Pot Reschedule

8/6/2019 Pot Reschedule

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40552 Federal Register / Vol. 76, No. 131 / Friday, July 8, 2011/ Proposed Rules

1Note that marihuana is the spelling originallyused in the Controlled Substances Act (CSA). Thisdocument uses the spelling that is more commonin current usage, marijuana.

DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Chapter II

[Docket No. DEA352N]

Denial of Petition To InitiateProceedings To Reschedule Marijuana

AGENCY: Drug EnforcementAdministration (DEA), Department of

Justice.

ACTION: Denial of petition to initiateproceedings to reschedule marijuana.

SUMMARY: By letter dated June 21, 2011,the Drug Enforcement Administration(DEA) denied a petition to initiaterulemaking proceedings to reschedulemarijuana.1 Because DEA believes thatthis matter is of particular interest tomembers of the public, the agency ispublishing below the letter sent to the

petitioner (denying the petition), alongwith the supporting documentation thatwas attached to the letter.

FOR FURTHER INFORMATION CONTACT:Imelda L. Paredes, Office of DiversionControl, Drug EnforcementAdministration, 8701 Morrissette Drive,Springfield, Virginia 22152; Telephone(202) 3077165.

SUPPLEMENTARY INFORMATION:

June 21, 2011.

Dear Mr. Kennedy:On October 9, 2002, you petitioned

the Drug Enforcement Administration

(DEA) to initiate rulemakingproceedings under the reschedulingprovisions of the Controlled SubstancesAct (CSA). Specifically, you petitionedDEA to have marijuana removed fromschedule I of the CSA and rescheduledas cannabis in schedule III, IV or V.

You requested that DEA removemarijuana from schedule I based onyour assertion that:

(1) Cannabis has an accepted medicaluse in the United States;

(2) Cannabis is safe for use undermedical supervision;

(3) Cannabis has an abuse potentiallower than schedule I or II drugs; and

(4) Cannabis has a dependenceliability that is lower than schedule I orII drugs.

In accordance with the CSArescheduling provisions, after gatheringthe necessary data, DEA requested ascientific and medical evaluation andscheduling recommendation from theDepartment of Health and Human

Services (DHHS). DHHS concluded thatmarijuana has a high potential for abuse,has no accepted medical use in theUnited States, and lacks an acceptablelevel of safety for use even undermedical supervision. Therefore, DHHSrecommended that marijuana remain inschedule I. The scientific and medicalevaluation and scheduling

recommendation that DHHS submittedto DEA is attached hereto.

Based on the DHHS evaluation and allother relevant data, DEA has concludedthat there is no substantial evidence thatmarijuana should be removed fromschedule I. A document prepared byDEA addressing these materials in detailalso is attached hereto. In short,marijuana continues to meet the criteriafor schedule I control under the CSA

because:(1) Marijuana has a high potential for

abuse. The DHHS evaluation and theadditional data gathered by DEA show

that marijuana has a high potential forabuse.

(2) Marijuana has no currentlyaccepted medical use in treatment inthe United States. According toestablished case law, marijuana has nocurrently accepted medical use

because: The drugs chemistry is notknown and reproducible; there are noadequate safety studies; there are noadequate and well-controlled studiesproving efficacy; the drug is notaccepted by qualified experts; and thescientific evidence is not widelyavailable.

(3) Marijuana lacks accepted safetyfor use under medical supervision. Atpresent, there are no U.S. Food andDrug Administration (FDA)-approvedmarijuana products, nor is marijuanaunder a New Drug Application (NDA)evaluation at the FDA for anyindication. Marijuana does not have acurrently accepted medical use intreatment in the United States or acurrently accepted medical use withsevere restrictions. At this time, theknown risks of marijuana use have not

been shown to be outweighed byspecific benefits in well-controlledclinical trials that scientifically evaluatesafety and efficacy.

You also argued that cannabis has adependence liability that is lower thanschedule I or II drugs. Findings as to thephysical or psychological dependenceof a drug are only one of eight factorsto be considered. As discussed furtherin the attached documents, DHHS statesthat long-term, regular use of marijuanacan lead to physical dependence andwithdrawal following discontinuationas well as psychic addiction ordependence.

The statutory mandate of 21 U.S.C.812(b) is dispositive. Congressestablished only one schedule, scheduleI, for drugs of abuse with no currentlyaccepted medical use in treatment in theUnited States and lack of acceptedsafety for use under medicalsupervision. 21 U.S.C. 812(b).

Accordingly, and as set forth in detailin the accompanying DHHS and DEAdocuments, there is no statutory basisunder the CSA for DEA to grant yourpetition to initiate rulemakingproceedings to reschedule marijuana.Your petition is, therefore, herebydenied.

Sincerely,

Michele M. Leonhart,

Administrator.

Attachments:

Marijuana. Scheduling Review Document:Eight Factor Analysis

Basis for the recommendation formaintaining marijuana in schedule I of theControlled Substances Act

Date: June 30, 2011

Michele M. LeonhartAdministrator

Department of Health and Human Services,Office of the Secretary Assistant Secretary for

Health, Office of Public Health and ScienceWashington, D.C. 20201.

December 6, 2006.The Honorable Karen P. TandyAdministrator, Drug Enforcement

Administration, U.S. Department ofJustice, Washington, D.C. 20537

Dear Ms. Tandy:

This is in response to your request of July2004, and pursuant to the ControlledSubstances Act (CSA), 21 U.S.C. 811(b), (c),and (f), the Department of Health and HumanServices (DHHS) recommends that marijuanacontinue to be subject to control underSchedule I of the CSA.

Marijuana is currently controlled underSchedule I of the CSA. Marijuana continuesto meet the three criteria for placing asubstance in Schedule I of the CSA under 21U.S.C. 812(b)(l). As discussed in the attachedanalysis, marijuana has a high potential forabuse, has no currently accepted medical usein treatment in the United States, and has alack of an accepted level of safety for useunder medical supervision. Accordingly,HHS recommends that marijuana continue to

be subject to control under Schedule I of theCSA. Enclosed is a document prepared byFDAs Controlled Substance Staff that is the

basis for this recommendation.Should you have any questions regarding

this recommendation, please contact CorinneP. Moody, of the Controlled Substance Staff,Center for Drug Evaluation and Research. Ms.Moody can be reached at 3018271999.

Sincerely yours,John O. Agwunobi,Assistant Secretary for Health.

Enclosure:

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40553Federal Register / Vol. 76, No. 131 / Friday, July 8, 2011/ Proposed Rules

2The CSA defines marijuana as the following:all parts of the plant Cannabis Sativa L., whether

growing or not; the seeds thereof; the resinextracted from any part of such plant; and everycompound, manufacture, salt, derivative, mixture,or preparation of such plant, its seeds or resin. Suchterm does not include the mature stalks of suchplant, fiber produced from such stalks, oil or cakemade from the seeds of such plant, any othercompound, manufacture, salt, derivative, mixture,or preparation of such mature stalks (except theresin extracted there from), fiber, oil, or cake, or thesterilized seed of such plant which is incapable ofgermination (21 U.S.C. 802(16)).

Basis for the Recommendation forMaintaining Marijuana in Schedule I of theControlled Substances Act

BASIS FOR THE RECOMMENDATION FORMAINTAINING MARIJUANA INSCHEDULE I OF THE CONTROLLEDSUBSTANCES ACT

On October 9, 2002, the Coalition forRescheduling Cannabis (hereafter known as

the Coalition) submitted a petition to theDrug Enforcement Administration (DEA)requesting that proceedings be initiated torepeal the rules and regulations that placemarijuana in Schedule I of the ControlledSubstances Act (CSA). The petition contendsthat cannabis has an accepted medical use inthe United States, is safe for use undermedical supervision, and has an abusepotential and a dependency liability that islower than Schedule I or II drugs. Thepetition requests that marijuana berescheduled as cannabis in either ScheduleIII, IV, or V of the CSA. In July 2004, the DEAAdministrator requested that the Departmentof Health and Human Services (HHS) providea scientific and medical evaluation of the

available information and a schedulingrecommendation for marijuana, inaccordance with the provisions of 21 U.S.C.811(b).

In accordance with 21 U.S.C. 811(b), DEAhas gathered information related to thecontrol of marijuana (Cannabis sativa) 2under the CSA. Pursuant to 21 U.S.C. 811(b),the Secretary is required to consider in ascientific and medical evaluation eightfactors determinative of control under theCSA. Following consideration of the eightfactors, if it is appropriate, the Secretary mustmake three findings to recommendscheduling a substance in the CSA. Thefindings relate to a substances abusepotential, legitimate medical use, and safetyor dependence liability.

Administrative responsibilities forevaluating a substance for control under theCSA are performed by the Food and DrugAdministration (FDA), with the concurrenceof the National Institute on Drug Abuse(NIDA), as described in the Memorandum ofUnderstanding (MOU) of March 8, 1985 (50FR 951820).

In this document, FDA recommends thecontinued control of marijuana in ScheduleI of the CSA. Pursuant to 21 U.S.C. 811(c),the eight factors pertaining to the schedulingof marijuana are considered below.

1. ITS ACTUAL OR RELATIVE POTENTIALFOR ABUSE

The first factor the Secretary must consider

is marijuanas actual or relative potential for

abuse. The term abuse is not defined in theCSA. However, the legislative history of theCSA suggests the following in determiningwhether a particular drug or substance has apotential for abuse:

a. Individuals are taking the substance inamounts sufficient to create a hazard to theirhealth or to the safety of other individuals orto the community.

b. There is a significant diversion of the

drug or substance from legitimate drugchannels.

c. Individuals are taking the substance ontheir own initiative rather than on the basisof medical advice from a practitionerlicensed by law to administer suchsubstances.

d. The substance is so related in its actionto a substance already listed as having apotential for abuse to make it likely that itwill have the same potential for abuse assuch substance, thus making it reasonable toassume that there may be significantdiversions from legitimate channels,significant use contrary to or without medicaladvice, or that it has a substantial capabilityof creating hazards to the health of the user

or to the safety of the community.Comprehensive Drug Abuse Prevention and

Control Act of 1970, H.R. Rep. No. 911444, 91st Cong., Sess. 1 (1970) reprintedin U.S.C.C.A.N. 4566, 4603.

