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 32]

Part 33. Marijuana Scientific knowledge Chemistry, Human Pharmacokinetics, smokes, oral, metabolism, excretion, cannabinoid, and medical use.

3. THE STATE OF CURRENT SCIENTIFIC KNOWLEDGE REGARDING THE DRUG OR OTHER SUBSTANCE

Under the third factor, the Secretary must consider the state of current scientific knowledge regarding marijuana. Thus, this section discusses the chemistry, human pharmacokinetics, and medical uses of marijuana.

Chemistry

Marijuana is one of the common names of Cannabis sativa L. in the family Cannabaceae. Cannabis is one of the oldest cultivated crops, providing a source of fiber, food, oil, and drug. Botanists still debate whether Cannabis should be considered as a single (The Plant List, 201 0) or three species, i.e., C. sativa, C. indica, and C. ruderalis (Hillig, 2005). Specifically, marijuana is developed as sativa and indica cultivated varieties (strains) or various hybrids.

The petition defines marijuana as including all Cannabis cultivated strains.

[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.]

Different marijuana samples derived from various cultivated strains may have very different chemical constituents including delta 9-THC and other cannabinoids (Appendino et al., 2011). As a consequence, marijuana products from different strains will have different safety, biological, pharmacological, and toxicological profiles. Thus, all Cannabis strains cannot be considered together because of the varying chemical constituents between strains.

Marijuana contains numerous naturally occurring constituents including cannabinoids. Overall, various Cannabis strains contain more than 525 identified natural constituents. Among those constituents, the most important ones are the 21 (or 22) carbon terpenoids found in the plant, as well as their carboxylic acids, analogues, and transformation products, known as cannabinoids (Agurell et al., 1984, 1986; Mechoulam, 1973; Appendino et al., 2011). Thus far, more than 100 compounds classified as cannabinoids have been characterized (ElSohly and Slade, 2005; Radwan, ElSohly et al., 2009; Appendino et al. 2011).

Cannabinoids primarily exist in Cannabis, and published data suggest that most major cannabinoid compounds occurring naturally have been chemically identified. New and minor cannabinoids and other new compounds are continuously being characterized (Pollastro et al., 2011). So far, only two cannabinoids (cannabigerol and its corresponding acid) have been obtained from a non-Cannabis source. A South African Helichrysum (Humbraculigerum) accumulates these compounds (Appendino et al. 2011).

Among the cannabinoids found in marijuana, delt a9-THC (alternate name delta 1-THC) and delta-8-tetrahydrocannabinol (delta 8 – THC, alternate name delta 6-THC) produce marijuana’s characteristic psychoactive effects. Because delta9-THC is more abundant than delta8-THC,

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marijuana’s psychoactivity is largely attributed to the former. Only a few varieties of marijuana analyzed contain delta 8-THC at significant amounts (Hively et al., 1966). Delta 9-­ THC is an optically active resinous substance, insoluble in water, and extremely lipid­

soluble. Chemically, delta 9-THC is (6aR-trans)-6a,7,8, 10a-tetrahydro-6,6,9-trimethy1-3­

pentyl-6H-dibenzo-[b,d]pyran-1-ol, or (-)-delta 9-(trans)-tetrahydrocannabinol. The (-)-trans

isomer of delta 9-THC is pharmacologically 6-100 times more potent than the (+)-trans

isomer (Dewey et al., 1984).

Other cannabinoids present in marijuana include CBD, CBC, and CBN. CBD, a major cannabinoid of marijuana, is insoluble in water and lipid-soluble. Chemically, CBD is 2­ [(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol. CBD · does not have cannabinol-like psychoactivity (Adams and Martin, 1996; Agurell et al., 1984, 1986; Hollister, 1986). CBC is another major cannabinoid in marijuana. Chemically, CBC is 2-methyl-2-(4-methylpent-3-enyl)-7-pentyl-5-chromenol. CBN, a major metabolite of

delta 9-THC, is also a minor naturally-occurring cannabinoid with weak psychoactivity.

Chemically, CBN is 6,6,9-trimethyl-3-pentyl-benzo[c]chromen-1-ol.

Different marijuana samples derived from various cultivated strains may differ in chemical constituents including delta 9-THC and other cannabinoids (Appendino et al. 2011). As a

consequence, marijuana products from different strains may have different safety, biological, pharmacological, and toxicological profiles. In addition to differences between cultivated strains, the concentration of delta9-THC and other cannabinoids in marijuana may vary with growing conditions and processing after harvest. In addition to genetic differences among Cannabis species, the plant parts collected-for example, flowers, leaves, and stems–can influence marijuana’s potency, quality, and purity (Adams and Martin, 1996; Agurell et al., 1984; Mechoulam, 1973). All these variations produce marijuana with potencies, as indicated by cannabinoid content, on average from as low as 1-2 percent to as high as 17

percent.

