, and half-life of the major administration of CBD and THC or estimates from the THC content. max THC metabolites in the blood. The THC marijuana extract (Chesher and Jackson, Smoking a 250 mg cigarette 1974; Hine et al., 1975a,b; Fernandes et containing 5.0 mg of ∆9-THC induced kinetics function showed a 7- to 15-fold increase in the area under the curve, a al., 1974; Karniol and Carlini, 1973; more reactions graded 3 and 4 than 10 Musty and Sands, 1978; Zuardi and or 20 mg of ∆9-THC. It was further 2- to 4-fold increase in the half-life, as well as the t . CBD pretreatments Karniol, 1983; Zuardi et al., 1984). Still observed that the psychological effects max other studies did not report any resulted in large increases in area under (subjective ‘‘high’’) started around 10 behavioral interaction between the CBD the curves and half-lives of all the THC min after the end of the inhalation, and and THC (Bird et al., 1980; Browne and metabolites in the mice brains. The reached a maximum 20 to 30 min later, Weissman, 1981; Hollister and inhibition of the metabolism of THC and subsiding within 1 to 3 hrs. The peak of Gillespie, 1975; Ja¨rbe and Henricksson, its psychoactive metabolites by CBD psychological disturbances, therefore, 1974; Ja¨rbe et al., 1977; Mechoulam et may underlie the potentiation in the did not coincide in time with the peak al., 1970; Sanders et al., 1979; Ten Ham subjective effects of THC by CBD in of pulse rate effects. Carlini et al., and DeLong, 1975). suggested that other constituents of the humans. A study to characterize the interaction marijuana were interacting In addition to THC, hemp material between CBD and THC was conducted synergistically with the THC to contains a variety of other substances using preclinical drug discrimination potentiate the subjective response (e.g., Hollister, 1974), including other procedures. Rats and pigeons trained to induced by the smoking of the cigarette. cannabinoids such as cannabidiol (CBD) discriminate the presence or absence of Karniol and colleagues (1973, 1974) and cannabinol (CBN). One THC, and tested with CBD administered have clearly demonstrated that comprehensive review described the alone and in combinations with THC cannabidiol (CBD) blocks some of the activities of 300 cannabinoid compound (Hiltunen and Ja¨rbe, 1986). effects induced by THC, such as in preclinical models (Razdan, 1986). Specifically, in rats trained to increased pulse rates and disturbed time Since CBD is always present in discriminate 3.0 mg/kg, i.p. THC, CBD perception. More importantly, CBD preparations of cannabis, it may (30.0 mg/kg) was administered alone blocked some of the psychological represent a high CBD:THC ratio in the and in combination with THC (0.3 and effects of THC, but not by altering the case of low THC cannabis. Therefore, it 1.0 mg/kg, i.p.). In pigeons trained to quantitative or intensity of the is important to understand the discriminate 0.56 mg/kg, i.m. THC, CBD psychological reactions. CBD seemed interactions of cannabidiol and ∆9-THC. (17.5 mg/kg) was administered alone better able to block the aversive effects Structure-activity studies of and in combination with THC (0.1, 0.3, of THC. CBD changed the symptoms cannabinoid compounds characterized and 0.56 mg/kg, i.m.). CBD prolonged reported by the subjects in such a way cannabidiol in relationship to ∆9-THC the discriminative stimulus effects of that the anxiety component produced by and other cannabinoids (Martin et al., THC in rats, but did not change the THC administration was actually 1981; Little et al., 1988). These and time-effect curve for THC in pigeons. In reduced. The animal subjects of one other studies have found that pigeons, the administration of CBD did study showed greater analgesia scores cannabidiol was inactive and did not not produce any differential effect under with a CBD+THC combination (1973) produce neuropharmacological effects a fixed ratio schedule of reinforcement and the human subjects from the other or discriminative stimulus, subjective (Hiltunen and Ja¨rbe, 1986). study (1974) showed less anxiety and effects and behavioral effects predictive These data suggest that CBD may panic but reported more pleasurable of psychoactive subjective effects somehow augment or prolong the effects. CBD may be best seen as an (Howlett, 1987; Howlett et al., 1992; c.f., actions of THC in rats and had no effect ‘‘entourage’’ compound (Mechoulam, Hiltunen and Ja¨rbe, 1986; Perez-Reyes et in pigeons. In the present study, the Fride, DiMarzo, 1998) which is al., 1973; Zuardi et al., 1982; Karniol et CBD/THC ratios ranged from 30:1 to administered along with THC and al., 1974). 100:1 in rats and enhanced the stimulus
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effects of THC. However, similar CBD/ profile of the abuser of specific lesser amounts from Colombia and THC ratios in pigeons (31:1, 58:1 and substances (cf., Larsen et al., 1995). Jamaica (NNICC, 1996). 175:1) did not result in any changes to Evidence of actual abuse is defined by Domestically, marijuana is distributed THC’s discriminative stimulus or episodes/mentions in the databases by groups or individuals, ranging from response rate effects (Hiltunen and indicative of abuse/dependence. Some large sophisticated organizations with Ja¨rbe, 1986). of the databases that are utilized by DEA controlled cultivation and interstate It should be noted that cannabidiol to provide data relevant to actual abuse trafficking, to small independent can be easily converted to delta-9- and of a substance include the Drug Abuse traffickers at the local level. delta-8-tetrahydrocannabinol. Even Warning Network (DAWN), National industrial hemp plant material (leaves), Household Survey on Drug Abuse, (2) Scientific Evidence of Its containing high concentrations of CBD, Monitoring the Future survey, FDA’s Pharmacological Effects, If Known can be treated in clandestine Spontaneous Adverse Events Reports, Cannabis sativa is unique in that it is laboratories to convert the CBD to delta- the American Association of Poison the only botanical source of the 9-tetrahydrocannabinol (Mechoulam, Control Centers database and reports of terpenophenolic substances referred to 1973) converting a supposedly the Community Epidemiology Work as cannabinoids which are responsible innocuous weed into a potent smoke Group (CEWG). for the psychoactive effects of Cannabis. product. Drug trafficking and diversion data There are roughly 60 different In conclusion, the ‘‘entourage’’ provide strong evidence that a drug or cannabinoids found in Cannabis (Nahas, compound, cannabidiol, does contribute other substance is being abused. In 1984; Murphy & Bartke, 1992; Agurell, to all of the effects ascribed to THC, order to determine the pattern, Dewey & Willette, 1984) but the however it also appears to lack incidence, and consequences of abuse psychoactive properties of Cannabis are cannabimimetic properties. However, and the demographics of abusers of a attributed to one or two of the major there is no credible scientific evidence particular substance to be controlled, cannabinoid substances, namely delta-9- that CBD is a pharmacological DEA relies on data collected from a tetrahydrocannabinol and delta-8- antagonist at the cannabinoid receptor number of sources, including the United tetrahydrocannabinol. In fresh, carefully (Howlett, Evans, & Houston, 1992). States government as well as state and dried marijuana, up to 95% of their There is clear evidence that CBD can local law enforcement groups. cannabinoids are present as (-)-delta-9- functionally antagonize some of the Information from these sources often (trans)-tetrahydrocannabinol carboxylic aversive effects of THC (Dewey, 1986). provides a first indication of an acid (Nahas, 1984; Murphy & Bartke, The data from the scientific literature emerging pattern of abuse of a particular 1992; Agurell, Dewey & Willette, 1984). cited above, clearly demonstrate the drug or substance, and when taken The acid form is not psychoactive, but ability of CBD to modify some very together with other data sources provide is readily decarboxylated upon heating specific effects of THC. Most strong evidence that can be used in to yield delta-9-tetrahydrocannabinol importantly, relative to the euphorigenic determining a substance’s placement in (neutral form). Therefore, plant material effects of THC (which contributes to its the schedules listed in the CSA. could be very high in its ‘‘pro-drug’’ abuse liability), CBD appears to The evidence from epidemiological acid form and very low in neutral form potentiate the psychological or studies conclude that marijuana use but still be very potent when smoked. subjective effects of THC by potentiating alone and in combination with other There are two primary factors that the blood and brain THC and 11-OH- illicit drugs is increasing. The most influence THC content: genetic THC levels and by functionally blocking recent ‘‘Monitoring the Future Study’’, predisposition and environmental the aversive (anxiety-like) properties of documented increases in lifetime, influences. Genetic factors are THC. annual and current (within the past 30 days) and daily use of marijuana by considered predominant in determining Abuse Liability Summary eighth and tenth graders; this increasing cannabinoid content, although, Preclinical and clinical experimental trend began in the early 1990’s. fluctuations in weather conditions have data demonstrate that marijuana and Similarly, according the NIDA’s greatly enhanced or diminished the ‘‘∆9-THC have similar abuse liabilities ‘‘National Household Survey’’, THC content. (i.e., drug discrimination, self- marijuana use is increasing with the Paris & Nahas (1984) have administration, subjective effects). Both greatest increase among the younger age admonished that marijuana is not a preclinical and clinical studies show groups (12–17 years of age). The single uniform plant like many of those that discontinuation of either marijuana frequency of marijuana use in the past encountered in nature, but a rather or ‘‘∆9-THC administration produces a year increases significantly among 12– deceptive weed with several hundred mild withdrawal syndrome. The effects 17 year olds. This survey also found that variants. The intoxicating substances of THC are dose-dependent and several youths who used marijuana at least once prepared from Cannabis vary studies have found that low-potency in their lives were more likely to engage considerably in potency according to THC is behaviorally active and can in violent or other antisocial behaviors. the varying mixtures of different parts of produce cannabimimetic-like subjective Marijuana is the most readily the plant, and according to the and physiological effects. available illicit drug in the United techniques of fabrication. According to States. Cannabis is cultivated in remote Paris & Nahas, this basic botanical fact Actual Abuse locations and frequently on public has been overlooked by physicians and There are dozens of data collection lands. Major domestic outdoor cannabis educators, who have written about and reporting systems that are useful for cultivation areas are found in California, marijuana as a simple, single substance, monitoring the United States’ problem Hawaii, Kentucky, New York and which uniformly yields a low with abuse of licit and illicit substances. Tennessee. Significant quantities of concentration of a single intoxicant. In These data collection and reporting marijuana were seized from indoor addition to changes due to its own systems provide quantitative data on cultivation operations; there were 3,532 genetic plasticity, marijuana has been many factors related to abuse of a seizures in 1996 compared to 3,348 modified throughout the ages by particular substance, including seized in 1995. Mexico is the major environmental factors and human incidence, pattern, consequence and source of foreign marijuana, along with manipulations, and is not yet a