In considering these concepts in a varietyof scheduling analyses over the last threedecades, the Secretary has analyzed a rangeof factors when assessing the abuse liabilityof a substance. These factors have includedthe prevalence and frequency of use in thegeneral public and in specific sub-populations, the amount of the material thatis available for illicit use, the ease withwhich the substance may be obtained ormanufactured, the reputation or status of thesubstance on the street, as well as evidence

relevant to population groups that may be atparticular risk.

Abuse liability is a complex determinationwith many dimensions. There is no singletest or assessment procedure that, by itself,provides a full and completecharacterization. Thus, no single measure ofabuse liability is ideal. Scientifically, acomprehensive evaluation of the relativeabuse potential of a drug substance caninclude consideration of the drugs receptor

binding affinity, preclinical pharmacology,reinforcing effects, discriminative stimuluseffects, dependence producing potential,pharmacokinetics and route ofadministration, toxicity, assessment of theclinical efficacy-safety database relative to

actual abuse, clinical abuse liability studies,and the public health risks followingintroduction of the substance to the generalpopulation. It is important to note that abusemay exist independent of a state of toleranceor physical dependence, because drugs may

be abused in doses or in patterns that do notinduce these phenomena. Animal data,human data, and epidemiological data are allused in determining a substances abuseliability. Epidemiological data can also be animportant indicator of actual abuse. Finally,evidence of clandestine production and illicittrafficking of a substance are also importantfactors.

a. There is evidence that individuals aretaking the substance in amounts sufficient tocreate a hazard to their health or to thesafety of other individuals or to thecommunity.

Marijuana is a widely abused substance.The pharmacology of the psychoactiveconstituents of marijuana, including delta9-tetrahydrocannabinol (delta9-THC), theprimary psychoactive ingredient in

marijuana, has been studied extensively inanimals and humans and is discussed inmore detail below in Factor 2, ScientificEvidence of its Pharmacological Effects, ifKnown. Data on the extent of marijuanaabuse are available from HHS through NIDAand the Substance Abuse and Mental HealthServices Administration (SAMHSA). Thesedata are discussed in detail under Factor 4,Its History and Current Pattern of Abuse;Factor 5, The Scope, Duration, andSignificance of Abuse; and Factor 6, What,if any, Risk There is to the Public Health?

According to SAMHSAs 2004 NationalSurvey on Drug Use and Health (NSDUH; thedatabase formerly known as the NationalHousehold Survey on Drug Abuse (NHSDA)),

the latest year for which complete data areavailable, 14.6 million Americans have usedmarijuana in the past month. This is anincrease of 3.4 million individuals since1999, when 11.2 million individuals reportedusing marijuana monthly. (See the discussionof NSDUH data under Factor 4).

The Drug Abuse Warning Network(DAWN), sponsored by SAMHSA, is anational probability survey of U.S. hospitalswith emergency departments (EDs) designedto obtain information on ED visits in whichrecent drug use is implicated; 2003 is thelatest year for which complete data areavailable. Marijuana was involved in 79,663ED visits (13 percent of drug-related visits).There are a number of risks resulting from

both acute and chronic use of marijuanawhich are discussed in full below underFactors 2 and 6.

b. There is significant diversion of thesubstance from legitimate drug channels.

At present, cannabis is legally availablethrough legitimate channels for researchpurposes only and thus has a limitedpotential for diversion. In addition, the lackof significant diversion of investigationalsupplies may result from the readyavailability of illicit cannabis of equal orgreater quality. The magnitude of the demandfor illicit marijuana is evidenced by DEA/Office of National Drug Control Policy(ONDCP) seizure statistics. Data on marijuanaseizures can often highlight trends in the

overall trafficking patterns. DEAs Federal-Wide Drug Seizure System (FDSS) providesinformation on total federal drug seizures.FDSS reports total federal seizures of2,700,282 pounds of marijuana in 2003, thelatest year for which complete data areavailable (DEA, 2003). This represents nearlya doubling of marijuana seizures since 1995,when 1,381,107 pounds of marijuana wereseized by federal agents.

c. Individuals are taking the substance ontheir own initiative rather than on the basisof medical advice from a practitionerlicensed by law to administer suchsubstances.



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The 2004 NSDUH data show that 14.6million American adults use marijuana on amonthly basis (SAMHSA, 2004), confirmingthat marijuana has reinforcing properties formany individuals. The FDA has notevaluated or approved a new drugapplication (NDA) for marijuana for anytherapeutic indication, although severalinvestigational new drug (IND) applicationsare currently active. Based on the large

number of individuals who use marijuana, itcan be concluded that the majority ofindividuals using cannabis do so on theirown initiative, not on the basis of medicaladvice from a practitioner licensed toadminister the drug in the course ofprofessional practice.

d. The substance is so related in its actionto a substance already listed as having apotential for abuse to make it likely that itwill have the same potential for abuse assuch substance, thus making it reasonable toassume that there may be significantdiversions from legitimate channels,significant use contrary to or withoutmedical advice, or that it has a substantialcapability of creating hazards to the health

of the user or to the safety of the community.The primary psychoactive compound in

botanical marijuana is delta9-THC. Othercannabinoids also present in the marijuanaplant likely contribute to the psychoactiveeffects.

There are two drug products containingcannabinoid compounds that are structurallyrelated to the active components inmarijuana. Both are controlled under theCSA. Marinol is a Schedule III drug productcontaining synthetic delta9-THC, knowngenerically as dronabinol, formulated insesame oil in soft gelatin capsules.Dronabinol is listed in Schedule I. Marinolwas approved by the FDA in 1985 for thetreatment of two medical conditions: nausea

and vomiting associated with cancerchemotherapy in patients that had failed torespond adequately to conventional anti-emetic treatments, and for the treatment ofanorexia associated with weight loss inpatients with acquired immunodeficiencysyndrome or AIDS. Cesamet is a drug productcontaining the Schedule II substance,nabilone, that was approved for marketing bythe FDA in 1985 for the treatment of nauseaand vomiting associated with cancerchemotherapy. All other structurally relatedcannabinoids in marijuana are already listedas Schedule I drugs under the CSA.

2. SCIENTIFIC EVIDENCE OF ITSPHARMACOLOGICAL EFFECTS, IF

KNOWNThe second factor the Secretary must

consider is scientific evidence of marijuanaspharmacological effects. There are abundantscientific data available on theneurochemistry, toxicology, andpharmacology of marijuana. This sectionincludes a scientific evaluation ofmarijuanas neurochemistry, pharmacology,and human and animal behavioral, centralnervous system, cognitive, cardiovascular,autonomic, endocrinological, andimmunological system effects. The overviewpresented below relies upon the most currentresearch literature on cannabinoids.

Neurochemistry and Pharmacology ofMarijuana

Some 483 natural constituents have beenidentified in marijuana, includingapproximately 66 compounds that areclassified as cannabinoids (Ross and ElSohly, 1995). Cannabinoids are not known toexist in plants other than marijuana, andmost of the cannabinoid compounds thatoccur naturally have been identifiedchemically. Delta9-THC is considered themajor psychoactive cannabinoid constituentof marijuana (Wachtel et al., 2002). Thestructure and function of delta9-THC wasfirst described in 1964 by Gaoni andMechoulam.

The site of action of delta9-THC and othercannabinoids was verified with the cloningof cannabinoid receptors, first from rat braintissue (Matsuda et al., 1990) and then fromhuman brain tissue (Gerard et al., 1991). Twocannabinoid receptors, CB1 and CB2, havesubsequently been characterized (Piomelli,2005).

Autoradiographic studies have providedinformation on the distribution ofcannabinoid receptors. CB1 receptors are

found in the basal ganglia, hippocampus, andcerebellum of the brain (Howlett et al., 2004)as well as in the immune system. It is

believed that the localization of thesereceptors may explain cannabinoidinterference with movement coordinationand effects on memory and cognition. Theconcentration of CB1 receptors isconsiderably lower in peripheral tissues thanin the central nervous system (Henkerham etal., 1990 and 1992).

CB2 receptors are found primarily in theimmune system, predominantly in Blymphocytes and natural killer cells(Bouaboula et al., 1993). It is believed thatthe CB2-type receptor is responsible formediating the immunological effects of

cannabinoids (Galiegue et al., 1995).However, CB2 receptors also have recently

been localized in the brain, primarily in thecerebellum and hippocampus (Gong et al.,2006).

The cannabinoid receptors belong to thefamily of G-protein-coupled receptors andpresent a typical seven transmembrane-spanning domain structure. Many G-protein-coupled receptors are linked to adenylatecyclase either positively or negatively,depending on the receptor system.Cannabinoid receptors are linked to aninhibitory G-protein (Gi), so that when thereceptor is activated, adenylate cyclaseactivity is inhibited, which prevents theconversion of adenosine triphosphate

(ATP)to the second messenger cyclicadenosine monophosphate (cAMP).Examples of inhibitory-coupled receptorsinclude: opioid, muscarinic cholinergic,alpha 2-adrenoreceptors, dopamine (D2), andserotonin (5HT1).