Overall, these variations in the concentrations of cannabinoids and other chemical constituents in marijuana complicate the interpretation of clinical data using marijuana. The lack of consistent concentrations of delta9- THC and other substances in marijuana from diverse sources makes interpreting the effect of different marijuana constituents difficult. In addition to different cannabinoid concentrations having different pharmacological and toxicological profiles, the non-cannabinoid components in marijuana, such as other terpenoids and flavonoids, might also contribute to the overall pharmacological and toxicological profiles of various marijuana strains and products derived from those strains.

The term marijuana is often used to refer to a mixture of the dried flowering tops and leaves from Cannabis. Marijuana in this limiting definition is one of three major derivatives sold as separate illicit products, which also include hashish and hash oil. According to the DEA, Cannabis sativa is the primary species of Cannabis currently marketed illegally in the United States.

Marijuana can vary in cannabinoid content and potency (Agurell et al., 1984, 1986; Mechoulam 1973, Cascini et al.,2012). In the usual mixture of leaves and stems distributed

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as marijuana, the concentration of delta 9-THC averages over 12 percent by weight.

However, specially grown and selected marijuana can contain 15 percent or greater delta ­9-THC (Appendino et al. 2011). Thus, a 1-gram marijuana cigarette might contain delta 9-THC

in a range from as little as 3 milligrams to as much as 150 milligrams or more. Additionally,

a recent systematic review and meta-analysis found that marijuana’s delta 9-THC content has

increased significantly from 1979-2009 (Cascini et al., 2012). In addition to smoking marijuana, individuals ingest marijuana through food made with butter or oil infused with marijuana and its extracts. These marijuana butters are generally made by adding marijuana to butter and heating it. The resultant butter is then used to cook a variety of foods. There are no published studies measuring the concentrations of cannabinoids in these marijuana food products.

Hashish consists of the dried and compressed cannabinoid-rich resinous material of Cannabis and comes in a variety of forms(e.g. balls and cakes). Individuals may break off pieces, place it into a pipe and smoke it. DEA reports that cannabinoid content in hashish averages six percent (DEA, 2005). With the development and cultivation of more high potency Cannabis strains, the average cannabinoid content in hashish will likely increase.

Hash oil is produced by solvent extraction of the cannabinoids from plant material. The extract’s color and odor vary, depending on the solvent type used. Hash oil is a viscous brown- or amber-colored liquid containing approximately 50 percent cannabinoids. One or two drops of the liquid placed on a cigarette purportedly produce the equivalent of a single marijuana cigarette (DEA, 2005).

In conclusion, marijuana has hundreds of cultivars containing variable concentrations of delta 9-THC, cannabinoids, and other compounds. Thus, marijuana is not a single chemical with a consistent and reproducible chemical profile or predictable and consistent clinical effects. A guidance for industry, entitled Botanical Drug Products, 4

[4 This guidance is available on the Internet at http://www.fda.gov/Drugs/default.htm under Guidance (Drugs). ]

provides information on the approval of botanical drug products. To investigate marijuana for medical use in a manner acceptable as support for marketing approval under an NDA, clinical studies under an [INVESTIGATIONAL NEW DRUG] IND of consistent batches of a particular marijuana product for particular disease indications should be conducted. In addition, information and data regarding the marijuana product’s chemistry, manufacturing and control, pharmacology, and animal toxicology data, among others must be provided and meet the requirements for new drug approval (See 21 CFR 314.50).

Human Pharmacokinetics

Marijuana can be taken in a variety of formulations by multiple routes of administration. Individuals smoke marijuana as a cigarette, weighing between 0.5 and 1.0 gram, or in a pipe. Additionally, individuals take marijuana orally in foods or as an extract in ethanol or other solvents. More recently, access to vaporizers provides another means for abusers to inhale marijuana,

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The absorption, metabolism, and pharmacokinetic profile of delta 9-THC, cannabinoids, and drug products containing delta 9-THC vary with route of administration and formulation

(Adams and Martin, 1996; Agurell et al., 1984, 1986).

Pharmacokinetics of Smoked Administration of Cannabinoids

Characterization of the pharmacokinetics of delta 9-THC and other cannabinoids from smoked marijuana is difficult because a subject’s smoking behavior during an experiment varies

(Agurell et al., 1986; Heming et al., 1986; Huestis et al., 1992a). Each puff delivers a

discrete dose of delta-9-THC. An experienced marijuana smoker can titrate and regulate the dose to obtain the desired acute psychological effects and minimize undesired effects. For example, under naturalistic conditions, users hold marijuana smoke in their lungs for an extended period of time which causes prolonged absorption and increases psychoactive effects. The effect of experience in the psychological response may explain why delta9-THC venous blood levels correlate poorly with intensity of effects and intoxication level (Agurell et al. 1986; Barnett et al. 1985; Huestis et al., 1992a). Puff and inhalation volumes should be recorded in studies as the concentration (dose) of cannabinoids administered can vary at different stages of smoking.