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stabilized botanical species (Paris & does not seem to be dependent upon 25). The lower, more developed leaves Nahas, 1984). environmental conditions. have a low cannabinoid content and the According to Paris & Nahas (1984) the 5. However, growing the same strain top leaves have a high cannabinoid terminology used by Fetterman et al. of Cannabis under different lighting content, especially when they are (1970, 1971) is somewhat misleading, conditions can produce plants that associated with the bracts of the plant. especially with respect to their range from 2.4 to 4.42% THC Cannabinoids are localized in the upper contention that environmental factors, concentration (based upon an analysis third of the ‘‘stalk’’ and in the flowers. including climate, are not as important of the upper leaves). And finally, Therefore, the THC content of specific as heredity in determining the 6. THC concentration are dramatically portions of a plant, which on a whole cannabinoid content of cutigens. The higher on dried flowering or vegetative plant basis did not exceed 1%, could analyses of Fetterman et al., (1970) were tops of the plants relative to middle or significantly exceed this threshold. Very performed according to the technique by lower portions. few marijuana users actually ‘‘smoke’’ Doorenbos et al., (1971) on plant In a similar study on the the leaves. It is the colas or the materials from variants that had been characterization of Cannabis accessions flowering portions of the plants which cut at the stem beneath the lowest with regard to cannabinoid content, vis- are utilized and these are exactly the leaves and air-dried. Seeds, bracts, a-vis other plant characters (deMeijer, portions of the plant which would be flowers, leaves and small stems were 1992), it was determined that: expected to have the highest then stripped from the plant. Most of 1. There exists considerable variation concentration of THC. the small stems were removed by a 10- within and among accessions for It is clearly recognized that Cannabis mesh screen, and the seeds were cannabinoid content; presents a high degree of genetic eliminated with a mechanical seed 2. Mean cannabinoid content is plasticity which results in extreme separator. This preparation of marijuana strongly affected by year of cultivation; polymorphism in its different varieties. contains less seed and stem than most 3. There is no strict relationship The hemp first grown in the United of the illicit material available in the between chemical and non-chemical States for fiber was of European origin. United States. Cannabinoids were then traits; and, The type basic to modern American extracted from the plant material and 4. It is uncommon, but some fiber production, known as Kentucky, analyzed by standard techniques. accessions combine high bark fiber came originally from China. In Europe, Other systems of separating Cannabis content and considerable psychoactive there are five to six varieties with one into drug, intermediate and non-drug potency. considered ‘‘exceptional’’—the type have been developed. These are In 1993 de Meijer reported the results Kymington. The plasticity of the typically determined by chemical of a government (Netherlands) funded European fiber variety has been clearly analyses based upon the method industrial hemp project designed to shown (Bouquet, 1951; Hamilton, 1912, described by Doorenbos (1971) which investigate the stem quality, yield, and 1915). European cultigens planted in utilizes manicured portions of the a comparative analysis to wood fibers. dry, warm areas of Egypt to supply fiber Cannabis plant only in determining deMeijer found that the commercial for rope-making were found to produce, percent concentration. grade industrial hemp seeds, Cannabis sativa has been referred to within several generations, plants with germplasms derived from <0.3% THC high psycho-active ingredients and very as a widely distributed and unstabilized chemovars, demonstrated a significant species. Cannabis exhibits extreme little fiber. Cannabis sativa’s botanical variation in the average THC content and chemical characteristics change polymorphism (ability to alter, change) which ranged from 0.06 to 1.77% in the in different varieties, dependent upon markedly as a result of environmental female dry leaf matter. deMeijer factors and human manipulation. many factors. For example, there are at concluded by stating, least twenty strains which are cultivated Doorenbos et al., (1971) cultivated a for fiber. There have been many Although high bark fiber content does not Mexican and Turkish variant in necessarily exclude high THC content, most attempts to classify Cannabis as a Mississippi for three consecutive fiber cultivars have very low THC content generations. During that period, the ∆9- function of intoxicant properties or fiber and thus possess no psychoactive potency properties. Such classification efforts THC content did not change in the are dependent upon the age of the While the data from his own study Mexican variant but increased in the sample. And there is no totally reliable refutes these conclusions he does Turkish variant. In the more controlled classification system based on a single conclude that the industrial hemp plant environment of a phytotron (light, chemical analysis. The plasticity of the does not preclude high THC content. humidity, and nutrition controlled), genus has prevented the development of A review of these and other studies in Braut-Boucher (1978), Braut-Boucher & such a system (Turner et al. 1980a,b). the scientific literature, indicate that Petiard (1981), Braut-Boucher, Paris, & In a study where twelve strains of THC concentrations vary within Cosson (1977) and Paris et al., (1975) Cannabis were grown out of doors in portions of the Cannabis plant (Hanus et found that the cannabinoid Southern England (Fairbairn and al., 1989, 1975). In some studies, the concentrations rose over a similar three Liebmann, 1974, Fairbairn et al., 1971), concentration of THC can increase as year period. The concentrations rose the following were determined: much as 100% from leafy to flowering more sharply in cool environments (22– ° 1. Warm climate are not necessary for portions of the same plant. THC 12 C: day-night) than in warm ° high THC content. concentrations are known to be elevated environments (32–12 C). Some authors 2. There is considerable THC content on the upper portions of the plant. In a have hypothesized that immediate variation within and between plants. study published by Fairbairn and environmentally caused changes are 3. Quantitative results of Liebmann, (1974) there was individual plant reactions, whereas the tetrahydrocannabinol concentration considerable variations between the progressive changes over generations are (THC) are highly dependent upon the flowering tops (bracts, flowers, linked with whole populations and specific plant part sampled, the stage of immature fruits at the ends of shoots) constitute a true natural selection. growth and the size of sample. and leafy portions of some specimens. Whether this evolution is caused by a 4. Certain strains of Cannabis can be THC content decreases with age and change of genetic equilibrium (caused THC or cannabidiol (CBD) rich which length of leaves (Paris & Nahas, 1984, p by the environment), or by a
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modification of the genetic capacity have described a number of biological high’’. Further, they found (over time), is impossible to say (Paris psychological factors (expectancy, social that as little as 1 mg of absorbed THC & Nahas, 1984). setting, etc.) that appear to was discriminable by all of their chronic In 1974 through 1976 the University synergistically interact to help generate user subjects. of Mississippi cultivated 7 variants of 12 the subjective experiences engendered In 1982, Barnett, Chiang, Perez-Reyes, Cannabis plants discovered and by marijuana smoking. & Owens had six subjects smoke a 1% collected in 1973 from different areas of Domino, Rennick, & Pearl (1976) THC-containing (industrial hemp, as Mexico. Cannabinoid content was administered THC injected into tobacco defined by the petitioner) marijuana analyzed weekly during the cultivation cigarettes to male volunteers. Similar to cigarette. Significant heart rate and period. Turner, Elsohly, Lewis, Lopez- findings described by Isbell et al., (1967) subjective measures of ‘‘high’’ were Santibanez & Carranza (1982) they report that 50 µg of THC into the measured for 2 hours after each summarized their findings as follows: cigarettes produced a ‘‘social high’’, cigarette. µ In 1974, vegetative plants of ME–H, ME– while 250 g/kg was ‘‘hallucinogenic’’. In 1971 Jones reported on the wide K, ME–L, ME–N and ME–O, at 13 weeks of Taking 80 kg as the mean weight of their variability in THC concentrations found age had higher ∆9-THC content that at weeks subjects the authors concluded that a in street samples: ∆9 12 and 14. They showed minimum -THC 4.0 mg total THC dose produced a Specimens gathered in the midwestern content at week 15. For the most part, 1974 ‘‘social high’’; a hallucinogenic dose United States contained only 0.1—0.5% staminate and pistillate plants grown in was 20 mg total THC by inhalation. A THC. Thirty specimens selected from seized ∆9 Mississippi produced a low -THC standard 1g cigarette of 1% THC fibre- samples in the Bureau of Narcotics and concentration * * *. type hemp provides 10 mg of THC. Even Dangerous Drugs Laboratory in San Francisco In all variants, the average ∆9-THC allowing for a 50% loss of THC from all contained less than 1% THC. Samples was higher in 1976 than in 1974. Also, sidestream smoke and pyrolysis, from the State of California Bureau of a greater fluctuation of ∆9-THC was Narcotic enforcement analyzed in our smoking this cigarette provides more laboratory contained as little as 0.1% THC observed in 1976 than in 1974. than enough THC to produce a ‘‘social and a maximum of 0.9% * * * In a survey These results further establish that high’’. done in Ontario, Canada, Marshman and Cannabis Sativa L. is not a stable hybrid In 1968 Weil, Norman, & Nelsen Gibbons found that of 36 samples alleged to plant, but rather, represents described a set of studies examining the be marijuana with high cannabinoid content, characteristics more similar to an physiological and psychological aspects 34% contained no marijuana at all, and much unstable weed. of smoked marijuana. The first batch of of the rest was cut with other plant Marijuana chemistry is complex and Mexican grown marijuana used in the substances. A generous assumption is that cannot be simplified or extrapolated marijuana generally available in the United study was found to contain only 0.3% States averages about 1.0% THC. from any one or two ‘‘active THC by weight. The potency of this compounds’’. As early as 1974 this fact product was considered to be ‘‘low’’ by It must be acknowledged that the THC was recognized by the United Nations the experimenters on the basis of the content of domestically grown and Division on Narcotic Drugs (UN Doc, doses needed to produce symptoms of imported marijuana has increased since 1974). As highlighted by Turner (1980), intoxication in the chronic users. This these reports. However, the description the chemistry of THC is not the low potency marijuana was able to by Weil, Zinberg & Nelson (1968), chemistry of marijuana and the produce a ‘‘high’’, but only with two 1 Agurell & Leander (1971), Jones (1971) pharmacology of marijuana is not the gram cigarettes. A second batch was and Barnett et al. (1982) highlight the pharmacology of THC. Recent findings used in later studies. Weil, Norman, & historical importance of low THC do suggest that the interactions between Nelsen report that marijuana assayed at concentrations contained in marijuana cannabinoids is one of many critical 0.9% THC (a quantity slightly less than which provided the basis for the factors in the analysis of the the 1% THC limit set forth by the marijuana culture that developed in the psychopharmacology of marijuana. petitioners) was rated by the chronic 1970s. The incident described by Jones According to Jones (1980), because of users in the study to be ‘‘good, average’’ was not an isolated case of the exposure to a wide range of plant marijuana, neither exceptionally strong inadvertent misrepresentation of the material and the cultural labeling nor exceptionally weak compared to the THC content of marijuana extracts. (almost like advertising) of much of the usual supplies. Users consistently Caldwell et al., (1969) found that the marijuana experience, marijuana users reported symptoms of intoxication after NIMH-supplied marijuana that they are particularly subject to the effects of smoking about 0.5 grams of the 0.9% reported to have contained 1.3% THC nonpharmacological variables that alter THC containing marijuana (half a joint). was analyzed by two independent the subjective response to marijuana With the high dose of marijuana (2.0 laboratories and found to contain as intoxication (Jones 1971, 1980; Cappell grams of 0.9% THC containing little as 0.2 to 0.5% THC. Similarly, & Pliner, 1974; Becker 1967). As marijuana) all chronic users became according to Paton & Pertwee (1973) the reviewed by Jones (1971), a number of ‘‘high’’ by their own accounts and in the THC content of material used by Clark studies suggest that experienced judgment of experimenters who had & Nakashima (1968), Weil et al., (1968), marijuana users are more subject to observed many persons under the Weil & Zinberg (1969), and Crancer et ‘‘placebo reactions’; that is, a degree of influence of marijuana. al., (1969) must be expected to be one- intoxication disproportionate to the Agurell & Leander (1971) examined third to one-sixth less than stated. This THC content of the material. This seems the physiological and psychological means that the positive results of all of particularly true if the individuals are effects of low THC-containing cannabis these studies were the result of a exposed to low potency marijuana in experienced users. They reported that surprisingly low THC-containing (<1.0% THC). Jones believes that this is 14–29% of the cannabinoid content of (<1.0%) marijuana. The early scientific a result of experience and practice at the cigarette was transferred to the main data on the subjective effects of recognizing minimal physiologic cues stream smoke. Based on qualitative and marijuana were generated with these together with the smell, taste and other quantitative analyses, Agurell & Leander samples by experienced smokers sensations associated with smoking a demonstrated that as little as 3–5 mg of smoking material in this potency range. marijuana cigarette (Jones 1980, 1971). THC was needed to be absorbed by the These experienced marijuana smokers Becker 1967 and Cappell & Pliner (1974) lung in order to produce a ‘‘normal were reporting that these marijuana