It has been shown that CB1, but not CB2receptors, inhibit N- and P/Q type calciumchannels and activate inwardly rectifyingpotassium channels (Mackie et al., 1995;Twitchell et al., 1997). Inhibition of the N-type calcium channels decreasesneurotransmitter release from several tissuesand this may be the mechanism by whichcannabinoids inhibit acetylcholine,

norepinephrine, and glutamate release fromspecific areas of the brain. These effectsmight represent a potential cellularmechanism underlying the antinociceptiveand psychoactive effects of cannabinoids(Ameri, 1999). When cannabinoids are givensubacutely to rats, there is a down-regulationof CB1 receptors, as well as a decrease inGTPgammaS binding, the second messengersystem coupled to CB1 receptors (Breivogel et

al., 2001).Delta9-THC displays similar affinity for

CB1 and CB2 receptors but behaves as a weakagonist for CB2 receptors, based on inhibitionof adenylate cyclase. The identification ofsynthetic cannabinoid ligands thatselectively bind to CB2 receptors but do nothave the typical delta9-THC-likepsychoactive properties suggests that thepsychotropic effects of cannabinoids aremediated through the activation of CB1-receptors (Hanus et al., 1999). Naturally-occurring cannabinoid agonists, such asdelta9-THC, and the synthetic cannabinoidagonists such as WIN55,2122 and CP55,940 produce hypothermia, analgesia,hypoactivity, and cataplexy in addition to

their psychoactive effects.In 2000, two endogenous cannabinoid

receptor agonists, anandamide andarachidonyl glycerol (2AG), werediscovered. Anandamide is a low efficacyagonist (Breivogel and Childers, 2000), 2AGis a highly efficacious agonist (Gonsiorek etal., 2000). Cannabinoid endogenous ligandsare present in central as well as peripheraltissues. The action of the endogenous ligandsis terminated by a combination of uptake andhydrolysis. The physiological role ofendogenous cannabinoids is an active area ofresearch (Martin et al., 1999).

Progress in cannabinoid pharmacology,including further characterization of thecannabinoid receptors, isolation of

endogenous cannabinoid ligands, synthesisof agonists and antagonists with variableaffinity, and selectivity for cannabinoidreceptors, provide the foundation for thepotential elucidation of cannabinoid-mediated effects and their relationship topsychomotor disorders, memory, cognitivefunctions, analgesia, anti-emesis, intraocularand systemic blood pressure modulation,

bronchodilation, and inflammation.

Central Nervous System Effects

Human Physiological and PsychologicalEffects

Subjective Effects

The physiological, psychological, and

behavioral effects of marijuana vary amongindividuals. Common responses tocannabinoids, as described by Adams andMartin (1996) and others (Hollister, 1986 and1988; Institute of Medicine, 1982) are listed

below:1) Dizziness, nausea, tachycardia, facial

flushing, dry mouth, and tremor initially2) Merriment, happiness, and even

exhilaration at high doses3) Disinhibition, relaxation, increased

sociability, and talkativeness4) Enhanced sensory perception, giving

rise to increased appreciation of music, art,and touch



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5) Heightened imagination leading to asubjective sense of increased creativity

6) Time distortions7) Illusions, delusions, and hallucinations,

especially at high doses8) Impaired judgment, reduced co-

ordination and ataxia, which can impededriving ability or lead to an increase in risk-taking behavior

9) Emotional lability, incongruity of affect,

dysphoria, disorganized thinking, inability toconverse logically, agitation, paranoia,confusion, restlessness, anxiety, drowsiness,and panic attacks, especially ininexperienced users or in those who havetaken a large dose

10) Increased appetite and short-termmemory impairment

These subjective responses to marijuanaare pleasurable to many humans and areassociated with drug-seeking and drug-taking(Maldonado, 2002).

The short-term perceptual distortions andpsychological alterations produced bymarijuana have been characterized by someresearchers as acute or transient psychosis(Favrat et al., 2005). However, the full

response to cannabinoids is dissimilar to theDSMIVTR criteria for a diagnosis of one ofthe psychotic disorders (DSMIVTR, 2000).

As with many psychoactive drugs, anindividuals response to marijuana can beinfluenced by that persons medical/psychiatric history and history with drugs.Frequent marijuana users (greater than 100times) were better able to identify a drugeffect from low dose delta9-THC thaninfrequent users (less than 10 times) andwere less likely to experience sedative effectsfrom the drug (Kirk and deWit, 1999). Dosepreferences have been demonstrated formarijuana in which higher doses (1.95percent delta9-THC) are preferred over lowerdoses (0.63 percent delta9-THC) (Chait and

Burke, 1994).Behavioral Impairment

Acute administration of smoked marijuanaimpairs performance on tests of learning,associative processes, and psychomotor

behavior (Block et al., 1992). These datademonstrate that the short-term effects ofmarijuana can interfere significantly with anindividuals ability to learn in the classroomor to operate motor vehicles. Administrationto human volunteers of 290 micrograms perkilogram (g/kg) delta9-THC in a smokedmarijuana cigarette resulted in impairedperceptual motor speed and accuracy, twoskills that are critical to driving ability(Kurzthaler et al., 1999). Similarly,administration of 3.95 percent delta9-THC in

a smoked marijuana cigarette increaseddisequilibrium measures, as well as thelatency in a task of simulated vehicle

braking, at a rate comparable to an increasein stopping distance of 5 feet at 60 mph(Liguori et al., 1998).

The effects of marijuana may not fullyresolve until at least 1 day after the acutepsychoactive effects have subsided, followingrepeated administration. Heishman et al.(1990) showed that impairment on memorytasks persists for 24 hours after smokingmarijuana cigarettes containing 2.57 percentdelta9-THC. However, Fant et al. (1998)showed minimal residual alterations in

subjective or performance measures the dayafter subjects were exposed to 1.8 percent or3.6 percent smoked delta9-THC.

The effects of chronic marijuana use havealso been investigated. Marijuana did notappear to have residual effects onperformance of a comprehensiveneuropsychological battery when 54monozygotic male twins (one of whom usedmarijuana, one of whom did not) were

compared 120 years after cessation ofmarijuana use (Lyons et al., 2004). Thisconclusion is similar to the results from anearlier study of marijuanas effects oncognition in 1,318 participants over a 15-yearperiod, where there was no evidence of long-term residual effects (Lyketsos et al., 1999).In contrast, Solowij et al. (2002)demonstrated that 51 long-term cannabisusers did less well than 33 non-usingcontrols or 51 short-term users on certaintasks of memory and attention, but users inthis study were abstinent for only 17 hoursat time of testing. A recent study noted thatheavy, frequent cannabis users, abstinent forat least 24 hours, performed significantlyworse than controls on verbal memory and

psychomotor speed tests (Messinis et al,2006).

Pope et al. (2003) reported that nodifferences were seen in neuropsychologicalperformance in early- or late-onset userscompared to non-using controls, afteradjustment for intelligence quotient (IQ). Inanother cohort of chronic, heavy marijuanausers, some deficits were observed onmemory tests up to a week followingsupervised abstinence, but these effectsdisappeared by day 28 of abstinence(Harrison et al., 2002). The authorsconcluded that, cannabis-associatedcognitive deficits are reversible and related torecent cannabis exposure, rather thanirreversible and related to cumulative

lifetime use. Other investigators havereported neuropsychological deficits inmemory, executive functioning, psychomotorspeed, and manual dexterity in heavymarijuana smokers who had been abstinentfor 28 days (Bolla et al., 2002). A follow upstudy of heavy marijuana users noteddecision-making deficits after 25 days ofabstinence (Bolla et al., 2005). Finally, whenIQ was contrasted in adolescents at 912years and at 1720 years, current heavymarijuana users showed a 4-point reductionin IQ in later adolescence compared to thosewho did not use marijuana (Fried et al.,2002).

Age of first use may be a critical factor inpersistent impairment resulting from chronic

marijuana use. Individuals with a history ofmarijuana-only use that began before the ageof 16 were found to perform more poorly ona visual scanning task measuring attentionthan individuals who started using marijuanaafter age 16 (Ehrenreich et al., 1999). Kandeland Chen (2000) assert that the majority ofearly-onset marijuana users do not go on to

become heavy users of marijuana, and thosethat do tend to associate with delinquentsocial groups.

Heavy marijuana users were contrastedwith an age matched control group in a case-control design. The heavy users reportedlower educational achievement and lower

income than controls, a difference thatpersisted after confounding variables weretaken into account. Additionally, the usersalso reported negative effects of marijuanause on cognition, memory, career, social life,and physical and mental health (Gruber etal., 2003).

Association with Psychosis

Extensive research has been conducted

recently to investigate whether exposure tomarijuana is associated with schizophreniaor other psychoses. While many studies aresmall and inferential, other studies in theliterature utilize hundreds to thousands ofsubjects.

At present, the data do not suggest acausative link between marijuana use and thedevelopment of psychosis. Although someindividuals who use marijuana have receiveda diagnosis of psychosis, most reportsconclude that prodromal symptoms ofschizophrenia appear prior to marijuana use(Schiffman et al., 2005). When psychiatricsymptoms are assessed in individuals withchronic psychosis, the schizophreniccluster of symptoms is significantly

observed among individuals who do not havea history of marijuana use, while moodcluster symptoms are significantly observedin individuals who do have a history ofmarijuana use (Maremmani et al., 2004).

In the largest study evaluating the linkbetween psychosis and drug use, 3 percent of50,000 Swedish conscripts who usedmarijuana more than 50 times went on todevelop schizophrenia (Andreasson et al.,1987). This was interpreted by the authors tosuggest that marijuana use increased the riskfor the disorder only among thoseindividuals who were predisposed todevelop psychosis. A similar conclusion wasdrawn when the prevalence of schizophreniawas modeled against marijuana use across

birth cohorts in Australia between the years1940 to 1979 (Degenhardt et al., 2003).Although marijuana use increased over timein adults born during the 4-decade period,there was not a corresponding increase indiagnoses for psychosis in these individuals.The authors conclude that marijuana mayprecipitate schizophrenic disorders only inthose individuals who are vulnerable todeveloping psychosis. Thus, marijuana per sedoes not appear to induce schizophrenia inthe majority of individuals who try orcontinue to use the drug.

