UTopiAH’s life expectancy and death rate are below the Marijuana states, which as of 2017, filled the top quintile state rankings. See Part 16. These parts contain the 2015 Drug Enforcement Agency’s response to a 2011 petition from the Governors of Washington and Rhode Island to legalize Marijuana, a DEA Schedule One Drug. . The letter is viewable at https://www.deadiversion.usdoj.gov/schedules/marijuana/Incoming_Letter_Department%20_HHS.pdf#search=marijuana.

[Continued from Part 36]

Part 37 – Marijuana’s PSYCHIC OR PHYSIOLOGIC DEPENDENCE PRECURSOR OF A SUBSTANCE pursuant to Controlled Substances Act, no medical use, and unsafe.

7. ITS PSYCHIC OR PHYSIOLOGIC DEPENDENCE LIABILITY

Under the seventh factor, the Secretary must consider marijuana’s psychic or physiological dependence liability.

Psychic or psychological dependence has been shown in response to marijuana’s ·psychoactive effects. Psychoactive responses to marijuana are pleasurable to many humans And are associated with drug-seeking and drug-taking(Maldonado, 2002). Moreover, high levels of psychoactive effects, notably positive reinforcement, are associated with increased marijuana use, abuse, and dependence (Scherrer et al., 2009; Zeiger et al., 2010). Epidemiological data support these findings through 20 12 NSDUH statistics that show that of individuals years 12 or older who used marijuana in the past month, an estimated 40.3 percent used marijuana on 20 or more days within the past month. This equates to approximately 7.6 million individuals aged 12 or older who used marijuana on a daily or almost daily basis. Additionally, the 2013 MTF data report the prevalence of daily marijuana use, defined as use on 20 or more days within the past 30 days, in 8^th \ 10^th , and 12^th graders is 1.1 percent, 4.0 percent, and 6.5 percent, respectively.

Tolerance is a state of adaptation where exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time (American Academy of Pain Medicine, American Pain Society and American Society of Addiction Medicine consensus document, 2001). Tolerance can develop to some, but not all, of marijuana’s effects. Specifically, tolerance does not seem to develop in response to many of marijuana’s psychoactive effects. This lack oft tolerance may relate to electrophysiological data demonstrating that chronic delta -9 THC administration does not affect increased neuronal firing in the ventral tegmental area, a region known to play a critical role in drug reinforcement and reward (Wu and French,2000). In the absence of other abuse indicators, such as rewarding properties, the presence of tolerance or physical dependence does not determine whether a drug has abuse potential.

However, humans can develop tolerance to marijuana’s cardiovascular, autonomic, and behavioral effects (Jones et al., 1981). Tolerance to some of marijuana’s behavioral effects seems to develop after heavy marijuana use, but not after occasional marijuana use. For instance, following acute administration of marijuana, heavy marijuana users did not exhibit impairments in tracking and attention tasks, as were seen in occasional marijuana users (Ramaekers et al., 2009). Furthermore, a neurophysiological assessment administered

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through an electroencephalograph (EEG) which measures event-related potentials (ERP) conducted in the same subjects as the previous study, found a corresponding effect in the

P100    [Footnote 22 The P100 component of ERPs are thought to relate to the visual processing of stimuli and can be modulated by attention. ]

compound of ERPs. Specifically, corresponding to performance on tracking and attention tasks, heavy marijuana users showed no changes in P 100 amplitudes following acute marijuana administration, although occasional users showed a decrease in P1 00 amplitudes (Theunissen et al., 2012). A possible mechanism underlying tolerance to marijuana’s effects may be the down-regulation of cannabinoid receptors (Hirvonen et al., 2012; Gonzalez et al., 2005; Rodriguez de Fonseca et al., 1994; Oviedo et al., 1993).

Importantly, pharmacological tolerance alone does not indicate a drug’s physical dependence liability. In order for physical dependence to exist, evidence of a withdrawal syndrome is needed. Physical dependence is a state of adaptation, manifested by a drug-class specific withdrawal syndrome produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration o f an antagonist (ibid). Many medications not associated with abuse or addiction can produce physical dependence and withdrawal symptoms after chronic use.