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samples were of ‘‘average quality’’ meter test, delayed auditory feedback, absorption a difficult problem for (Mechoulam, 1973). verbal output, reverse reading, reverse pharmacologists. Many different In an early study, Jones (1971) counting, progressive counting, simple methods for suspending, solubilizing, or utilized 1 gram of plant material with a addition, subtraction, addition +7, emulsifying ∆9-THC have been used. THC concentration of 0.9% (9 mg of subtract +7, and color differentiation. None of these methods are without THC). Experienced marijuana smokers These low potency cigarettes also difficulty and without influence on were asked to freely smoke marijuana produced significant pulse rate absorption and pharmacological cigarettes for 10 minutes. The smoking increases and significant increases on a activity. The fact that many methods topography of the smokers widely somatic symptoms checklist. have been used by various investigators varied and was not controlled in this set Unsolicited verbal comments from the makes quantitative comparisons of experiments. Subjects were asked to subjects verified that the subjects were difficult. smoke the entire cigarette. Subjective ‘‘high’’ on these low potency marijuana ∆9-THC is the primary active state was measured by asking the cigarettes. ingredient of marijuana that produces subjects to make global estimates of his Kiplinger, Manno, Rodda, Forney, the subjective ‘‘high’’ associated with degree of intoxication on a 0–100 scale. Haine, Ease, & Richards (1971) smoking the plant material and is the A score of 0 was defined as ‘‘sober’’ and conducted a randomized block, double- chemical basis for cannabis abuse. a score of 100 as the most intoxicated blind study designed to establish a dose- Studies in several species of laboratory or most ‘‘stoned’’ they had ever been in response analysis of the THC content in animals, including rhesus monkeys, rats any social situation. At the end of the marijuana using a variety of behavioral and pigeons, have found session (about 3 hrs), the subject also and subjective effects measures. pharmacological specificity for ∆9-THC filled out a 272-item symptom checklist Marijuana cigarettes were manufactured at the cannabinoid receptors, and for (SDEQ: subjective drug effects to deliver doses of 0, 6.25, 12.5, 25, and cannabinoid drugs that bind with high questionnaire) which taps some of the 50 µg/kg of ∆9-THC. Based on an average affinity to brain cannabinoid receptors, more unusual emotional, perceptual and 70 kg man, the total delivered doses of and is psychoactive in humans and cognitive effects produced by THC were 0, 0.43, 0.875, 1.75, and 3.5 animals (Browne and Weissman, 1981; psychoactive drugs. The mean potency mg. Based on the assumption of a 50% Balster and Prescott, 1992; Compton et rating was 61 for the marijuana loss of THC from pyrolysis and al., 1993; Wiley et al., 1995a,b). In containing only 9 mg of THC. There was sidestream smoke these doses would be general, the doses that produce its acute a tremendous range in the rating made equivalent to smoking cigarettes therapeutic effects and its by individual smokers. Jones concluded containing 0, 0.08%, 0.16%, 0.3%, and cannabimimetic effects are similar that the smokers may obtain 0.7% THC containing hemp. The lower (Devine et al., 1987; Consroe and intermittent reinforcement from THC concentrations of THC were used Sandyk, 1992). but where much of the behavior and because these doses are found in the Central Nervous System Effects subsequent response is maintained by weaker ‘‘hemp’’ or fiber type marijuana ‘‘conditioned reinforcers’’ such as the commonly grown in the United States. It has been reported that in man, whole ritual of lighting up, the All doses of THC, including the two doses above 1 milligram of ∆9-THC associated stimuli of smell, taste, visual lowest doses, increased the subjective absorbed by smoking marijuana are stimuli and so on. ratings on both the ARCI and Cornell sufficient to cause a ‘‘high’’ (Agurell et Manno, Kiplinger, Haine, Bennett, & Medical Indexes, produced heart-rate al., 1986). Further, Agurell et al. (1986) Forney (1970) asked subjects to smoke increases, increased motoric decrements suggested based on mouse data, that a an entire 1 gram cigarette containing 1% in pursuit meter, and produced pronounced ‘‘high’’ would be caused by THC (10 mg; low potency). The subjects decrements in mental performance the presence of as little as 10 were told to take 2 to 4 seconds to using the delayed auditory feedback micrograms of ∆9-THC in the brain, inhale and to hold the draw for 30 to 60 test. Most importantly, 80% of subjects immediately after smoking a marijuana seconds. The expired smoke was correctly identified the lowest dose cigarette. These conclusions, based on a collected and analyzed for THC content, (6.25 µg/kg; 0.43 mg THC) as active diverse array of pharmacokinetic as well. During the experiment the marijuana. The authors suggested that studies, suggest that ‘‘fiber-type’’ subjects smoked the entire cigarette; in even lower doses might have marijuana clearly has the capacity to all cases, less than 0.5 mg of THC measurable effects. Holtzman (1971) has deposit these levels of THC into the remained in the residue of each suggested that one of the best predictors brain of man soon after smoking a 1% cigarette. Manno et al. reported that the of a drug’s abuse liability is the THC-containing marijuana cigarette quantity of THC or other cannabinols identification of the substance as ‘‘drug- (assuming the typical ‘‘joint’’ of 1 g, present in a marijuana cigarette was not like’’ by experienced drug users. The with 10mg THC). ∆9-THC exerts its most a reliable indicator of the amount of identification of the lowest dose of prominent effects on the CNS and the cannabinols that were delivered in the marijuana in the Kiplinger et al. and the cardiovascular system. smoke of the cigarette. Controlled other studies, discussed above, clearly Administration of ∆9-THC via smoked smoking experiments through a suggests that industrial ‘‘fiber-type’’ cannabis is associated with decrements manufactured smoking machine marijuana has abuse potential. in motivation, cognition, judgement, demonstrated that approximately 50% Many of the studies examining the memory, motor coordination, and of the ∆9-THC originally present in the behavioral effects of marijuana in alterations in perception (especially cigarette was delivered unchanged in animals have chosen to administer THC time perception), sensorium, and mood the smoke. Manno et al. concluded that because of the difficulties in controlling (cf., Jaffe, 1993). Most commonly ∆9- a dose of approximately 5 mg of ∆9-THC and administering exact doses within THC produces an increase in well-being was delivered which was estimated to and between subjects when using and euphoria accompanied by feelings be an administered dose in the range of pyrolyzed forms of marijuana to of relaxation and sleepiness. The 50 to 75 µg per kilogram. These low animals. Accurate small-animal smoke consequences produced by ∆9-THC- potency marijuana cigarettes produced delivery systems are not yet available. induced behavioral impairments can significant motor and mental The lack of water solubility of ∆9-THC greatly impact the public health and performance measures on the pursuit has made its administration and safety, given that individuals may be
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attending school, working, or driving a intermediate levels of reactive oxygen once a day for years) cannabis smokers. motor vehicle under the influence of the species. A brief, 30-minute exposure to Moreover, cannabis increases the risk of drug (i.e., marijuana). marijuana smoke, regardless of the THC head and neck cancer in a dose- Preclinical studies show that ∆9-THC content, also induced necrotic cell death response manner for frequency and produces decrements in short-term that increased steadily up to 48 hours duration of use. THC seems to have a memory, as evidenced by disruptions in after administration. Sarafian et al., specific carcinogenic effect different acquisition and performance of maze concluded that marijuana smoke from that of the pyrolysis products behavior, conditioned emotional containing THC is a potent source of produced by (nicotine) cigarette responses, and passive avoidance cellular oxidative stress that could smoking. responses, impairment on the retention contribute significantly to cell injury (3) The State of Current Scientific in delayed matching and alternation and dysfunction in the lungs of Knowledge Regarding the Drug or Other tests, and increases in resistance to smokers. extinction (Drew and Miller, 1974, The low incidence of carcinogenicity Substance Nakamura et al., 1991; Ja¨arbe and may be related to the fact that In general, the petitioner argues that Mathis, 1992; Lichtman and Martin, intoxication from marijuana does not the chemistry, toxicology and 1996). Recent studies in rats found that require large amounts of smoked pharmacology of marijuana has been these ∆9-THC-induced impairments in material. This may be especially true subjected to extensive study and peer spatial working memory were reversible today since marijuana has been reported review, and have been well after long abstinence (Nakamura et al., to be more potent now than a generation characterized in the scientific literature. 