However, as might be expected, the acuteintoxication produced by marijuana doesexacerbate the perceptual and cognitivedeficits of psychosis in individuals who have

been previously diagnosed with thecondition (Schiffman et al., 2005; Hall et al.,2004; Mathers and Ghodse, 1992;Thornicroft, 1990). This is consistent with a25-year longitudinal study of over 1,000individuals who had a higher rate ofexperiencing some symptoms of psychosis(but who did not receive a diagnosis ofpsychosis) if they were daily marijuana usersthan if they were not (Fergusson et al., 2005).A shorter, 3-year longitudinal study withover 4,000 subjects similarly showed thatpsychotic symptoms, but not diagnoses, weremore prevalent in subjects who usedmarijuana (van Os et al., 2002).



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Additionally, schizophrenic individualsstabilized with antipsychotics do not responddifferently to marijuana than healthy controls(DSouza et al., 2005), suggesting thatpsychosis and/or antipsychotics do not

biochemically alter cannabinoid systems inthe brain.

Interestingly, cannabis use prior to a firstpsychotic episode appeared to spareneurocognitive deficits compared to patients

who had not used marijuana (Stirling et al.,2005). Although adolescents diagnosed witha first psychotic episode used moremarijuana than adults who had their firstpsychotic break, adolescents and adults hadsimilar clinical outcomes 2 years later(Pencer et al., 2005).

Heavy marijuana users, though, do notperform differently than non-users on theStroop task, a classic psychometricinstrument that measures executive cognitivefunctioning. Since psychotic individuals donot perform the Stroop task well, alterationsin executive functioning consistent with apsychotic profile were not apparentfollowing chronic exposure to marijuana(Gruber and Yurgelun-Todd, 2005; Eldreth et

al., 2004).Alteration in Brain Structure

Although evidence suggests that somedrugs of abuse can lead to changes in thedensity or structure of the brain in humans,there are currently no data showing thatexposure to marijuana can induce suchalterations. A recent comparison of long-termmarijuana smokers to non-smoking controlsubjects using magnetic resonance imaging(MRI) did not reveal any differences in thevolume of grey or white matter, in thehippocampus, or in cerebrospinal fluidvolume, between the two groups (Tzilos etal., 2005).

Behavioral Effects of Prenatal Exposure

The impact of in utero marijuana exposureon performance in a series of cognitive taskshas been studied in children at differentstages of development. However, since manymarijuana users have abused other drugs, itis difficult to determine the specific impactof marijuana on prenatal exposure.

Differences in several cognitive domainsdistinguished the 4-year-old children ofheavy marijuana users. In particular, memoryand verbal measures are negativelyassociated with maternal marijuana use(Fried and Watkinson, 1987). Maternalmarijuana use is predictive of poorerperformance on abstract/visual reasoningtasks, although it is not associated with anoverall lowered IQ in 3-year old children(Griffith et al., 1994). At 6 years of age,prenatal marijuana history is associated withan increase in omission errors on a vigilancetask, possibly reflecting a deficit in sustainedattention (Fried et al., 1992). When the effectof prenatal exposure in 912 year oldchildren is analyzed, in utero marijuanaexposure is negatively associated withexecutive function tasks that require impulsecontrol, visual analysis, and hypothesistesting, and it is not associated with globalintelligence (Fried et al., 1998).

Marijuana as a Gateway Drug

The Institute of Medicine (IOM) reportedthat the widely held belief that marijuana is

a gateway drug, leading to subsequentabuse of other illicit drugs, lacks conclusiveevidence (Institute of Medicine, 1999).Recently, Fergusson et al. (2005) in a 25-yearstudy of 1,256 New Zealand childrenconcluded that use of marijuana correlates toan increased risk of abuse of other drugs,including cocaine and heroin. Other sources,however, do not support a direct causalrelationship between regular marijuana and

other illicit drug use. In general, such studiesare selective in recruiting individuals who, inaddition to having extensive histories ofmarijuana use, are influenced by myriadsocial, biological, and economic factors thatcontribute to extensive drug abuse (Hall andLynskey, 2005). For most studies that test thehypothesis that marijuana causes abuse ofharder drugs, the determinative measure ofchoice is any drug use, rather than DSMIVTR criteria for drug abuse or dependence(DSMIVTR, 2000).

According to Golub & Johnson (2001), therate of progression to hard drug use by youth

born in the 1970s, as opposed to youth bornbetween World War II and the 1960s, issignificantly decreased, although overall

marijuana use among youth appears to beincreasing. Nace et al. (1975) reported thateven in the Vietnam-era soldiers whoextensively abused marijuana and heroin,there was a lack of correlation of a causalrelationship demonstrating marijuana useleading to heroin addiction. A recentlongitudinal study of 708 adolescentsdemonstrated that early onset marijuana usedid not lead to problematic drug use (Kandeland Chen, 2000). Similarly, among 2,446adolescents followed longitudinally,cannabis dependence was uncommon butwhen it did occur, it was predicted primarily

by parental death, deprived socio-economicstatus, and baseline use of illicit drugs otherthan marijuana (von Sydow et al., 2002).

Animal behavioral effects

Self-Administration

Self-administration is a method thatassesses whether a drug produces rewardingeffects that increase the likelihood of

behavioral responses in order to obtainadditional drug. Drugs that are self-administered by animals are likely toproduce rewarding effects in humans, whichis indicative of abuse liability. Generally, agood correlation exists between those drugsthat are self-administered by rhesus monkeysand those that are abused by humans (Balsterand Bigelow, 2003).

Interestingly, self-administration ofhallucinogenic-like drugs, such as

cannabinoids, lysergic acid diethylamide(LSD), and mescaline, has been difficult todemonstrate in animals (Yanagita, 1980).However, when it is known that humansvoluntarily consume a particular drug (suchas cannabis) for its pleasurable effects, theinability to establish self-administration withthat drug in animals has no practicalimportance in the assessment of abusepotential. This is because the animal test isa predictor of human behavioral response inthe absence of naturalistic data.

The experimental literature generallyreports that nave animals will not self-administer cannabinoids unless they have

had previous experience with other drugs ofabuse. However, when squirrel monkeys arefirst trained to self-administer intravenouscocaine, they will continue to bar-press at thesame rate as when delta9-THC is substitutedfor cocaine, at doses that are comparable tothose used by humans who smoke marijuana(Tanda et al., 2000). This effect is blocked bythe cannabinoid receptor antagonist, SR141716. New studies show that monkeys

without a history of any drug exposure canbe successfully trained to self-administerdelta9-THC intravenously (Justinova et al.,2003). The maximal rate of responding is 4g/kg/injection, which is 23 times greaterthan that observed in previous studies usingcocaine-experienced monkeys.

These data demonstrate that under specificpretreatment conditions, an animal model ofreinforcement by cannabinoids now exists forfuture investigations. Rats will self-administer delta9-THC when it is appliedintracerebroventricularly (i.c.v.), but only atthe lowest doses tested (0.010.02 g/infusion) (Braida et al., 2004). This effect isantagonized by the cannabinoid antagonistSR141716 and by the opioid antagonist

naloxone (Braida et al., 2004). Additionally,mice will self-administer WIN 55212, a CB1receptor agonist with a non-cannabinoidstructure (Martellotta et al., 1998).

There may be a critical dose-dependenteffect, though, since aversive effects, ratherthan reinforcing effects, have been describedin rats that received high doses of WIN 55212(Chaperon et al., 1998) or delta9-THC(Sanudo-Pena et al., 1997). SR 141716reversed these aversive effects in bothstudies.

Conditioned Place Preference

Conditioned place preference (CPP) is aless rigorous method than self-administrationof determining whether drugs haverewarding properties. In this behavioral test,animals are given the opportunity to spendtime in two distinct environments: one wherethey previously received a drug and onewhere they received a placebo. If the drug isreinforcing, animals will choose to spendmore time in the environment paired withthe drug than the one paired with theplacebo, when both options are presentedsimultaneously.

Animals show CPP to delta9-THC, but onlyat the lowest doses tested (0.0750.75 mg/kg,i.p.) (Braida et al., 2004). This effect isantagonized by the cannabinoid antagonist,SR141716, as well as by the opioidantagonist, naloxone (Braida et al., 2004).However, SR141716 may be a partial agonist,rather than a full antagonist, since it is alsoable to induce CPP (Cheer et al., 2000).Interestingly, in knockout mice, animalswithout -opioid receptors do not developCPP to delta9-THC (Ghozland et al., 2002).

Drug Discrimination Studies

Drug discrimination is a method in whichanimals indicate whether a test drugproduces physical or psychic perceptionssimilar to those produced by a known drugof abuse. In this test, an animal learns topress one bar when it receives the knowndrug of abuse and another bar when itreceives placebo. A challenge session withthe test drug determines which of the two



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bars the animal presses more often, as anindicator of whether the test drug is like theknown drug of abuse.

Animals, including monkeys and rats(Gold et al., 1992), as well as humans (Chait,1988), can discriminate cannabinoids fromother drugs or placebo. Discriminativestimulus effects of delta9-THC arepharmacologically specific for marijuana-containing cannabinoids (Balster and

Prescott, 1992; Barnett et al., 1985; Browneand Weissman, 1981; Wiley et al., 1993;Wiley et al., 1995). Additionally, the majoractive metabolite of delta9-THC, 11-hydroxy-delta9-THC, also generalizes to the stimuluscue elicited by delta9-THC (Browne andWeissman, 1981). Twenty-two othercannabinoids found in marijuana also fullysubstitute for delta9-THC.

The discriminative stimulus effects of thecannabinoid group appear to provide uniqueeffects because stimulants, hallucinogens,opioids, benzodiazepines, barbiturates,NMDA antagonists, and antipsychotics donot fully substitute for delta9-THC.