Discontinuation of heavy, chronic marijuana use has been shown to lead to physical dependence and withdrawal symptoms (American Psychiatric Association DSM-V, 2013; Budney and Hughes, 2006; Haney et al., 1999). In heavy, chronic marijuana users, the most commonly reported withdrawal symptoms are sleep difficulties, decreased appetite or weight loss, irritability, anger, anxiety or nervousness, and restlessness. Some less commonly reported withdrawal symptoms are depressed mood, sweating, shakiness, physical discomfort, and chills (Budney and Hughes, 2006; Haney et al., 1999). The occurrence of marijuana withdrawal symptoms in light or non-daily marijuana users has not been established. The American Psychiatric Association’s DSM-V (2013) includes a list of symptoms of “cannabis withdrawal.” Most marijuana withdrawal symptoms begin within 24-48 hours of discontinuation, peak within 4-6 days, and last for 1-3 weeks. Marijuana withdrawal syndrome has been reported in adolescents and adults admitted for substance abuse treatment.

Based on clinical descriptions, this syndrome appears to be mild compared to classical alcohol and barbiturate withdrawal syndromes, which can include more serious symptoms such as agitation, paranoia, and seizures. Multiple studies comparing marijuana and tobacco withdrawal symptoms in humans demonstrate that the magnitude and time course of the two withdrawal syndromes are similar (Budney et al., 2008; Vandrey et al., 2005, 2008).

8. WHETHER THE SUBSTANCE IS AN IMMEDIATE PRECURSOR OF A SUBSTANCE ALREADY CONTROLLED UNDER THIS ARTICLE

Under the eight factor analysis, the Secretary must consider whether marijuana is an immediate precursor of a controlled substance. Marijuana is not an immediate precursor of another controlled substance.

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RECOMMENDATION

After consideration of the eight factors discussed above, FDA [FOOD AND DRUG ADMINISTRATION] recommends that marijuana remain in Schedule I of the CSA. NIDA concurs with this scheduling recommendation. Marijuana meets the three criteria for placing a substance in Schedule I of the CSA [CONTROLLED SUBSTANCES ACT]under 21 U.S.C. 812(b)(l):

1) Marijuana has a high potential for abuse:

A number of factors indicate marijuana’s high abuse potential, including the large number of individuals regularly using marijuana, marijuana’s widespread use, and the vast amount of marijuana available for illicit use. Approximately 18.9 million individuals in the United States(7.3 percent of the U.S. population) used marijuana monthly in 2012. Additionally, approximately 4.3 million individuals met diagnostic criteria for marijuana dependence or abuse in the year prior to the 2012 NSDUH survey. A 2013 survey indicates that by 12^th grade, 36.4 percent of students report using marijuana within the past year, and 22.7 percent report using marijuana monthly. In 2011, 455,668 ED visits were marijuana-related, representing 36.4 percent of a illicit drug-related episodes. Primary marijuana use accounted for 18.1 percent of admissions to drug treatment programs in 2011. Additionally, marijuana has dose-dependent reinforcing effects, as demonstrated by data showing that humans prefer relatively higher doses to lower doses. Furthermore, marijuana use can result in psychological dependence.

2) Marijuana has no currently accepted medical use in treatment in the United States:

FDA [FOOD AND DRUG ADMINISTRATION] has not approved a marketing application for a marijuana drug product for any indication. The opportunity for scientists to conduct clinical research with marijuana exists, and there are active INDs for marijuana; however, marijuana does not have a currently accepted medical use for treatment in the United States, nor does marijuana have an accepted medical use with severe restrictions.

A drug has a “currently accepted medical use” if all of the following five elements have been satisfied:

1. the drug’s chemistry is known and reproducible;
2. there are adequate safety studies;
3. there are adequate and well-controlled studies proving efficacy;
4. the drug is accepted by qualified experts; and
5. the scientific evidence is widely available.