1991) and can be blocked by the ago and individuals typically titrate In addition, the discovery of the cannabinoid receptor antagonist their drug consumption to consistent cannabinoid receptor has shed new light SR141716A (Lichtman and Martin, levels of intoxication. However, several on the effects of marijuana and its 1996). cases of lung cancer in young marijuana mechanism of action. Memory disturbances are one of the users with no have been reported (Fung The literature cited by the petitioner well-documented effects of ‘‘∆9-THC et al., 1999). (Tashkin et al., 1987, 1988, 1990, 1991, and marijuana on human behavior However, a recent study (Zhang et al., 1993; Barbers et al., 1991; Sherman et (Mendelson et al., 1974; Jaffe, 1993; 1999, below) has suggested that al., 1991a, 1991b; Wu et al., 1992) Hollister, 1986; Chait and Pierri, 1992). marijuana use may dose-dependently provide data about the effects of Clinical investigators of ∆9-THC and interact with mutagenic sensitivity, marijuana smoke on the lungs, which, marijuana’s effects in memory have cigarette smoking and alcohol use to by the petitioner’s own admission, is suggested that the drug produces a increase the risk of head and neck inherently unhealthy. Data show that deficit in memory for recent events, and cancer. THC is known to suppress smoking marijuana is associated with inhibition of the passage of memory macrophage natural killer cells and T- more tar than cigarettes and holding from short-term to long-term storage lymphocytes and reduce resistance to your breath (a common practice of (Drew and Miller, 1974; Darley 1973a,b). viral and bacterial infections. As shown marijuana smokers) increases carbon Heishman, Huestis, Henningfield, & below, Zhu et al., demonstrated that monoxide concentration. His assertion Cone (1990) demonstrated cognitive THC probably interacts with the T-cell that Schedule I policy makes promoting performance decrements in marijuana cannabinoid CB2 receptor to produce safer marijuana smoking habits smokers. Performance remained these effects. As shown in the figure, impossible has no basis in law (exact impaired on arithmetic and recall tests below, these researchers found that THC citations are found in petition). on the day after smoke administration. promoted tumor growth in two Pulmonary effects of smoked The authors suggested that performance immunocompetent mice lines. In two marijuana include bronchodilation after decrements from smoking two to four different weakly immunogenic murine acute exposure. Chronic bronchitis and marijuana cigarettes may be evident for lung cancer models, intermittent pharyngitis are associated with repeated 24 to 31 hours. These data identify a administration of THC led to accelerated pulmonary illness. With chronic particular set of performance growth of tumor implants compared marijuana smoking, large airway decrements which characterize a with treatment with placebo alone. The obstruction and cellular inflammatory marijuana-induced abstinence immune inhibitory cytokines IL–10 and abnormalities appear in bronchial syndrome in man. TGF-beta were augmented, while IFN- epithelium (Adams and Martin, 1996). gamma was down-regulated at both the Chronic marijuana use is associated Cardiovascular Effects tumor site and in the spleens of THC- with the same types of health problems In humans, ∆9-THC produces an treated mice. This has been the first as cigarette smoking: increased increase in heart rate, an increase in clear demonstration that THC promotes frequency of bronchitis, emphysema systolic blood pressure while supine, tumor growth and supports the and asthma. The ability of alveolar decreases in blood pressure while epidemiological evidence of an macrophages to inactivate bacteria in standing, and a marked reddening of the increased risk of cancer among the lung is impaired. Local irritation conjunctivae (cf., Jaffe, 1993). The marijuana smokers. and narrowing of airways also increase in heart rate is dose-dependent In a recent comprehensive review of contribute to problems in these patients. and its onset and duration varies but the existing literature base, Carriot & Work by Perez-Reyes et al. (1991) and lags behind the peak of ∆9-THC levels in Sasco (2000) reported that users under Agurell et al. (1989) provides data about the blood. the age of 40 years of age were more the pharmacokinetics of THC from susceptible to squamous-cell carcinoma smoked marijuana. Respiratory Effects of the upper aerodigestive tract, When marijuana is smoked, THC in Marijuana smoking produces particularly of the tongue and larynx, the form of an aerosol in the inhaled inflammation, edema, and cell injury in and possibly the lung. Others tumors smoked is absorbed within seconds and the tracheobronchial mucosa of smokers being suspected are non-lymphoblastic delivered to the brain rapidly and and may be a risk factor for lung cancer acute leukemia and astrocytoma. In efficiently. Peak venous blood levels (Sarafian et al., 1999). Smoke from head and neck cancer carcinogenicity 75–150 ng/ml usually occur by the end marijuana has been shown to stimulate was observed for regular (i.e. more than of smoking a cigarette and level of THC
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in the arterial system is probably much exposed to THC for even a relatively (IOM, 1982). Chronic marijuana use can higher (Agurell et al., 1986). short period of time (Adams and Martin, be associated with behavior Toxicity by definition is the ability of 1996). Clinical pharmacology of the characterized by apathy and loss of an agent to produce injury or cause antagonist has not been studied in motivation along with impaired harm (morbidity/mortality). It is not humans. educational performance (Pope and clear that the effects of marijuana use Most of what is known about human Yurgelun-Todd, 1996). are ‘‘well-established,’’ but what is pharmacology of smoked marijuana DEA has found that since HHS’s last known about the psychoactive effects, comes from experiments with plant medical and scientific evaluation on lung effects, endocrine effects etc. material containing about 2 percent marijuana (1986), there have been a would suggest that smoking marijuana THC or less. Very few controlled studies significant number of new findings is not benign. have been done with elderly, relating to THC: The cardiovascular effects of smoked inexperienced or unhealthy users and 1. Cannabinoid receptors have been or oral marijuana have not presented data suggest that adverse effects may identified in the brain and spleen; any health problems for healthy and differ from healthy volunteers (Hollister 2. The CNS cannabinoid receptor has relatively young users. However, 1986, 1988). been cloned; marijuana smoking by older patients, Most of what is written about the 3. An endogenous arachidonic acid particularly those with some degree of pharmacological effects of marijuana is derivative ligand (anandamide) has been coronary artery disease, is likely to pose inferred from experiments on pure THC. identified; greater risks because of the resulting The amount of Cannabidiol and other 4. A high density of cannabinoid increased cardiac work, increased cannabinoids in smoked marijuana receptors have been located in the catecholamines, carboxyhemoglobin could modify the effects of THC. cerebral cortex, hippocampus, striatum and postural hypotension (Benzowitz Tolerance to marijuana’s psychoactive and cerebellum; and and Martin, 1996; Hollister, 1988). effect probably results from down 5. An antagonist to the cannabinoid The endocrine system effects include regulation of cannabinoid receptors receptor has been developed moderate depression of spermatogenesis which is a form of desensitization of In addition, a significant body of and sperm motility and decrease in neuronal cells. In general, tolerance to literature has been amassed regarding plasma testosterone on males. Prolactin, marijuana’s effects is often associated the effects of marijuana. FSH, LH, and GH levels are decreased with an increased dependence liability. For example: in females (Mendelson and Mello, Data indicate that people escalate the 1. Studies on the acute and chronic 1984). Relatively little study has been amount of marijuana they smoke and effects of marijuana on the endocrine done on human female endocrine or continue to use marijuana despite system; reproductive function. negative consequences. These are 2. Effect of marijuana on learning and THC and other cannabinoids in classic signs of developing dependence. memory; marijuana have immunosuppressant After repeated smoked or oral 3. Effect of marijuana on pregnant properties producing impaired cell- marijuana doses, marked tolerance is females and their offspring mediated and humoral immune system rapidly acquired to many of marijuana’s development; responses. THC and other cannabinoids effects: cardiovascular, autoimmune and 4. Effect on the immune system; suppress antibody formation, cytokine many subjective effects. After exposure 5. Effect on the lungs; and production, leukocyte migration and is stopped, tolerance is lost with similar 6. Effects of chronic use with regard killer-cell activity (Adams and Martin, rapidity (Jones et al., 1981) to tolerance, dependence and 1996). Withdrawal symptoms and signs ‘‘amotivational syndrome.’’ Marijuana may cause membrane appearing within hours after cessation While many of the petitioner’s perturbations in cells. At the marijuana of repeated marijuana use have been arguments are based on new research conference in July, 1995 sponsored by reported in clinical settings (Duffy and findings, the interpretation of those NIH, NIDA and DHHS, Dr. Cabral stated Milan, 1996; Mendelson et al., 1984). findings requires clarification. that THC effects body functions by Typical symptoms and signs were As was pointed out by the NIH expert accumulating in fatty tissue. While a restlessness, insomnia, irritability, committee on the medical utility of receptor-based mechanism of action has salivation, diarrhea, increased body marijuana, marijuana is not a single been determined, localized and temperature and sleep disturbances drug. It is a variable and complex characterized it is not clear that this (Jones et al., 1981). mixture of plant parts with a varying necessarily negates membrane (high Data on the immune system indicates mix of biologically active material. fatty acids) effects. that marijuana does effect the body’s Characterizing the clinical Mechanisms for marijuana’s ability to resist microbes including pharmacology is difficult especially psychoactive effects were thought to be bacteria, viruses and fungi and when the plant is smoked or eaten. through interactions of the lipid decreases the body’s antitumor activity. Some of the inconsistency or component of cell membranes. The THC effects macrophages, T- uncertainty in scientific reports discovery of the cannabinoid receptor lymphocytes and B-lymphocyts. A THC describing the clinical pharmacology of has changed that thinking and it is now receptor has been found in the spleen. marijuana results from the inherently believed that most of the effects of These effects may be receptor mediated. variable potency of the plant material. marijuana are mediated through In a person with compromised immune Inadequate control over drug dose cannabinoid receptors. Receptors are function marijuana could pose a health together with the use of research located in brain areas concerned with risk. subjects with variable experience in memory, cognition and motor Acute effects of transient anxiety, using marijuana contributes to the coordination. An endogenous ligand, panic, feelings of depression and other uncertainty about what marijuana does anandamide, has been identified but not dysphoric moods have been reported by or does not do. studied in humans (Thomas et al. 1996). 17 percent of regular marijuana users in There are studies in the scientific A specific THC antagonist, SR141716A, a large study (Tart, 1971). Whether literature that have evaluated dose- produces intense withdrawal signs and marijuana can produce lasting mood related subjective and reinforcing effects behaviors in rodents that have been disorders or schizophrenia is less clear of Cannabis sativa in humans. These