Tolerance and Physical Dependence

Tolerance is a state of adaptation in whichexposure to a drug induces changes thatresult in a diminution of one or more of thedrugs effects over time (American Academyof Pain Medicine, American Pain Society andAmerican Society of Addiction Medicineconsensus document, 2001). Physicaldependence is a state of adaptationmanifested by a drug class-specificwithdrawal syndrome produced by abruptcessation, rapid dose reduction, decreasing

blood level of the drug, and/oradministration of an antagonist (ibid).

The presence of tolerance or physicaldependence does not determine whether adrug has abuse potential, in the absence ofother abuse indicators such as rewarding

properties. Many medications that are notassociated with abuse or addiction, such asantidepressants, beta-blockers, and centrallyacting antihypertensive drugs, can producephysical dependence and withdrawalsymptoms after chronic use.

Tolerance to the subjective andperformance effects of marijuana has not

been demonstrated in studies with humans.For example, reaction times are not altered

by acute administration of marijuana in longterm marijuana users (Block and Wittenborn,1985). This may be related to recentelectrophysiological data showing that theability of delta9-THC to increase neuronalfiring in the ventral tegmental area (a regionknown to play a critical role in drug

reinforcement and reward) is not reducedfollowing chronic administration of the drug(Wu and French, 2000). On the other hand,tolerance can develop in humans tomarijuana-induced cardiovascular andautonomic changes, decreased intraocularpressure, and sleep alterations (Jones et al.,1981). Down-regulation of cannabinoidreceptors has been suggested as themechanism underlying tolerance to theeffects of marijuana (Rodriguez de Fonseca etal., 1994; Oviedo et al., 1993).

Acute administration of marijuanacontaining 2.1 percent delta9-THC does notproduce hangover effects (Chait et al.,

1985). In chronic marijuana users, though, amarijuana withdrawal syndrome has beendescribed that consists of restlessness,irritability, mild agitation, insomnia, sleepEEG disturbances, nausea, and cramping thatresolves within a few days (Haney et al.,1999). However, the American PsychiatricAssociations Diagnostic and StatisticalManual (DSMIVTR, 2000) does not includea listing for cannabis withdrawal syndrome

because, symptoms of cannabis withdrawal. . . have been described . . . but theirclinical significance is uncertain. A reviewof all current clinical studies on cannabiswithdrawal led to the recommendation byBudney et al. (2004) that the DSM introducea listing for cannabis withdrawal thatincludes such symptoms as sleep difficulties,strange dreams, decreased appetite,decreased weight, anger, irritability, andanxiety. Based on clinical descriptions, thissyndrome appears to be mild compared toclassical alcohol and barbiturate withdrawalsyndromes, which can include more serioussymptoms such as agitation, paranoia, andseizures. A recent study comparingmarijuana and tobacco withdrawal symptoms

in humans demonstrated that the magnitudeand timecourse of the two withdrawalsyndromes are similar (Vandrey et al., 2005).

The production of an overt withdrawalsyndrome in animals following chronicdelta9-THC administration has been variablydemonstrated under conditions of naturaldiscontinuation. This may be the result of theslow release of cannabinoids from adiposestorage, as well as the presence of the majorpsychoactive metabolite, 11-hydroxy-delta9-THC. When investigators have shown such awithdrawal syndrome in monkeys followingthe termination of cannabinoidadministration, the behaviors includedtransient aggression, anorexia, biting,irritability, scratching, and yawning (Budney

et al., 2004). However, in rodents treatedwith a cannabinoid antagonist followingsubacute administration of delta9-THC,pronounced withdrawal symptoms,including wet dog shakes, can be provoked(Breivogel et al., 2003).

Behavioral Sensitization

Sensitization to the effects of drugs is theopposite of tolerance: instead of a reductionin behavioral response upon repeated drugadministration, animals that are sensitizeddemonstrate an increase in behavioralresponse. Cadoni et al. (2001) demonstratedthat repeated exposure to delta9-THC caninduce sensitization to a variety ofcannabinoids. These same animals also have

a sensitized response to administration ofopioids, an effect known as cross-sensitization. Conversely, when animals weresensitized to the effects of morphine, therewas cross-sensitization to cannabinoids.Thus, the cannabinoid and opioids systemsappear to operate symmetrically in terms ofcross-sensitization.

Cardiovascular and Autonomic Effects

Single smoked or oral doses of delta9-THCproduce tachycardia and may increase bloodpressure (Capriotti et al., 1988; Benowitz and

Jones, 1975). However, prolonged delta9-THCingestion produces significant heart rate

slowing and blood pressure lowering(Benowitz and Jones, 1975). Both plant-derived cannabinoids and endocannabinoidshave been shown to elicit hypotension and

bradycardia via activation of peripherally-located CB1 receptors (Wagner et al., 1998).This study suggests that the mechanism ofthis effect is through presynaptic CB1receptor-mediated inhibition ofnorepinephrine release from peripheral

sympathetic nerve terminals, with possibleadditional direct vasodilation via activationof vascular cannabinoid receptors.

The impaired circulatory responsesfollowing delta9-THC administration tostanding, exercise, Valsalva maneuver, andcold pressor testing suggest thatcannabinoids induce a state of sympatheticinsufficiency. In humans, tolerance candevelop to the orthostatic hypotension(Jones, 2002; Sidney, 2002), possibly relatedto plasma volume expansion, but does notdevelop to the supine hypotensive effects(Benowitz and Jones, 1975). During chronicmarijuana ingestion, nearly completetolerance develops to tachycardia andpsychological effects when subjects are

challenged with smoked marijuana.Electrocardiographic changes are minimaleven after large cumulative doses of delta9-THC. (Benowitz and Jones, 1975).

It is notable that marijuana smoking byolder patients, particularly those with somedegree of coronary artery or cerebrovasculardisease, poses risks related to increasedcardiac work, increased catecholamines,carboxyhemoglobin, and posturalhypotension (Benowitz and Jones, 1981;Hollister, 1988).

Respiratory Effects

Transient bronchodilation is the mosttypical effect following acute exposure tomarijuana (Gong et al., 1984). Long-term use

of marijuana can lead to an increasedfrequency of chronic bronchitis andpharyngitis, as well as chronic cough andincreased sputum. Pulmonary function testsreveal that large-airway obstruction can occurwith chronic marijuana smoking, as cancellular inflammatory histopathologicalabnormalities in bronchial epithelium(Adams and Martin, 1996; Hollister, 1986).

The evidence that marijuana may lead tocancer associated with respiratory effects isinconsistent, with some studies suggesting apositive correlation while others do not(Tashkin, 2005). Several cases of lung cancerhave been reported in young marijuana userswith no history of tobacco smoking or othersignificant risk factors (Fung et al., 1999).

Marijuana use may dose-dependently interactwith mutagenic sensitivity, cigarette smokingand alcohol use to increase the risk of headand neck cancer (Zhang et al., 1999).However, in the largest study to date with1,650 subjects, no positive association wasfound between marijuana use and lungcancer (Tashkin et al., 2006). This findingheld true regardless of extent of marijuanause, when tobacco use and other potentialconfounding factors were controlled.

The lack of evidence for carcinogenicityrelated to cannabis may be related to the factthat intoxication from marijuana does notrequire large amounts of smoked material.



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This may be especially pertinent sincemarijuana is reportedly more potent todaythan a generation ago. Thus, individuals mayconsume much less marijuana than inprevious decades to reach the desiredsubjective effects, exposing them to lesspotential carcinogens.

Endocrine System

The presence of in vitro delta9-THC

reduces binding of the corticosteroid,dexamethasone, in hippocampal tissue fromadrenalectomized rats, suggesting aninteraction with the glucocorticoid receptor(Eldridge et al., 1991). Acute delta9-THCreleases corticosterone, but tolerancedevelops to this effect with chronicadministration (Eldridge et al., 1991).

Experimental administration of marijuanato humans does not consistently alterendocrine parameters. In an early study, malesubjects who experimentally receivedsmoked marijuana showed a significantdepression in luteinizing hormone and asignificant increase in cortisol were observed(Cone et al., 1986). However, two laterstudies showed no changes in hormones.

Male subjects who were experimentallyexposed to smoked delta9-THC (18 mg/marijuana cigarette) or oral delta9-THC (10mg t.i.d. for 3 days and on the morning of thefourth day) showed no changes in plasmaprolactin, ACTH, cortisol, luteinizinghormone, or testosterone levels (Dax et al.,1989). Similarly, a study with 93 men and 56women showed that chronic marijuana usedid not significantly alter concentrations oftestosterone, luteinizing hormone, folliclestimulating hormone, prolactin, or cortisol(Block et al., 1991).

Relatively little research has beenperformed on the effects of experimentallyadministered marijuana on femalereproductive system functioning. Inmonkeys, delta9-THC administrationsuppressed ovulation (Asch et al., 1981) andreduced progesterone levels (Almirez et al.,1983). However, when women were studiedfollowing experimental exposure to smokedmarijuana, no hormonal or menstrual cyclechanges were observed (Mendelson andMello, 1984). Brown and Dobs (2002) suggestthat the discrepancy between animal andhuman hormonal response to cannabinoidsmay be attributed to the development oftolerance in humans.

Recent data suggest that cannabinoidagonists may have therapeutic value in thetreatment of prostate cancer, a type ofcarcinoma in which growth is stimulated byandrogens. Research with prostate cancercells shows that the mixed CB1/CB2 agonist,

WIN552122, induces apoptosis in prostatecancer cell growth, as well as decreases inexpression of androgen receptors andprostate-specific antigens (Sarfaraz et al.,2005).

Immune System

Immune functions are altered bycannabinoids, but there can be differences

between the effects of synthetic, natural, andendogenous cannabinoids, often in anapparently biphasic manner depending ondose (Croxford and Yamamura, 2005).