Smoked marijuana results in absorption of delta 9-THC in the form of an aerosol within

seconds. Psychoactive effects occur immediately following absorption, with mental and

behavioral effects measurable for up to 6 hours (Grotenhermen, 2003; Hollister 1986, 1988).

Delta 9-THC is delivered to the brain rapidly and efficiently as expected of a very lipid­

soluble drug.

The bioavailability of the delta9-THC, from marijuana in a cigarette or pipe, can range from 1 to 24 percent with the fraction absorbed rarely exceeding 10 to 20 percent (Agurell et al.,

1986; Hollister, 1988). The relatively low and variable bioavailability results from 9

significant loss of delta 9-THC in side-stream smoke, variation in individual smoking behaviors, cannabinoid pyrolysis, incomplete absorption of inhaled smoke, and metabolism in the lungs. An individual’s experience and technique with smoking marijuana also determines the dose absorbed (Heming et al., 1986; Johansson et al., 1989). After smoking, delta9-THC venous levels decline precipitously within minutes, and continue to go down to about 5 to 10 percent of the peak level within an hour (Agurell et al., 1986, Huestis et al., 1992a, 1992b).

Pharmacokinetics for Oral Administration of Cannabinoids

After oral administration of delta 9- THC or marijuana, the onset of effects starts within 30 to 90 minutes, reaches its peak after 2 to 3 hours and then remains for 4 to 12 hours

(Grotenhermen, 2003; Adams and Martin, 1996; Agurell et al., 1984, 1986). Due to the delay in onset of effects, users have difficulty in titrating oral delta 9- THC doses compared to 9

smoking marijuana. Oral bioavailability of delta 9-THC, whether pure or in marijuana, is low

and extremely variable, ranging between 5 and 20 percent (Agurell et al., 1984, 1986). 99

Following oral administration of radioactive-labeled delta 9-THC, delta 9 -THC plasma levels are low relative to plasma levels after smoking or intravenous administration. Inter- and

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intra-subject variability occurs even with repeated dosing under controlled conditions. The low and variable oral bioavailability of delta9-THC is a consequence of its first-pass hepatic [Ed-liver] elimination from blood and erratic absorption from stomach and bowel.

Cannabinoid Metabolism and Excretion

Cannabinoid metabolism is complex. Delta 9-THC is metabolized via microsomal

hydroxylation to both active and inactive metabolites (Lemberger et al., 1970, 1972a, 1972b;

Agurell et al., 1986; Hollister, 1988). The primary active metabolite of delta 9-THC

following oral ingestion is 11-hydroxy-delta 9-THC. This metabolite is approximately

equipotent to delta 9-THC in producing marijuana-like subjective effects (Agurell et al., 1986,

Lemberger and Rubin, 1975). After oral administration, metabolite levels may exceed that of

delta 9-THC and thus contribute greatly to the pharmacological effects of oral delta 9-THC or

marijuana.

Plasma clearance of delta 9-THC approximates hepatic blood flow at about 950 ml/min [Editor-‘ml’ milliliters or ‘cc’ cubic centimeters of volume per minute of time] or greater. The rapid disappearance of delta 9-THC from blood is largely due to redistribution to

other tissues in the body, rather than to metabolism (Agurell et al., 1984, 1986). Metabolism

in most tissues is relatively slow or absent. Slow release of delta 9- THC and other

cannabinoids from tissues and subsequent metabolism results in a long elimination half-life.

The terminal half-life of delta 9-THC ranges from approximately 20 hours to as long as 10 to

13 days, though reported estimates vary as expected with any slowly cleared substance and

the use of assays with variable sensitivities (Hunt and Jones, 1980). Lemberger et al. (1970)

determined the half-life of delta 9 -THC to range from 23 to 28 hours in heavy marijuana users to 60 to 70 hours in naive users. In addition to 11-hydroxy-delta 9-THC, some inactive

carboxy metabolites have terminal half-lives of 50 hours to 6 days or more. The latter substances serve as long-term markers in urine tests for earlier marijuana use.

The majority of the absorbed delta 9-THC dose is eliminated in feces, and about 33 percent in urine. Delta 9-THC enters enterohepatic circulation and undergoes hydroxylation and

oxidation to 11-nor-9-carboxy-delta 9-THC. The glucuronide is excreted as the major urine

metabolite along with about 18 non-conjugated metabolites. Frequent and infrequent marijuana users metabolize delta 9-THC similarly (Agurell et al., 1986).

[Continued next Part 34]

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