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studies have assessed the subjective and 3.55% THC in seven male moderate dimensions (cf., Chait et al., 1988; reinforcing effects of cannabis cigarettes users of marijuana. Orderly dose- Nemeth-Coslett et al., 1986). containing different potencies of THC response curves were produced for As described above in Factors 1 and and/or which have manipulated the subjective drug effects, heart rate, and 2, there are data to show that the effects THC dose by varying the volume of THC plasma concentration, as a function of of THC are dose-dependent and several smoke inhaled (Azorlosa et al., 1992; THC content and number of puffs. After studies have found that low-potency Lukas et al., 1995; Chait et al., 1988; smoking the 1.75% THC cigarette, THC is behaviorally active and can Chait and Burke, 1994; Kelly et al., maximal plasma THC levels were 57 ng/ produce cannabimimetic-like subjective 1993; Kipplinger et al, 1971, Manno et ml immediately after smoking, 18.3 ng/ and physiological effects. Preclinical al., 1970). ml 15 minutes after smoking, 10.3 ng/ and clinical experimental data Chait et al. (1988) studied the ml 30 minutes after smoking, and 7.7 demonstrate that marijuana and ∆9-THC discriminative stimulus effects of ng/ml 45 minutes after smoking. have similar abuse liabilities (i.e., drug smoked marijuana cigarettes containing The study also show that subjects discrimination, self-administration, THC contents of 0%, 0.9%, 1.4%, 2.7%. could smoke more of the low THC subjective effects). Both preclinical and Marijuana smokers were trained to cigarette to produced effects that were clinical studies show that discriminate smoked marijuana from similar to the high THC dose cigarette discontinuation of either marijuana and placebo using 4 puff of a 2.7%-THC (Azorlosa et al., 1992). There were ∆9-THC administration produces a mild cigarettes. Subjective ratings of ‘‘high’’, nearly identical THC levels produced by withdrawal syndrome. Most of what is mean peak ‘‘high’’ scores, and 10-puff low-THC cigarette (98.6 ng/ml) known about human pharmacology of physiological measures (i.e., heart rate) and 4-puff high THC cigarette (89.4 ng/ smoked marijuana comes from were significantly and dose- ml). Similarly, the subjective effects experiments with plant material dependently increased after smoking the ratings, including high, stoned, containing about 2–3% percent THC or 0.9%, 1.4%, 2.7%. Marijuana cigarettes impaired, confused, clear-headed and less, in cigarette form provided by NIDA containing 1.4% THC completely sluggish, produced under the 10 puff (cf., NIDA, 1996). Very few controlled substituted for 2.7%-THC on drug low- and high-THC and 25 puff low- studies have been done with elderly, identification tasks, however, 0.9%-THC THC conditions did not differ inexperienced or unhealthy users and did not. The authors found that the significantly from each other. data suggests that adverse effects may onset of discriminative stimulus effects As with most drugs of abuse, higher differ from healthy volunteers (Hollister was within 90 seconds after smoking 1986, 1988). began (after the first two puffs). Since doses of marijuana are preferred over the 1.4%-THC cigarette substituted for lower dose. Although not preferred, Cannabidiol (CBD) does not have 2-puffs of the 2.7%-THC cigarette, the these lower doses still produce psychotomimetic properties and does authors estimate that an inhaled dose of cannabimimetic effects. Twelve regular not appear to produce a subjective THC as low as 3 mg can produce marijuana smokers participated in a ‘‘high’’ in human subjects (Musty, discriminable subjective effects. study designed to determine the 1984). This does not mean that CBD Similarly, Lukas et al. (1995) reported preference of a low potency (0.64%- does not have CNS effects or that it does that marijuana cigarettes containing THC) vs. a high potency (1.95%-THC) not contribute to the subjective high either 1.26% or 2.53% THC produced marijuana cigarette (Chait and Burke, produced by the cannabinoids. CBD has significant and dose-dependent 1994). The subjects first sampled the been clearly shown to have anti- increases in level of intoxication and marijuana of two different potencies in convulsant effects as demonstrated by euphoria in male occasional marijuana one session, then chose which potency several techniques such as electroshock- smokers. Four of the six subjects that and how much to smoke. During induced seizures, kindled seizures, smoked the 1.26%-THC cigarette sampling sessions, there were pentylenetetrazole-induced seizures reported marijuana effects and 75% of significant dose-dependent increases in (Carlini et al., 1973; Izquierdo & these subjects reported euphoria. All six heart rate and subjective effects, Tannhauser, 1973). The suggestion that of the subjects that smoked 2.53% THC including ratings of peak ‘‘high’’, CBD does not have abuse liability is reported marijuana effects and euphoria. strength of drug effects, stimulated, and based in part on the findings that CBD Peak levels of self-reported intoxication drug liking. During choice sessions, the does not produce THC-like occurred at 15 and 30 minutes after higher dose marijuana was chosen over discriminative stimulus effects in smoking and returned to control levels the lower dose marijuana on 87.5% of animals (Ford, Balster, Dewey, by 90–105 minutes. There was no occasions. Not surprising, there was a Rosecrans, & Harris, 1984; but see difference between latency to or significant positive correlation between below). However, these tests were duration of euphoria after smoking the total number of cigarettes smoked conducted with CBD administered alone either the 1.26% or 2.53% THC and the ratings of subjective effects, and at only one or two time-points cigarettes. The higher dose-marijuana strength of drug effect, drug ‘‘liking’’, (however, see Jarbe below). The normal cigarette produced a more rapid onset expired air carbon monoxide, and heart route of administration of THC and CBD and longer duration of action than the rate increases. The authors state it is not in humans is by smoking. This mode of lower dose marijuana cigarette (1.26% necessary valid to assume that the administration provides a variable THC). Plasma THC levels peaked 5–10 preference observed in the present study proportion of cannabinoid ratios to the minutes after smoking began; the for the high-potency marijuana was due individual subject. As stated above, the average peak level attained after the to greater CNS effects from its higher chemistry of marijuana is not just the low- and high-dose marijuana cigarette THC content. The present study found chemistry of ∆9-THC , but at a was 36 and 69 ng/ml respectively. that the low- and high-potency minimum, a combination of In order to determine marijuana dose- marijuana cigarettes also differ on cannabinoids. According to Turner effects on subjective and performance several sensory dimensions; the high- (1980) kinetic interactions have been measures over a wide dose range, potency THC was found to ‘‘fresher’’ reported to occur among the Azorlosa et al. (1992) evaluated the and ‘‘hotter’’. Other studies found that cannabinoids since the early 1970s. effects of 4, 10, or 25 puffs from marijuana cigarettes containing different Control studies with varying ratios of marijuana cigarettes containing 1.75 or THC contents varied in sensory cannabinoid administrations and
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complete time-effect functions have still relief of the anxiety and/or in pigeons. In the present study, the not been conducted. psychotomimetic properties of THC by CBD/THC ratios ranged from 30:1 to Domino, Domino, & Domino (1984) the co-administration of CBD may 100:1 in rats and enhanced the stimulus have shown that the rate-of-change of effectively function as a ‘‘negative effects of THC. However, similar CBD/ the subjective high after marijuana reinforcer’’, increasing the likelihood of THC ratios in pigeons (31:1, 58:1 and administration does not follow the rate- continued abuse. 175:1) did not result in any changes to of-change of plasma or brain THC levels. Other studies have reported that THC’s discriminative stimulus or While plasma THC function show a cannabidiol has cannabinoid properties, response rate effects (Hiltunen and sharp ascending limb and exponential including anticonvulsant effects in Ja¨rbe, 1986). decline after administration, the animal and human models (Consroe et In conclusion, although cannabidiol subjective ‘‘high’’ peaks after the peak in al., 1981; Carlini et al., 1981; Doyle and does contribute to the other effects of THC and shows a protracted slow Spence, 1995), hypnotic effects (Monti cannabis, it appears to lack decline. The proportional ratios et al., 1977), and rate-decreasing effects cannabimimetic properties. In addition, between the cannabinoids and their on operant behavior (Hiltunen et al., there does not appear to be a scientific metabolites in inhaled marijuana, acting 1988). Experiments with cannabidiol in consensus that cannabidiol as entourage substances, may have combination with THC have found that pharmacologically antagonizes, in a emergent properties that cannot be certain behavioral responses induced by classic sense, the effects of THC. Certain ascribed to any one component of the THC (i.e., operant, schedule-controlled functional blockades have been complex stimulus administered in the responding) were attenuated by demonstrated. As presented in the smoke (Gauvin & Baird, 1999). These cannabidiol (Borgen and Davis, 1974; scientific literature cited above, the cannabinoid ratios may play a critical Brady and Balster, 1980; Consroe et al., ability of cannabidiol to modify the role in the initiation, maintenance, and 1977; Dalton et al., 1976; Karniol and effects of THC may be specific to only relapse of marijuana smoking. Carlini, 1973; Karniol et al., 1974; some effects of THC. Most importantly, CBD has been clearly shown to have Welburn et al., 1976; Zuardi and CBD appears to potentiate the anxiolytic (Guima˜res et al, 1990, 1994; Karniol, 1983; Zuardi et al., 1981, 1982; euphorigenic and reinforcing effects of Musty, 1984; Onaivi, Green, & Martin, Hiltunen et al., 1988). However, other THC which suggests that the interaction 1990; Zuardi et al., 1982) and affects produced by THC are augmented between THC and CBD is synergistic antipsychotic (Zuardi et al., 1995; or prolonged by the combined and may actually contribute to the abuse Zuardi, Antunes Rodrigues, & Cunha, administration of CBD and THC or of marijuana. 1991) effects in both animal and man. In marijuana extract (Chesher and Jackson, (4) Its History and Current Pattern of the sense that many studies which have 1974; Hine et al., 1975a,b; Fernandes et Abuse examined the subjective profiles of al., 1974; Karniol and Carlini, 1973; marijuana have demonstrated an Musty and Sands, 1978; Zuardi and The federal databases documenting ‘‘anxiety’’ component to THC and Karniol, 1983; Zuardi et al., 1984). Still the actual abuse of marijuana are marijuana use, it should not be other studies did not report any distributed and maintained by the HHS, surprising that CBD’s anxiolytic effects behavioral interaction between the CBD therefore, we acknowledge and concur block some of these discriminative and THC (Bird et al., 1980; Browne and with HHS’s review of this factor properties. However, it should not be Weissman, 1981; Hollister and analysis. concluded from these results that CBD’s Gillespie, 1975; Ja¨rbe and Henricksson, (5) The Scope, Duration, and anxiolytic properties do not have or 1974; Ja¨rbe et al., 1977; Mechoulam et Significance of Abuse cannot acquire reinforcing efficacy. It al., 1970; Sanders et al., 1979; Ten Ham has been suggested that the affective and DeLong, 1975). The basis of the petition to remove baseline of the drug abuser plays a A study to characterize the interaction marijuana from Schedules I and II is not critical role in the stimulus properties of between CBD and THC was conducted based on data required by 21 U.S.C. 811 drugs (Gauvin, Harland, & Holloway, using preclinical drug discrimination (c) (i.e., the scope, duration, and 1989). The anxiolytic properties of CBD procedures. Rats and pigeons trained to significance of use of the substances). may serve to diminish the anxiety states discriminate the presence or absence of The petitioner seems to assume that associated with many THC, and tested with CBD administered the concept, use of an illegal substance psychopathological states, thus alone and in combinations with THC is abuse of that substance, is a concept effectively functioning as a ‘‘negative (Hiltunen and Ja¨rbe, 1986). Specifically, which is universally held to the reinforcer’’. As such, CBD may function in rats trained to discriminate 3.0 mg/ exclusion of any other definition of to increase the likelihood of its kg, i.p. THC, CBD (30.0 mg/kg) was abuse of a substance. While this concept administration by its ability to remove administered alone and in combination is valid in general terms because the negative affective states in anxious with THC (0.3 and 1.0 mg/kg, i.p.). In marijuana is not a legitimately marketed patients. A number of authors have pigeons trained to discriminate 0.56 mg/ product therefore it has no legitimate summarized the process by which kg, i.m. THC, CBD (17.5 mg/kg) was use, holding that all adhere to this marijuana smokers ‘‘learn to get high’’ administered alone and in combination definition of abuse denigrates the (cf. Jones, 1971, 1980; Cappell & Pliner, with THC (0.1, 0.3, and 0.56 mg/kg, intellectual capacity of all researchers 1974). Karniol et al., (1974) have clearly i.m.). CBD prolonged the discriminative who investigate the topic. The petitioner demonstrated that the co-administration stimulus effects of THC in rats, but did neglects to recognize the efforts of the of CBD with THC actually blocks the not change the time-effect curve for THC DHHS and many groups which expend anxiety induced by ∆9-THC, leaving the in pigeons. In pigeons, the a great deal of time and money in subjects less tense and potentiating the administration of CBD did not produce research efforts directed toward reinforcing effects of the THC as any differential effect under a fixed ratio developing and implementing drug- demonstrated by the subjects verbal schedule of reinforcement (Hiltunen abuse prevention programs. The reports of enjoying the experience even and Ja¨rbe, 1986). petitioner also rejects the notion that more. Very few experienced marijuana These data suggest that CBD may there are individuals who abuse smokers report symptoms of anxiety (cf somehow augment or prolong the marijuana even though the National Jones, 1971, 1980; Petersen, 1980). The actions of THC in rats and had no effect Household Survey, to which the