Abrams et al. (2003) investigated the effectof marijuana on immunological functioning

in 62 AIDS patients who were taking proteaseinhibitors. Subjects received one of thefollowing three times a day: smokedmarijuana cigarette containing 3.95 percentdelta9-THC; oral tablet containing delta9-THC(2.5 mg oral dronabinol); or oral placebo.There were no changes in CD4+ and CD8+cell counts or HIV RNA levels or proteaseinhibitor levels between groups,demonstrating no short-term adverse

virologic effects from using cannabinoids inindividuals with compromised immunesystems.

These human data contrast with datagenerated in immunodeficient mice showingthat exposure to delta9-THC in vivosuppresses immune function, increases HIVco-receptor expression, and acts as a cofactorto enhance HIV replication (Roth et al.,2005).

3. THE STATE OF CURRENT SCIENTIFICKNOWLEDGE REGARDING THE DRUG OROTHER SUBSTANCE

The third factor the Secretary mustconsider is the state of current scientificknowledge regarding marijuana. Thus, this

section discusses the chemistry, humanpharmacokinetics, and medical uses ofmarijuana.

Chemistry

According to the DEA, Cannabis sativa isthe primary species of cannabis currentlymarketed illegally in the United States ofAmerica. From this plant, three derivativesare sold as separate illicit drug products:marijuana, hashish, and hashish oil.

Each of these derivatives contains acomplex mixture of chemicals. Among thecomponents are the 21 carbon terpenes foundin the plant as well as their carboxylic acids,analogues, and transformation productsknown as cannabinoids (Agurell et al., 1984and 1986; Mechoulam, 1973). The

cannabinoids appear to naturally occur onlyin the marijuana plant and most of the

botanically-derived cannabinoids have beenidentified. Among the cannabinoids, delta9-THC (alternate name delta1-THC) and delta-8-tetrahydrocannabinol (delta8-THC,alternate name delta6-THC) are both found inmarijuana and are able to produce thecharacteristic psychoactive effects ofmarijuana. Because delta9-THC is moreabundant than delta8-THC, the activity ofmarijuana is largely attributed to the former.Delta8-THC is found only in few varieties ofthe plant (Hively et al., 1966).

Delta9-THC is an optically active resinoussubstance, insoluble in water, and extremelylipid soluble. Chemically delta9-THC is (6aR-

trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo-[b,d]pyran-1-ol or(-)-delta9-(trans)-tetrahydrocannabinol. The(-)-trans isomer of delta9-THC ispharmacologically 6 to 100 times morepotent than the (+)-trans isomer (Dewey etal., 1984).

Other cannabinoids, such as cannabidiol(CBD) and cannabinol (CBN), have beencharacterized. CBD is not considered to havecannabinol-like psychoactivity, but isthought to have significant anticonvulsant,sedative, and anxiolytic activity (Adams andMartin, 1996; Agurell et al., 1984 and 1986;Hollister, 1986).

Marijuana is a mixture of the driedflowering tops and leaves from the plant andis variable in content and potency (Agurell etal., 1984 and 1986; Graham, 1976;Mechoulam, 1973). Marijuana is usuallysmoked in the form of rolled cigarettes whilehashish and hash oil are smoked in pipes.Potency of marijuana, as indicated bycannabinoid content, has been reported toaverage from as low as 1 to 2 percent to as

high as 17 percent.The concentration of delta9-THC and other

cannabinoids in marijuana varies withgrowing conditions and processing afterharvest. Other variables that can influencethe strength, quality, and purity of marijuanaare genetic differences among the cannabisplant species and which parts of the plant arecollected (flowers, leaves, stems, etc.)(Adams and Martin, 1996; Agurell et al.,1984; Mechoulam, 1973). In the usualmixture of leaves and stems distributed asmarijuana, the concentration of delta9-THCranges widely from 0.3 to 4.0 percent byweight. However, specially grown andselected marijuana can contain even 15percent or greater delta9-THC. Thus, a 1 gm

marijuana cigarette might contain as little as3 mg or as much as 150 mg or more of delta9-THC.

Hashish consists of the cannabinoid-richresinous material of the cannabis plant,which is dried and compressed into a varietyof forms (balls, cakes, etc.). Pieces are then

broken off, placed into a pipe and smoked.DEA reports that cannabinoid content inhashish averages 6 percent.

Hash oil is produced by solvent extractionof the cannabinoids from plant material.Color and odor of the extract vary, dependingon the type of solvent used. Hash oil is aviscous brown or amber-colored liquid thatcontains approximately 15 percentcannabinoids. One or two drops of the liquid

placed on a cigarette purportedly produce theequivalent of a single marijuana cigarette(DEA, 2005).

The lack of a consistent concentration ofdelta9-THC in botanical marijuana fromdiverse sources complicates theinterpretation of clinical data usingmarijuana. If marijuana is to be investigatedmore widely for medical use, informationand data regarding the chemistry,manufacturing, and specifications ofmarijuana must be developed.

Human Pharmacokinetics

Marijuana is generally smoked as acigarette (weighing between 0.5 and 1.0 gm),or in a pipe. It can also be taken orally in

foods or as extracts of plant material inethanol or other solvents.

The absorption, metabolism, andpharmacokinetic profile of delta9-THC (andother cannabinoids) in marijuana or otherdrug products containing delta9-THC varywith route of administration and formulation(Adams and Martin, 1996; Agurell et al., 1984and 1986). When marijuana is administered

by smoking, delta9-THC in the form of anaerosol is absorbed within seconds. Thepsychoactive effects of marijuana occurimmediately following absorption, withmental and behavioral effects measurable upto 6 hours (Grotenhermen, 2003; Hollister,



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1986 and 1988). Delta9-THC is delivered tothe brain rapidly and efficiently as would beexpected of a very lipid-soluble drug.

The bioavailability of the delta9-THC frommarijuana in a cigarette or pipe can rangefrom 1 to 24 percent with the fractionabsorbed rarely exceeding 10 to 20 percent(Agurell et al., 1986; Hollister, 1988). Therelatively low and variable bioavailabilityresults from the following: significant loss of

delta9

-THC in side-stream smoke, variationin individual smoking behaviors,cannabinoid pyrolysis, incompleteabsorption of inhaled smoke, and metabolismin the lungs. A individuals experience andtechnique with smoking marijuana is animportant determinant of the dose that isabsorbed (Herning et al., 1986; Johansson etal., 1989).

After smoking, venous levels of delta9-THCdecline precipitously within minutes, andwithin an hour are about 5 to 10 percent ofthe peak level (Agurell et al., 1986; Huestiset al., 1992a and 1992b). Plasma clearance ofdelta9-THC is approximately 950 ml/min orgreater, thus approximating hepatic bloodflow. The rapid disappearance of delta9-THC

from blood is largely due to redistribution toother tissues in the body, rather than tometabolism (Agurell et al., 1984 and 1986).Metabolism in most tissues is relatively slowor absent. Slow release of delta9-THC andother cannabinoids from tissues andsubsequent metabolism results in a longelimination half-life. The terminal half-life ofdelta9-THC is estimated to range fromapproximately 20 hours to as long as 10 to13 days (Hunt and Jones, 1980), thoughreported estimates vary as expected with anyslowly cleared substance and the use ofassays of variable sensitivities. Lemberger etal. (1970) determined the half-life of delta9-THC to range from 23 to 28 hours in heavymarijuana users to 60 to 70 hours in naveusers.

Characterization of the pharmacokineticsof delta9-THC and other cannabinoids fromsmoked marijuana is difficult (Agurell et al.,1986; Herning et al., 1986; Huestis et al.,1992a), in part because a subjects smoking

behavior during an experiment is variable.Each puff delivers a discrete dose of delta9-THC. An experienced marijuana smoker cantitrate and regulate the dose to obtain thedesired acute psychological effects and toavoid overdose and/or minimize undesiredeffects. For example, under naturalisticconditions, users will hold marijuana smokein the lungs for an extended period of time,in order to prolong absorption and increasepsychoactive effects. The effect of experiencein the psychological response may explain

why venous blood levels of delta9-THCcorrelate poorly with intensity of effects andlevel of intoxication (Agurell et al., 1986;Barnett et al., 1985; Huestis et al., 1992a).

Additionally, puff and inhalation volumechanges with phase of smoking, tending to behighest at the beginning and lowest at theend of smoking a cigarette. Some studiesfound frequent users to have higher puffvolumes than less frequent marijuana users.During smoking, as the cigarette lengthshortens, the concentration of delta9-THC inthe remaining marijuana increases; thus, eachsuccessive puff contains an increasingconcentration of delta9-THC.

In contrast to smoking, the onset of effectsafter oral administration of delta9-THC ormarijuana is 30 to 90 min, which peaks after2 to 3 hours and continues for 4 to 12 hours(Grotenhermen, 2003; Adams and Martin,1996; Agurell et al., 1984 and 1986). Oral

bioavailability of delta9-THC, whether pureor in marijuana, is low and extremelyvariable, ranging between 5 and 20 percent(Agurell et al., 1984 and 1986). Following

oral administration of radioactive-labeleddelta9-THC, delta9-THC plasma levels arelow relative to those levels after smoking orintravenous administration. There is inter-and intra-subject variability, even whenrepeated dosing occurs under controlledconditions. The low and variable oral

bioavailability of delta9-THC is aconsequence of its first-pass hepaticelimination from blood and erraticabsorption from stomach and bowel. It ismore difficult for a user to titrate the oraldelta9-THC dose than marijuana smoking

because of the delay in onset of effects afteran oral dose (typically 1 to 2 hours).