[57 FR 10499, March 26, 1992]

Marijuana does not meet any of the elements for having a “currently accepted medical use.” First, FDA [FOOD AND DRUG ADMINISTRATION] broadly evaluated marijuana, and did not focus its evaluation on particular strains of marijuana or components or derivatives of marijuana. Since different strains may have different chemical constituents, marijuana, as identified in this petition,

[Ed. Petitions were submitted in 2011 to the DEA, by Governors Chafee of Rhode Island and Gregoire of Washington, to repeal rules placing Marijuana in Schedule I of the Controlled Substance Act, contending it is accepted and safe for medical use, with low abuse potential. The DEA Administrator requested HHS evaluate scientific and medical information with recommendations. The Secretary HHS, Controlled Substance Staff, Center for Drug Evaluation and Research, FDA replied to the DEA in 2015.]

does not have a

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known and reproducible chemistry, which would be needed to provide standardized doses.

Second, there are not adequate safety studies on marijuana in the medical literature in relation to a specific, recognized disorder. Third, there are no published adequate and well­ controlled studies proving efficacy of marijuana. Fourth, there is no evidence that qualified experts accept marijuana for use in treating a specific, recognized disorder. Lastly, the scientific evidence regarding marijuana’s chemistry in terms o f a specific Cannabis strain that could produce standardized and reproducible doses is not currently available, so the scientific evidence on marijuana is not widely available.

Alternately, a Schedule II drug can be considered to have a “currently accepted medical use with severe restrictions”(21 U.S.C. 812(b)(2)(B)). Yet as stated above, the lack of accepted medical use for a specific, recognized disorder precludes the use o f marijuana even under conditions where its use is severely restricted.

In conclusion, to date, research on marijuana’s medical use has not developed to the point where marijuana is considered to have a “currently accepted medical use” or a “currently accepted medical use with severe restrictions.”

3) There is a lack of accepted safety for use of marijuana under medical supervision:

There are currently no FDA [FOOD AND DRUG ADMINISTRATION]-approved marijuana drug products. Marijuana does not have a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions. Thus, FDA has not determined that marijuana is safe for use under medical supervision.

In addition, FDA cannot conclude that marijuana has an acceptable level o f safety relative to · its effectiveness in treating a specific, recognized disorder without evidence that the substance is contamination free, and assurance of a consistent and predictable dose. Investigations into the medical use of marijuana should include information and data regarding the chemistry, manufacturing, and specifications of marijuana. Additionally, a procedure for delivering a consistent dose of marijuana should also be developed. Therefore, FDA concludes marijuana does not currently have an accepted level of safety for use under medical supervision.

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Addiction Research Center Inventory (ARCI)

adenosine triphosphate (ATP)

adrenocorticotropic hormone (ACTH),

biologics license application (BLA)

cannabinoid receptor type 1 (CB1)

cannabichromene (CBC)

cannabidiol (CBD)

cannabinol (CBN)

Conditioned place preference (CPP)

Controlled Substances Act (CSA)

Controlled Substance Staff, Center for Drug Evaluation and Research, FDA

delta 9-THC

Diagnostic and Statistical Manual (DSM-5)

Drug Abuse Warning Network (DAWN) SAMHSA

Emergency Department [ED]

FDA Center for Drug Evaluation and Research

Food and Drug Administration (FDA)

U.S. Department of Health and Human Services (HHS)

International Classification of Diseases (ICD-10

[Investigational new drug] IND

IQ Intelligence Quotient

Monitoring the Future (MTF) survey

National Institutes of Health’s National Institute on Drug Abuse (NIH/NIDA)

[National Survey on Drug Use and Health] (NSDUH)

[new drug application] NDA

NMDA antagonists; N-Methyl-D-aspartate -anesthetics that antagonize, or inhibit the action

Substance Abuse and Mental Health Services Administration (SAMHSA)

System to Retrieve Information from, Drug Evidence (STRIDE) DEA’s

tetrahydrocannabinol (THC)

Treatment Episode Data Set (TEDS) 2011

[Continued next Part 38]

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