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petitioner refers, would indicate that is United States in the past decade and of daily use in high school females. The the case. remained steady at the end of the 1990s authors also found that cigarette It has not been established that despite efforts to reduce prevalence. smoking was an important predictor of marijuana is effective in treating any Between 1991 and 1997, rates of past both initiation and persisting cannabis medical condition. (NIH Workshop on 30-day marijuana use had more than use. the Medical Utility of Marijuana, 1997) doubled among U.S. 10th grade Farrelly et al., (2001) reviewed the At this time, there is no body of secondary school students and more NHSDA from 1990 through 1996 and knowledge to which a physician can than tripled among seniors, after a compared those statistics with State law turn to learn which medical condition decade of decline. Between 1997 and enforcement policies and prices that in which patient will be ameliorated at 1999, rates of marijuana use among affect marijuana use in the general which dosage schedule of smoked secondary school students declined for public. These authors found evidence marijuana nor can he/she determine in the first time in the 1990s mainly among that both higher fines for marijuana which patient the benefits will exceed the older students (16–17 yrs old). possession and increased probability of the risks associated with such treatment. Disturbing are the findings that arrest decreased the probability that a The petitioner, therefore, is advocating marijuana use is steadily increasing young adult will use marijuana. These that individuals become their own among 8th, 10th and 12th graders at all new data refute the petitioner’s physicians, a notion that even primitive prevalence levels. According to the 1996 suggestion that legal control of man found unsatisfactory. survey results from the Monitoring the marijuana does not have a dampening There is nothing absolute in the Future Study, 45% of seniors and 35% effect on its use. placement of a substance into a of 10th graders claimed to have used (6) What, if any, Risks are There to particular CSA schedule. The placement marijuana at least once. Among eighth Public Health of a substance in a CSA schedule is the graders, annual prevalence rates more government’s mechanism for seeing that nearly tripled 1992 to 1996. There are human data demonstrating the availability of certain psychoactive Accompanying the increased use of that marijuana and ∆9-THC produce an substances is limited to the industrial, marijuana among High School seniors is increase in heart rate, an increase in scientific and medical needs which are a decreasing perceived risk or harm of systolic blood pressure while supine, accepted as being legitimate. The marijuana use (Johnston et al., 1996). In and decreases in blood pressure while placement of a substance into Schedule reality, the harm associated with the standing (cf., Jaffe, 1993). The increase I does not preclude research of that abuse of marijuana is increasing; the in heart rate is dose-dependent and its substance, nor does it preclude marijuana emergency room and onset and duration correlate with levels development of a marketable product. treatment admission rates continue to of ∆9-THC in the blood. The National Institute on Drug Abuse, increase in recent years. When DEA evaluates a drug for an element of the Department of Health Gledhill-Hoyt, Lee, Strote, & Wechsler control or rescheduling, the question of and Human Services, convened a (2000) examined rates and patterns of whether the substance creates dangers conference in 1995 and with NIDA’s marijuana use among different types of to the public health, in addition to, or parent organization, the National students and colleges in 1999, and because of, its abuse potential must be Institutes of Health, assembled an ad changes in use since 1993. 15,403 considered. A drug substances’ risk to hoc group of experts in 1997 to address students in 1993, 14,724 students in the public health manifests itself in issues related to the use, abuse, and 1997, and 14,138 students in 1999 were many ways. Abuse of a substance may medical utility of marijuana. With assessed. The prevalence of past 30-day affect the physical and/or psychological regard to the medical utility of and annual marijuana use increased in functioning of an individual abuser. In marijuana, the experts concluded that nearly all student demographic addition, it may have disruptive effects the scientific process should be allowed subgroups, and at all types of colleges. on the abuser’s family, friends, work to evaluate the potential therapeutic Nine out of 10 students (91%) who used environment, and society in general. effects of marijuana for certain marijuana in the past 30 days had used Abuse of certain substances leads to a disorders, dissociated from the societal other illicit drugs, smoked cigarettes, number of antisocial behaviors, debate over the potential harmful effects and/or engaged in binge drinking. including violent behavior, endangering of nonmedical marijuana use. All Twenty-nine percent of past 30-day others, criminal activity, and driving decisions on the ultimate usefulness of marijuana users first used marijuana while intoxicated. Data examined under a medical intervention are based on a and 34% began to use marijuana this specific factor of the CSA ranges benefit/risk calculation, and marijuana regularly at or after the age of 18, when from preclinical toxicity to should be no exception to this generally most were in college. postmarketing adverse reactions in accepted principle. Coffey, Lynskey, Wolfe, & Patton humans. DEA reviews data from many The cause and effect relationship (2000) examined predictors of cannabis sources, including forensic laboratory which the petitioner poses is neither use initiation, continuity and analyses, crime laboratories, medical substantiated nor relevant. Estimates are progression to daily use in adolescents. examiners, poison control centers, useful when attempting to allocate Over 2,000 students were examined. substance abuse treatment centers, and resources but they are not necessary for Peer cannabis use, daily smoking, the scientific and medical literature. effective eradication of marijuana. Each alcohol use, antisocial behavior and Adverse effects associated with year, millions of plants are destroyed high rates of school-level cannabis use marijuana and THC as determined by before their product reaches the market. were associated with middle-school clinical trials, FDA adverse drug effects In addition, federal law enforcement cannabis use and independently and World Health Organization data, are activities result in the seizure of another predicted high-school uptake. Cannabis described elsewhere (cf., Chait and million or more pounds of product use persisted into high-school use in Zacny, 1988; Chait and Zacny, 1992; annually. 80% of all middle-school users. Middle- Cone et al., 1988; and Pertwee, 1991). A As reviewed by Gledhill, Lee, Strote, school use independently predicted recent press release from the Substance & Wechsler (2000), rates of illicit drug incidents in high-school daily use in Abuse and Mental Health Service use, especially marijuana, have risen males, while high-dose alcohol use and Administration reported that uniformly among the youth in the antisocial behavior predicted incidence adolescents, age 12 to 17, who use
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marijuana weekly are nine times more reflex, ataxia, and severe decreases in drug abusers. Of the 837 persons likely than non-users to experiment body temperature leading to cessation of sampled 84% had onset to more serious with illegal drugs or alcohol; six times respiration from 10 to 40 hours after a drugs by the time of the interviews. more likely to run away from home; five single oral dose (Thompson et al., 1972). Most of the sample reported having times more likely to steal; nearly four No consistent pathologic changes were used marijuana (91%). Two-thirds of the times more likely to engage in violence; observed in any organs. The cause of drug abusers reported having used and three times more likely to have death in dogs or monkeys (when it marijuana prior to onset to more serious thoughts about committing suicide. It rarely occurred) did not appear to be via drugs and an additional 19% reported was also reported that adolescents also the same mechanism as in the rats. having onset to marijuana and more associated social withdrawal, physical In humans, the estimated lethal dose serious drugs in the same year. These complaints, anxiety, and depression, of intravenous dronabinol [(¥)-∆9-THC] data strongly suggest that marijuana attention problems, and thoughts of is 30 mg/kg (2100 mg/70 kg). In does plan an important role on the suicide with past-year marijuana use antiemetic studies, significant CNS pathway to more serious drugs use. (SAMHSA, 1999). Budney, Novy, & symptoms were observed following oral Further, the proportion who onset to Hughes (1999) have recently examined doses of 0.4 mg/kg (28 mg/70 kg) (PDR, marijuana before or in the same year as the withdrawal symptomology in 1997). Signs and symptoms of mild more serious drugs was reported to have chronic marijuana users seeking dronabinol intoxication include increased substantially with time from a treatment for their dependence. The drowsiness, euphoria, heightened low of 78% for persons born from 1928 majority of the subjects (85%) reported sensory awareness, altered time to 1952 to 95% for the most recent birth that they had experienced symptoms of perception, reddened conjunctiva, dry cohort of the study (1968–1973). These at least moderate severity and 47% mouth and tachycardia. Following findings further suggest that marijuana’s experienced greater than four symptoms moderate dronabinol intoxication role as a gateway to more serious rated as severe. The most reported mood patients may experience memory substance sue has become more symptoms associated with the impairment, depersonalization, mood pronounced over time. withdrawal state were irritability, alterations, urinary retention, and Ferguson & Horwood (2000) have nervousness, depression, and anger. reduced bowel motility. Signs and examined the relationship between Some of the behavioral characteristics of symptoms of severe dronabinol cannabis use in adolescence and the the marijuana withdrawal syndrome intoxication include decreased motor onset of other illicit drug use. Data were were craving, restlessness, sleep coordination, lethargy, slurred speech, gathered over the course of a 21 year disruptions, strange dreams, changes in and postural hypotension. Dronabinol longitudinal study of a birth cohort of appetite, and violent outbursts. These may produce panic reactions in 1,265 children. By the age of 21, just data clearly support the validity and apprehensive patients or seizures in over a quarter of this cohort reported clinical significance of a marijuana those with an existing seizure disorder using various forms of illicit drugs on at withdrawal syndrome in man. (PDR, 1997). least one occasion. In agreement with Toxic Effects of Marijuana and THC Thus, large doses of THC ingested by the predictions of a ‘‘stage-theory’’ of mouth were not often associated with the ‘‘gateway hypothesis’’ there was Although a median lethal dose (LD50) toxicity in dogs, nonhuman primates of THC has not been established in strong evidence of a temporal sequence and humans. However, it did produce in which the use of cannabis preceded humans, it has been found in laboratory fatalities in rodents as a result of animals (Phillips et al., 1971). In mice, the onset of the use of other illicit drugs. profound CNS depression. Thus, the Of those reporting the use of illicit the LD50 for THC was 481.9, 454.9 and evidence from studies in laboratory 28.6 mg/kg after oral, intraperitoneal, drugs, all but three (99%) had used animals and human case reports cannabis prior to the use of other illicit and intravenous routes of indicates that the lethal dose of THC is administration. In rats, the LD50 for THC drugs. However, the converse was not quite large. The adverse effects