Cannabinoid metabolism is extensive.Delta9-THC is metabolized via microsomal

hydroxylation to both active and inactivemetabolites (Lemberger et al., 1970, 1972a,and 1972b; Agurell et al., 1986; Hollister,1988) of which the primary active metabolitewas 11-hydroxy-delta9-THC. This metaboliteis approximately equipotent to delta9-THC inproducing marijuana-like subjective effects(Agurell et al., 1986; Lemberger and Rubin,1975). After oral administration, metabolitelevels may exceed that of delta9-THC andthus contribute greatly to thepharmacological effects of oral delta9-THC ormarijuana. In addition to 11-hydroxy-delta9-THC, some inactive carboxy metabolites haveterminal half-lives of 50 hours to 6 days ormore. The latter substances serve as long-term markers of earlier marijuana use in

urine tests. The majority of the absorbeddelta9-THC dose is eliminated in feces, andabout 33 percent in urine. Delta9-THC entersenterohepatic circulation and undergoeshydroxylation and oxidation to 11-nor-9-carboxy-delta9-THC. The glucuronide isexcreted as the major urine metabolite alongwith about 18 nonconjugated metabolites.Frequent and infrequent marijuana users aresimilar in the way they metabolize delta9-THC (Agurell et al., 1986).

Medical Uses for Marijuana

A NDA for marijuana/cannabis has notbeen submitted to the FDA for any indicationand thus no medicinal product containing

botanical cannabis has been approved for

marketing. However, small clinical studiespublished in the current medical literaturedemonstrate that research with marijuana is

being conducted in humans in the UnitedStates under FDA-authorized investigationalnew drug (IND) applications.

HHS states in a published guidance that itis committed to providing research-grademarijuana for studies that are the most likelyto yield usable, essential data (HHS, 1999).The opportunity for scientists to conductclinical research with botanical marijuanahas increased due to changes in the processfor obtaining botanical marijuana from NIDA,the only legitimate source of the drug for

research in the United States. In May 1999,HHS provided guidance on the proceduresfor providing research-grade marijuana toscientists who intend to study marijuana inscientifically valid investigations and well-controlled clinical trials (DHHS, 1999). Thisaction was prompted by the increasinginterest in determining whethercannabinoids have medical use throughscientifically valid investigations.

In February 1997, a National Institutes ofHealth (NIH)-sponsored workshop analyzedavailable scientific information andconcluded that in order to evaluate varioushypotheses concerning the potential utility ofmarijuana in various therapeutic areas, moreand better studies would be needed (NIH,1997). In addition, in March 1999, theInstitute of Medicine (IOM) issued a detailedreport that supported the need for evidence-

based research into the effects of marijuanaand cannabinoid components of marijuana,for patients with specific disease conditions.The IOM report also emphasized that smokedmarijuana is a crude drug delivery systemthat exposes individuals to a significantnumber of harmful substances and that if

there is any future for marijuana as amedicine, it lies in its isolated components,the cannabinoids and their syntheticderivatives. As such, the IOM recommendedthat clinical trials should be conducted withthe goal of developing safe delivery systems(Institute of Medicine, 1999). Additionally,state-level public initiatives, includingreferenda in support of the medical use ofmarijuana, have generated interest in themedical community for high quality clinicalinvestigation and comprehensive safety andeffectiveness data.

For example, in 2000, the state ofCalifornia established the Center forMedicinal Cannabis Research (CMCR)(www.cmcr.ucsd.edu) in response toscientific evidence for therapeuticpossibilities of cannabis and local legislativeinitiatives in favor of compassionate use(Grant, 2005). State legislation establishingthe CMCR called for high quality medicalresearch that will enhance understanding ofthe efficacy and adverse effects of marijuanaas a pharmacological agent, but stressed thatthe project should not be construed asencouraging or sanctioning the social orrecreational use of marijuana. CMCR hasthus far funded studies on the potential useof cannabinoids for the treatment of multiplesclerosis, neuropathic pain, appetitesuppression and cachexia, and severe painand nausea related to cancer or its treatment

by chemotherapy. To date, though, no NDAsutilizing marijuana for these indications have

been submitted to the FDA.However, FDA approval of an NDA is not

the sole means through which a drug can bedetermined to have a currently acceptedmedical use under the CSA. According toestablished case law, a drug has a currentlyaccepted medical use if all of the followingfive elements have been satisfied:

a. the drugs chemistry is known andreproducible;

b. there are adequate safety studies;c. there are adequate and well-controlled

studies proving efficacy;d. the drug is accepted by qualified

experts; and

http://www.cmcr.ucsd.edu/http://www.cmcr.ucsd.edu/http://www.cmcr.ucsd.edu/


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e. the scientific evidence is widelyavailable.

[Alliance for Cannabis Therapeutics v. DEA,15 F.3d 1131, 1135 (D.C. Cir. 1994)]

Although the structures of manycannabinoids found in marijuana have beencharacterized, a complete scientific analysisof all the chemical components found inmarijuana has not been conducted. Safetystudies for acute or subchronicadministration of marijuana have beencarried out through a limited number ofPhase 1 clinical investigations approved bythe FDA, but there have been no NDA-qualitystudies that have scientifically assessed theefficacy and full safety profile of marijuanafor any medical condition. A materialconflict of opinion among experts precludesa finding that marijuana has been accepted

by qualified experts. At this time, it is clearthat there is not a consensus of medicalopinion concerning medical applications ofmarijuana. Finally, the scientific evidenceregarding the safety or efficacy of marijuanais typically available only in summarizedform, such as in a paper published in the

medical literature, rather than in a raw dataformat. As such, there is no opportunity foradequate scientific scrutiny of whether thedata demonstrate safety or efficacy.

Alternately, a drug can be considered tohave a currently accepted medical use withsevere restrictions (21 U.S.C. 812(b)(2)(B)),as allowed under the stipulations for aSchedule II drug. However, as stated above,a material conflict of opinion among expertsprecludes a finding that marijuana has beenaccepted by qualified experts, even underconditions where its use is severelyrestricted. Thus, to date, research on themedical use of marijuana has not progressedto the point that marijuana can be consideredto have a currently accepted medical use

or a currently accepted medical use withsevere restrictions.

4. ITS HISTORY AND CURRENT PATTERNOF ABUSE

The fourth factor the Secretary mustconsider is the history and current pattern ofabuse of marijuana. A variety of sourcesprovide data necessary to assess abusepatterns and trends of marijuana. The data

indicators of marijuana use include NSDUH,Monitoring the Future (MTF), DAWN, andTreatment Episode Data Set (TEDS), whichare described below:

National Survey on Drug Use and Health

The National Survey on Drug Use andHealth (NSDUH, 2004; http://oas.samhsa.gov/nsduh.htm) is conductedannually by SAMHSA, an agency of HHS.NSDUH provides estimates of the prevalenceand incidence of illicit drug, alcohol, andtobacco use in the United States. Thisdatabase was known until 2001 as theNational Household Survey on Drug Abuse.The survey is based on a nationallyrepresentative sample of the civilian, non-

institutionalized population 12 years of ageand older. The survey identifies whether anindividual used a drug during a certainperiod, but not the amount of the drug usedon each occasion. Excluded groups includehomeless people, active military personnel,and residents of institutions, such as jails.

According to the 2004 NSDUH, 19.1million individuals (7.9 percent of the U.S.population) illicitly used drugs other thanalcohol and nicotine on a monthly basis,compared to 14.8 million (6.7 percent of theU.S. population) users in 1999. This is anincrease from 1999 of 4.3 million (2.0 percentof the U.S. population). The most frequentlyused illicit drug was marijuana, with 14.6million individuals (6.1 percent of the U.S.

population) using it monthly. Thus, regularillicit drug use, and more specificallymarijuana use, for rewarding responses isincreasing. The 2004 NSDUH estimated that96.8 million individuals (40.2 percent of theU.S. population) have tried marijuana at leastonce during their lifetime. Thus, 15 percentof those who have tried marijuana on oneoccasion go on to use it monthly, but 85percent of them do not.

Monitoring the Future

MTF (2005, http://www.monitoringthefuture.org) is a NIDA-sponsored annual national survey that tracksdrug use trends among adolescents in theUnited States. The MTF surveys 8th, 10th,and 12th graders every spring in randomlyselected U.S. schools. The MTF survey has

been conducted since 1975 for 12th gradersand since 1991 for 8th and 10th graders bythe Institute for Social Research at theUniversity of Michigan under a grant fromNIDA. The 2005 sample sizes were 17,3008th graders; 16,70010th graders; and15,40012th graders. In all, a total of 49,300students in 402 schools participated.

Since 1999, illicit drug use among teensdecreased and held steady through 2005 inall three grades (Table 1). Marijuanaremained the most widely used illicit drug,though its use has steadily decreased since1999. For 2005, the annual prevalence ratesfor marijuana use in grades 8, 10, and 12were, respectively, 12.2 percent, 26.6percent, and 33.6 percent. Current monthlyprevalence rates for marijuana use were 6.6percent, 15.2 percent, and 19.8 percent. (SeeTable 1). According to Gruber and Pope(2002), when adolescents who usedmarijuana reach their late 20s, the vastmajority of these individuals will havestopped using marijuana.

TABLE 1TRENDS IN ANNUAL AND MONTHLY PREVALENCE OF USE OF VARIOUS DRUGS FOR EIGHTH, TENTH, ANDTWELFTH GRADERS, FROM MONITORING THE FUTURE. PERCENTAGES REPRESENT STUDENTS IN SURVEY RESPOND-ING THAT THEY HAD USED A DRUG EITHER IN THE PAST YEAR OR IN THE PAST 30 DAYS

Annual 30-Day

2003 2004 2005 2003 2004 2005

Any illicit drug (a):8th Grade .......................................................................................... 16.1 15.2 15.5 9.7 8.4 8.510th Grade ........................................................................................ 32.0 31.1 29.8 19.5 18.3 17.312th Grade ........................................................................................ 39.3 38.8 38.4 24.1 23.4 23.1

Any illicit drug other than cannabis (a):8th Grade .......................................................................................... 8.8 7.9 8.1 4.7 4.1 4.110th Grade ........................................................................................ 13.8 13.5 12.9 6.9 6.9 6.412th Grade ........................................................................................ 19.8 20.5 19.7 10.4 10.8 10.3

Marijuana/hashish:8th Grade .......................................................................................... 12.8 11.8 12.2 7.5 6.4 6.610th Grade ........................................................................................ 28.2 27.5 26.6 17.0 15.9 15.2

12th Grade ............................................................................................... 34.9 34.3 33.6 21.2 19.9 19.8

SOURCE: The Monitoring the Future Study, the University of Michigan.a. For 12th graders only, any illicit drug includes any use of marijuana, LSD, other hallucinogens, crack, other cocaine, or heroin, or any use

of other opiates, stimulants, barbiturates, or tranquilizers not under a doctors orders. For 8th and 10th graders, the use of other opiates and bar-biturates was excluded.