true and the majority (63%) of those (extracted from marijuana) was 666.0, associated with THC use are generally 372.9 and 42.5 mg/kg after oral, using cannabis did not progress to the extensions of the CNS effects of the drug use of other forms of illicit drugs. In intraperitoneal, and intravenous routes and are similar to those reported after of administration. Another study addition, to these findings there was a administration of marijuana (cf., Chait strong dose-response relationship examined the toxicity of THC in rats, and Zacny, 1988; Chait and Zacny, dogs and monkeys (Thompson et al., between the extent of cannabis use and 1992; Cone et al., 1988; and Pertwee, the onset of illicit drug use. The analysis 1972). Similarly this study found that in 1991). rats, the LD50 for THC was 1140.0, 400.0 suggested that those using cannabis in and 20.0 mg/kg after oral, Health and Safety Risks of ∆9-THC Use any given year on at least 50 occasions intraperitoneal, and intravenous routes The recent Institute of Medicine had hazards of using other illicit drugs of administration. There was no LD50 report on the scientific basis for the that were over 140 times higher than attained in monkeys and dogs by the medicinal use of cannabinoid products those who did not use in the year. oral route. Over 3000 mg/kg of THC was stated the following: Furthermore, hazards of the onset of administered without lethality to dogs other illicit drug use increased steadily and monkeys. A dose of about 1000 mg/ Not surprisingly, most users of other illicit with increasing cannabis use. The very drugs have used marijuana first. In fact, most kg was the lowest dose that caused drug users begin with alcohol and nicotine strong gradient in risk reflected the facts death in any animal. Behavioral changes before marijuana—usually before they are of that: (1) Among non-users of cannabis in the survivors included sedation, legal age. In the sense that marijuana use the use of other forms of illicit drugs huddled postures, muscle tremors, typically precedes rather than follows was almost non-existent and (2) among hypersensitivity to sound and initiation of other illicit drug use, it is indeed regular users of cannabis the use of immobility. a ‘‘gateway’’ drug (Institute of Medicine other illicit drugs was common. To The cause of death in the rats and Report 1999, p. ES.7). address the issue of ‘‘confounding mice after oral THC was profound Golub and Johnson (1994) examined factors’’, the associations between depression leading to dyspnea, the developmental pathway followed by cannabis use and the onset of illicit drug prostration, weight loss, loss of righting a sample of persons who became serious use were adjusted for a series of
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prospectively measured confounding Taylor et al. (2000) evaluated the cannabis. Early-onset cannabis use factors that included measures of social relationship between cannabis (onset before the age of 16) showed disadvantage, family functioning, dependence and respiratory symptoms significant impairments in attention in parental adjustment, individual and lung function in young adults, 21 adulthood. These persistent attentional characteristics, attitudes to drug use and years of age, while controlling for the deficits may interact with the activities early adolescent behavior. After effects of cigarette smoking. The of daily living, such as operating an adjustments for these factors, there was researchers found significant respiratory automobile. still evidence of strong dose-response symptoms and changes in spirometry Kurzthaler et al., (1999) examined the relationships between the extent of occur in cannabis-dependent effects of cannabis on a cognitive test cannabis use in a given year and the individuals at age 21 years, even though battery and driving performance skills. onset of illicit drug use—the hazards of the cannabis smoking history is of The demonstrated significant the onset of illicit drug use was 100 relatively short duration. The likelihood impairments in the verbal memory and times those of non-users. of reporting a broad range of respiratory the trail making tests in this study Critics of the ‘‘gateway theory’’ point symptoms was significantly increased in reflect parallel compromises in to the presence of other confounding those who were either cannabis- associative control that is acknowledged factors and processes that encourage dependent or smoked tobacco or both as a cognitive process inherent in both cannabis use and other forms of compared to non-smokers. The memory function immediately after illicit drug use. Despite these factors, symptoms most frequently and smoking cannabis. Applied to the the Ferguson & Horwood (2000) study significantly associated with cannabis question of driving ability, the authors provide a compelling set of results that dependence were early morning sputum suggest that the missing functions support the hypothesis that cannabis production (144% greater prevalence would signify that a driver under acute use may encourage other forms of illicit than non-smokers). Overall, respiratory cannabis influences would not be able drug use, including the following: symptoms in study members who met to use acquired knowledge from earlier 1. Temporal sequence: There was clear strict criteria for cannabis dependence experiences adequately to ensure road evidence that the use of cannabis almost were comparable to those of tobacco safety. invariably preceded the onset of other forms smokers consuming 1–10 cigarettes Recently, the National Highway of illicit drug use. daily. In subjects who were both tobacco Traffic Safety Administration (NHTSA; 2. Dose-Response: There was clear users and were cannabis-dependent, 1998, 1999, 2000) conducted a study evidence of a very strong and consistent some effects seem to be additive, with the Institute for Human dose-response relationship in which notably early morning sputum Psychopharmacology at Maastricht increasing cannabis use was associated with production, which occurred 8 times University in The Netherlands. Low increasing risks of the onset of illicit drug dose and high dose THC administered use. more frequently than non-smokers. 3. Resilience to control for confounding: One of the greatest concerns to society alone, and with alcohol were examined Even following control for a range of regarding ∆9-THC is the behavioral in two on-road driving situations: (1) prospectively measured social, family and toxicity produced by the drug. ∆9-THC The Road Tracking Test, measuring a individual factors, strong and consistent intoxication is associated with driver’s ability to maintain a constant associations remained between cannabis use impairments in memory, motor speed of 62 mph and a steady lateral and the onset of other forms of illicit drug coordination, cognition, judgement, position between the boundaries of the use. And, motivation, sensation, perception and right traffic lane; and (2) the Car 4. Specificity of associations: The Following Test, measuring a drivers’ association could not be explained as mood (cf., Jaffe, 1993). The ∆9 reflecting a more general process of transition consequences produced by -THC- reaction times and ability to maintain to adolescent deviant behavior since even induced behavioral impairments can distance between vehicles while driving after control for contemporaneously assessed greatly impact the individual and 164 ft. behind a vehicle that executed a measures of juvenile offending, alcohol use, society in general. These impairments series of alternating accelerations and cigarette smoking, unemployment and result in occupational, household, or decelerations. Both levels of THC alone, related measures, strong and consistent airplane, train, truck, bus or automobile and alcohol alone, significantly relationships between cannabis use and the accidents, given that individuals may be impaired performances on BOTH road onset of other forms of illicit drugs remained. attending school, working, or operating tests compared with baseline. Alcohol A suggested view of the ‘‘gateway a motor vehicle under the influence of and the high dose of THC produced hypothesis’’ states that the use of the drug. In the most general sense, 36% decrements in reaction time; cannabis may be associated with impaired driving can be seen as a failure because the test vehicles were traveling increasing risks of other forms of illicit to exercise the expected degree of at 59 mph, the delayed reaction times drug use, with this relationship being prudence or control necessary to ensure meant that the vehicle traveled, on mediated by affiliations with deviant road safety. The operations of a motor average, an additional 139 feet beyond peers and other non-observed processes vehicle are clearly a skilled performance the point where the subjects began to that may encourage those who use that requires controlled and flexible use decelerate. Even the lower dose of THC cannabis (and particularly heavy users) of a person’s intellectual and perceptual by itself retarded reaction times by 0.9 to experiment with, and use, other illicit resources. Cannabis interferes with seconds. The NHTSA concluded that drugs. resource allocations in both cognitive even in low to moderate doses, While marijuana is clearly not the and attentional tasks. marijuana impairs driving performance. only gateway to the use of other illicit In 1999, Ehrenreich et al., examined In a related analysis, Yesavage, Leirer, drugs it is one of the three most typical the detrimental effects of chronic Denari, & Hollister (1985) examined the drugs in the adolescent’s interference by cannabis with the acute and delayed effects of smoking armamentarium. The increased avenues endogenous cannabinoid systems one marijuana cigarette containing 1.9% to imported and ‘‘home-grown’’ during peripubertal development in THC (19 mg of THC) on aircraft pilot marijuana which contain behaviorally- humans. As an index of cannabinoid performance. Ten private pilot licensed active doses of THC and CBD pose a action, visual scanning and other subjects were trained in a flight serious threat to the health and well- attentional factors were examined in 99 simulator prior to marijuana exposure. being of this dimension of society. individuals who exclusively used Flight simulator performance was
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measured by the number of aileron The risk to the public health of a (7) Its Psychic or Physiological (lateral control), elevator (vertical substance may manifest itself in many Dependence Liability control) and throttle changes; the size of ways. Abuse of a substance may affect The ‘‘dopaminergic hypothesis of these control changes; the distance off the physical and/or psychological drug abuse’’ is not the only explanation the center of the runway on landing; functioning of an individual abuser, it for the neurochemical actions of drugs. and the average lateral and vertical may have disruptive effects on the The nucleus accumbens/ventral deviation from an ideal glideslope and abuser’s family, friends, work striatum areas of the brain, typically center line over the final mile of the environment, and society in general. referred to as simply the Nucleus approach. Compared to baseline Abuse of certain substances leads to a Accumbens (NAc), represents a critical performance, significant differences number of antisocial behaviors, site for mediating the rewarding or occurred in all variables at 1 and 4 including violent behavior, endangering hedonic properties of several classes of hours after smoking, except for the others, criminal activity, and driving abused drugs, including alcohol, numbers of throttle and elevator while intoxicated. Data examined under opioids, and psychomotor stimulants changes at 4 hours. Most importantly, at this factor ranges from preclinical (Gardner & Vorel, 1998; Koob, 1992; 24 hours after a single marijuana toxicity to postmarketing adverse Koob et al., 1998; Wise, 1996; Wise & cigarette, there were significant reactions in humans. DEA reviews data Bozarth, 1987). It is generally impairments in the number and size of from many sources, including forensic appreciated that all of these drugs aileron (lateral control) changes, size of laboratory analyses, crime laboratories, augment extracellular dopamine levels elevator changes, distance off-center on medical examiners, poison control in the NAc and that this action landing, and vertical and lateral centers, substance abuse treatment contributes to their rewarding deviations on approach to landing. centers, and the scientific and medical properties. However, recent evidence Interestingly, despite these performance literature. deficits, the pilots reported no also suggests that many drugs of abuse In its official report titled ‘‘Marijuana significant subjective awareness of their have dopamine-independent impairments at 24 hours. It is and Medicine: Assessing the Science interactions with Nac neuronal activity noteworthy that a fatal crash in which Base’’, the Institute of Medicine (Carlezon & Wise, 1996; Chieng & a pilot had a positive THC screen highlighted a number of risks to the Williams, 1998; Koob, 1992; Martin et involved similar landing misjudgments. public health as a result of cannabis al., 1997; Yuan et al., 1992). Recent In addition to causing unsafe consumption: studies conducted at the Cellular conditions, marijuana use results in (1) Cognitive impairments associated with Neurobiology Branch of the NIDA by decreased performance and lost acutely administered marijuana limit the Hoffman & Lupica (2001) concluded productivity in the workplace, activities that people would be able to do that THC modulates NAc glutamatergic including injuries, absenteeism, and safely or productively. For example, no one functioning of dopamine. These authors increased health care costs. A NIDA under the influence of marijuana or THC suggested that increases in Nac report on drugs in the workplace should drive a vehicle or operate potentially dopamine levels may be a useful summarized the prevalence of dangerous equipment (Page 107). neurochemical index of drug reward but marijuana use in the workplace and its (2) The most compelling concerns do not fully account for the complex impact on society. This report found regarding marijuana smoking in HIV/AIDS processing of fast synaptic activity by that in 1989, one in nine working patients are the possible effects of marijuana this neuromodulator in the Nac. on immunity. Reports of opportunistic fungal people (11%) reported current use of Moreover, because both glutamatergic and bacterial pneumonia in AIDS patients marijuana (Gust and Walsh, 1989). who used marijuana suggest that marijuana and GABAergic inputs to medium spiny Recent DAWN data and other surveys smoking either suppresses the immune neurons are directly inhibited by indicate that marijuana use is system or exposes patients to an added dopamine, as well as by drugs of abuse. increasing, especially among younger burden of pathogens. In summary, patients It is likely that these effects contribute and working age individuals. with pre-existing immune deficits due to to the abuse liability of marijuana. Bray, Zarkin, Ringwalt, & Qi (2000) AIDS should be expected to be vulnerable to In addition, the petitioner’s global estimated the impact of age of dropout serious harm caused by smoking marijuana. statements about the role of dopamine, on the relationship between marijuana The relative contribution of marijuana smoke the reinforcing effects of marijuana and use and high school dropouts using four versus THC or other cannabinoids is not other drugs, and the predictive validity longitudinal surveys from students in known. (Page 116–117) of animal self-administration studies the Southeastern U.S. public school (3) DNA alterations are known to be early with marijuana and abuse potential in system. Their results suggested that events in the development of cancer, and humans are not supported by the marijuana initiation was positively have been observed in the lymphocytes of scientific literature. For example: related to high school dropout. pregnant marijuana smokers and in those of (1) There are drugs that do not Although the magnitude and the their newborns. This is an important study function through dopaminergic systems significance of the relationship varied because the investigators were careful to that are self-administered by animals with age of dropout and the other exclude tobacco smokers; a problem in and humans (i.e., barbiturates, substances used, the overall effect previous studies that cited mutagenic effects benzodiazepines, PCP). represented an odds-ratio of of marijuana smoke. (Page 118–119) (4) * * * factors influence the safety of approximately 2.3. These data suggest (2) There are drugs that are readily marijuana or cannabinoid drugs for medical self-administered by animals that are that an individual is approximately 2.3 use: the delivery system, the use of plant times more likely to drop out of school not abused by man (antihistamines) material, and the side effects of cannabinoid (3) There are drugs that are abused by than an individual who has not initiated drugs. (1) Smoking marijuana is clearly humans that are not readily self- marijuana use. harmful, especially in people with chronic When DEA evaluates a drug for conditions, and is not an ideal drug delivery administered by animals (hallucinogens control or rescheduling, whether the system. (2) Plants are of uncertain and hallucinogenic phenethylamines, substance creates dangers to the public composition, which renders their effects nicotine, caffeine). health, in addition to or because of its equally uncertain, so they constitute an (4) There are drugs that have no effect abuse potential, must be considered. undesirable medication. (Page 127) on dopamine that are self-administered
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by animals and not abused by humans and restlessness. By approximately 24 consumption (cf. Gauvin, Cheng, (i.e., antihistamines). hours after THC discontinuation, there Holloway, 1993). As described above, Haney et al. have Physical Dependence in Animals was an intensification of withdrawal symptoms to include ‘‘hot flashes’’, recently described abstinence symptoms ∆9 Abrupt withdrawal from -THC can sweating, rhinorrhea, loose stools, of an acute withdrawal syndrome produce a mild spontaneous withdrawal hiccoughs, and anorexia. These following high (30 mg q.i.d.) and low syndrome in animals, including withdrawal symptoms gradually (20 mg q.i.d) dose administrations of increased motor activity and grooming dissipated over the next 48 hours. EEG oral THC (Haney et al., 1999a) and in rats, decreased seizure threshold in changes consistent with the effects of following 5 puffs of high (3.1%) and low mice and increased aggressiveness, drug withdrawal (hyperexcitation) were (1.8%) THC-containing smoked irritability and altered operant recorded in patients after abrupt marijuana cigarettes (Haney et al., performance in rhesus monkeys (cf., challenge. Patients also complained of 1999b). Both of these studies have Pertwee, 1991). The failure to observe disturbed sleep for several weeks after delineated a withdrawal syndrome from profound withdrawal signs following concentrations of THC significantly discontinuation of high doses of abrupt discontinuation of ∆9-THC may lower than those reported in any other dronabinol. The intensity of the be due to (1) its long half-life in plasma previous study and, for the first time, cannabinoid withdrawal syndrome is and (2) slowly waning levels of ∆9-THC clearly identified a marijuana and its metabolites that continue to related by the chronic dose and by the withdrawal syndrome detected at low permit receptor adaptation. frequency of chronic administration. levels of THC exposure that do not Recently the discovery of a There is also evidence that the produce tolerance. These data suggest cannabinoid receptor antagonist cannabinoid withdrawal symptoms can that dependence on THC may in fact be demonstrates that a profound be reversed by the administration of an important consequence of repeated, ∆9 precipitated withdrawal syndrome can marijuana and -THC, or by treatment daily exposure to cannabinoids and that be produced in ∆9-THC tolerant animals with a barbiturate (hexobarbital) or daily marijuana use may be maintained, after twice daily injections (Tsou et al., ethanol (Pertwee, 1991). at least in part, by the alleviation of 1995) or continuous infusion (Aceto et An acute withdrawal syndrome or abstinence symptoms. al., 1995, 1996). In rats continuously ‘‘hangover’’ has been reported by Chait, As stated above, Budney, Novy, & ∆9 infused with low doses -THC for four Fischman, & Schuster (1985) developing Hughes (1999) have recently examined days, the cannabinoid antagonist approximately 9 hours after smoking a the withdrawal symptomology in precipitated a behavioral withdrawal 1 g marijuana cigarette containing 2.9% chronic marijuana users seeking syndrome, including scratching, face THC. Five of twelve subjects reported treatment for their dependence. The rubbing, licking, wet dog shakes, arched themselves as ‘‘dopey and hung over’’ majority of the subjects (85%) reported back and ptosis (Aceto et al., 1996). This the morning after smoking the single that they had experienced symptoms of chronic low dose regimen consisted of cigarette. In a 10 second and 30 second at least moderate severity and 47% ∆9 0.5, 1, 2, 4 mg/kg/day -THC on days time-production task significant experienced greater than four symptoms ∆9 1 through 4; 5 and 25-fold higher - marijuana hangover effects were found. rated as severe. The most reported mood THC doses were used for the medium The effect on the time production task symptoms associated with the and high dose regimens, respectively. is of interest since the effect obtained withdrawal state were irritability, The precipitated withdrawal syndrome the morning after smoking marijuana nervousness, depression, and anger. was dose-dependently more severe in was opposite to that observed acutely Some of the behavioral characteristics of the marijuana withdrawal syndrome the medium and high THC dose groups. after smoking marijuana. These data were craving, restlessness, sleep Physical Dependence in Humans may suggest an opponent compensatory disruptions, strange dreams, changes in rebound which may underlie the Signs of withdrawal have been appetite, and violent outbursts. These 9 development of tolerance over periods demonstrated after studies with ∆ -THC. data clearly support the validity and Although the intensity of the of chronic marijuana exposure. Scores clinical significance of a marijuana withdrawal syndrome is related to the on the benzedrine-group (BG) scale, a withdrawal syndrome in man. Large- daily dose and frequency of stimulant scale of the Addiction scale population studies have also administration, in general, the signs of Research Center Inventory (ARCI) reported significant rates of cannabis ∆9-THC withdrawal have been relatively consisting mainly of terms relating to dependence (Kessler et al., 1994; Farrell mild (cf., Pertwee, 1991). This intellectual efficiency and energy, were et al., 1998), particularly in prison and withdrawal syndrome has been significantly higher the morning after homeless populations. Similar reports of compared to that of a short-term, low marijuana smoking, as well. Chait, cannabis dependence in withdrawal in dose treatment with an opioid or Fischman, & Schuster also reported other populations have been previously ethanol, and includes changes in mood, increases on the amphetamine (A) scale discussed (above; Crowley et al. (1998); sleep, heart rate body temperature, and of the ARCI, a measure of the dose- Kouri & Pope (2000)). appetite. Other signs such as irritability, related effects of d-amphetamine. restlessness, tremor mild nausea, hot Cousens & DiMascio (1973) have Psychological Dependence in Humans flashes and sweating have also been previously reported a similar In addition to the physical noted (cf., Jones, 1983). ‘‘hangover’’ and ‘‘speed of thought dependence produced by abrupt A withdrawal syndrome was reported alterations’’ in subjects the morning withdrawal from ∆9-THC, psychological after the discontinuation of oral THC in after they had received a 30 mg oral dependence on ∆9-THC can also be volunteers receiving dronabinol dosages dose of ∆9-THC. Like the ‘‘hangover’’ demonstrated. Case reports and clinical of 210 mg/day for 12 to 16 consecutive associated with high dose ethyl alcohol studies show that frequency of ∆9-THC days (PDR, 1997). This was 42-times the consumption, the hangover from use (most often as marijuana) escalates recommended dose of 2.5 mg, b.i.d. marijuana may be qualitatively identical over time, there is evidence that Within 12 hours after discontinuation, to, and differ only on an intensity individuals increase the number, doses, these volunteers manifested withdrawal dimension from, the withdrawal and potency of marijuana cigarettes. symptoms such as irritability, insomnia, syndrome produced from chronic Data have clearly shown that tolerance
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