Drug Abuse Warning Network

DAWN (2006, http://dawninfo.samhsa.gov/) is a nationalprobability survey of U.S. hospitals with EDs

designed to obtain information on ED visitsin which recent drug use is implicated. TheED data from a representative sample ofhospital emergency departments are

weighted to produce national estimates. It iscritical to note that DAWN data andestimates for 2004 are not comparable tothose for any prior years because of vast

http://oas.samhsa.gov/nsduh.htmhttp://oas.samhsa.gov/nsduh.htmhttp://oas.samhsa.gov/nsduh.htmhttp://www.monitoringthefuture.org/http://www.monitoringthefuture.org/http://www.monitoringthefuture.org/http://dawninfo.samhsa.gov/http://dawninfo.samhsa.gov/http://dawninfo.samhsa.gov/http://dawninfo.samhsa.gov/http://dawninfo.samhsa.gov/http://oas.samhsa.gov/nsduh.htmhttp://oas.samhsa.gov/nsduh.htmhttp://www.monitoringthefuture.org/http://www.monitoringthefuture.org/


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changes in the methodology used to collectthe data. Further, estimates for 2004 are thefirst to be based on a new, redesigned sampleof hospitals. Thus, the most recent estimatesavailable are for 2004.

Many factors can influence the estimates ofED visits, including trends in the ED usagein general. Some drug users may have visitedEDs for a variety of reasons, some of whichmay have been life-threatening, whereas

others may have sought care at the ED fordetoxification because they neededcertification before entering treatment.DAWN data do not distinguish the drugresponsible for the ED visit from others usedconcomitantly. As stated in a recent DAWNreport, Since marijuana/hashish isfrequently present in combination with otherdrugs, the reason for the ED contact may bemore relevant to the other drug(s) involvedin the episode.

For 2004, DAWN estimates a total of1,997,993 (95 percent confidence interval[CI]: 1,708,205 to 2,287,781) drug-related EDvisits for the entire United States. During thisperiod, DAWN estimates 940,953 (CI:773,124 to 1,108,782) drug-related ED visits

involved a major drug of abuse. Thus, nearlyhalf of all drug-related visits involved alcoholor an illicit drug. Overall, drug-related EDvisits averaged 1.6 drugs per visit, includingillicit drugs, alcohol, prescription and over-the-counter (OTC) pharmaceuticals, dietarysupplements, and non-pharmaceuticalinhalants.

Marijuana was involved in 215,665 (CI:175,930 to 255,400) ED visits, while cocainewas involved in 383,350 (CI: 284,170 to482,530) ED visits, heroin was involved in162,137 (CI: 122,414 to 201,860) ED visits,and stimulants, including amphetamine andmethamphetamine, were involved in 102,843(CI: 61,520 to 144,166) ED visits. Other illicitdrugs, such as PCP, MDMA, and GHB, were

much less frequently associated with EDvisits.

Approximately 18 percent of ED visitsinvolving marijuana were for patients underthe age of 18, whereas this age groupaccounts for less than 1 percent of the EDvisits involving heroin/morphine andapproximately 3 percent of the visitsinvolving cocaine. Since the size of thepopulation differs across age groups, ameasure standardized for population size isuseful to make comparisons. For marijuana,the rates of ED visits per 100,000 populationwere highest for patients aged 18 to 20 (225ED visits per 100,000) and for patients aged21 to 24 (190 ED visits per 100,000).

Treatment Episode Data SetTEDS (TEDS, 2003; http://oas.samhsa.gov/

dasis.htm#teds2) system is part ofSAMHSAs Drug and Alcohol ServicesInformation System (Office of AppliedScience, SAMHSA). TEDS comprises data ontreatment admissions that are routinelycollected by States in monitoring theirsubstance abuse treatment systems. TheTEDS report provides information on thedemographic and substance usecharacteristics of the 1.8 million annualadmissions to treatment for abuse of alcoholand drugs in facilities that report toindividual State administrative data systems.

TEDS is an admission-based system, andTEDS admissions do not representindividuals. Thus, a given individualadmitted to treatment twice within a givenyear would be counted as two admissions.Additionally, TEDS does not include alladmissions to substance abuse treatment.TEDS includes facilities that are licensed orcertified by the States to provide substanceabuse treatment and that are required by the

States to provide TEDS client-level data.Facilities that report TEDS data are those thatreceive State alcohol and/or drug agencyfunds for the provision of alcohol and/ordrug treatment services. The primary goal forTEDS is to monitor the characteristics oftreatment episodes for substance abusers.

Primary marijuana abuse accounted for15.5 percent of TEDS admissions in 2003, thelatest year for which data are available.Three-quarters of the individuals admittedfor marijuana were male and 55 percent ofthe admitted individuals were white. Theaverage age at admission was 23 years. Thelargest proportion (84 percent) of admissionsto ambulatory treatment was for primarymarijuana abuse. More than half (57 percent)

of marijuana treatment admissions werereferred through the criminal justice system.

Between 1993 and 2003, the percentage ofadmissions for primary marijuana useincreased from 6.9 percent to 15.5 percent,comparable to the increase for primaryopioid use from 13 percent in 1993 to 17.6percent in 2003. In contrast, the percentageof admissions for primary cocaine usedeclined from 12.6 percent in 1993 to 9.8percent in 2003, and for primary alcohol usefrom 56.9 percent in 1993 to 41.7 percent in2003.

Twenty-six percent of those individualswho were admitted for primary use ofmarijuana reported its daily use, although34.6 percent did not use marijuana in the

past month. Nearly all (96.2 percent) ofprimary marijuana users utilized the drug bysmoking it. Over 90 percent of primarymarijuana admissions used marijuana for thefirst time before the age of 18.

5. THE SCOPE, DURATION, ANDSIGNIFICANCE OF ABUSE

The fifth factor the Secretary must consideris the scope, duration, and significance ofmarijuana abuse. According to 2004 datafrom NSDUH and MTF, marijuana remainsthe most extensively used illegal drug in theUnited States, with 40.6 percent of U.S.individuals over age 12 (96.6 million) and44.8 percent of 12th graders having usedmarijuana at least once in their lifetime.

While the majority of individuals over age 12(85 percent) who have used marijuana do notuse the drug monthly, 14.6 millionindividuals (6.1 percent of the U.S.population) report that they used marijuanawithin the past 30 days. An examination ofuse among various age cohorts in NSDUHdemonstrates that monthly use occursprimarily among college age individuals,with use dropping off sharply after age 25.

DAWN data show that marijuana wasinvolved in 79,663 ED visits, which amountsto 13 percent of all drug-related ED visits.Minors accounted for 15 percent of thesemarijuana-related visits, making marijuana

the drug most frequently associated with EDvisits for individuals under the age of 18years.

Data from TEDS show that 15.5 percent ofall admissions were for primary marijuanaabuse. Approximately 90 percent of theseprimary marijuana admissions were forindividuals under the age of 18 years.

6. WHAT, IF ANY, RISK THERE IS TO THE

PUBLICThe sixth factor the Secretary must

consider is the risk marijuana poses to thepublic health. The risk to the public healthas measured by emergency room episodes,marijuana-related deaths, and drug treatmentadmissions is discussed in full under Factors1, 4, and 5, above. Accordingly, Factor 6focuses on the health risks to the individualuser.

All drugs, both medicinal and illicit, havea broad range of effects on the individualuser that are dependent on dose and durationof use among others. FDA-approved drugproducts can produce adverse events (orside effects) in some individuals even atdoses in the therapeutic range. When

determining whether a drug product is safeand effective for any indication, FDAperforms an extensive risk-benefit analysis todetermine whether the risks posed by thedrug products potential or actual side effectsare outweighed by the drug productspotential benefits. As marijuana is not FDA-approved for any medicinal use, anypotential benefits attributed to marijuana usehave not been found to be outweighed by therisks. However, cannabinoids are generallypotent psychoactive substances and arepharmacologically active on multiple organsystems.

The discussion of marijuanas centralnervous system, cognitive, cardiovascular,autonomic, respiratory, and immune system

effects are fully discussed under Factor 2.Consequences of marijuana use and abuse arediscussed below in terms of the risk fromacute and chronic use of the drug to theindividual user (Institute of Medicine, 1999).

Risks from acute use of marijuana

Acute use of marijuana impairspsychomotor performance, includingperformance of complex tasks, which makesit inadvisable to operate motor vehicles orheavy equipment after using marijuana(Ramaekers et al., 2004). Dysphoria andpsychological distress, including prolongedanxiety reactions, are potential responses ina minority of individuals who use marijuana(Haney et al., 1999).

Risks from chronic use of marijuana

Chronic exposure to marijuana smoke isconsidered to be comparable to tobaccosmoke with respect to increased risk ofcancer, lung damage, and poor pregnancyoutcome. Although a distinctive marijuanawithdrawal syndrome has been identified,indicating that marijuana produces physicaldependence, this phenomenon is mild andshort-lived (Budney et al., 2004), as describedabove under Factor 2.

The Diagnostic and Statistical Manual(DSMIVTR, 2000) of the AmericanPsychiatric Association states that the

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