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 31]

Part 32. Marijuana’s Neurochemistry and Pharmacology under Controlled Substance Act, as of 2015 and Scientific Evidence.

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2. SCIENTIFIC EVIDENCE OF ITS PHARMACOLOGICAL EFFECTS, IF KNOWN

Under the second factor, the Secretary must consider the scientific evidence of marijuana’s pharmacological effects. Abundant scientific data are available on the neurochemistry, toxicology, and pharmacology of marijuana. This section includes a scientific evaluation of marijuana’s neurochemistry; pharmacology; and human and animal behavioral, central nervous system, cognitive, cardiovascular, autonomic, endocrinological and immunological system effects. The over view presented below relies upon the current research literature on cannabinoids available in the public domain.

Neurochemistry and Pharmacology of Marijuana

Marijuana is a plant that contains numerous natural constituents, such as cannabinoids, that have a variety of pharmacological actions. 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 MJ 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 biological and pharmacological profiles.

According to ElSohly and Slade (2005) and Appendino et al. (2011), marijuana contains approximately 525 identified natural constituents, including approximately 100 compounds classified as cannabinoids. Cannabinoids primarily exist in Cannabis, and published data suggests that most major cannabinoid compounds occurring naturally have been identified chemically. 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). The chemistry of marijuana is described in more detail in Factor 3, “The State of Current Scientific Knowledge Regarding the Drug or Other Substance.”

The site of cannabinoid action is at the cannabinoid receptors. Cloning of cannabinoid receptors, first from rat brain tissue (Matsuda et al., 1990) and then from human brain tissue (Gerard et al., has verified the site of action. Two cannabinoid receptors, CB1 and CB2, were characterized (Battista et al., 2012; Piomelli, 2005). Evidence of a third cannabinoid receptor exists, but it has not been identified (Battista et al., 2012).

The cannabinoid receptors, CB1 and CB2, belong to the family of G-protein-coupled receptors, and present a typical seven transmembrane -spanning domain structure. Cannabinoid receptors link to an inhibitory G-protein (Gi), such that adenylate cyclase activity is inhibited when a ligand binds to the receptor. This, in turn, prevents the conversion of ATP to the second messenger, cyclic AMP (cAMP). Examples of inhibitory­ coupled receptors include   opioid, muscarinic cholinergic, alpha2-adrenoreceptors, dopamine (D2), and serotonin (5-HT).

Cannabirioid receptor activation inhibits N- and P/Q-type calcium channels and activates inwardly rectifying potassium channels (Mackie et al., 1995; Twitchell et al., 1997). N-type

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calcium channel inhibition decreases neurotransmitter release from several tissues. Thus, calcium channel inhibition may be the mechanism by which cannabinoids inhibit acetylcholine, norepinephrine, and glutamate release from specific are as of the brain. These effects may represent a potential cellular mechanism underlying cannabinoids’ antinociceptive and psychoactive effects (Ameri, 1999).

CB receptors are found primarily in the central nervous system, but are also present in peripheral tissues. CB receptors are located mainly in the basal ganglia, hippocampus, and cerebellum of the brain (Howlett et al., 2004). The localization of these receptors may explain cannabinoid interference with movement coordination and effects on memory and cognition. Additionally, CB receptors are found in the immune system and numerous other peripheral tissues (Petrocellis and DiMarzo, 2009). However, the concentration of CB1 receptors is considerably lower in peripheral tissues than in the central nervous system (Herkenham et a!., 1990 and 1992).

CB2 receptors are found primarily in the immune system, but are also present in the central nervous system and other peripheral tissues. In the immune system, CB2 receptors are found predominantly in B lymphocytes and natural killer cells (Bouaboula et al, 1993). CB2 receptors may mediate cannabinoids’ immunological effects (Galiegue et al, 1995). Additionally, CB2 receptors have been localized in the brain, primarily in the cerebellum and hippocampus (Gong et al., 2006). The distribution of CB2 receptors throughout the body is less extensive than the distribution of CB1 receptors (Petrocellis and Di Marzo, 2009). However, both CB1 and CB2 receptors are present in numerous tissues of the body.

Cannabinoid receptors have endogenous ligands. In 1992 and 1995, two endogenous cannabinoid receptor agonists, anandamide and arachidonyl glycerol (2-AG), respectively, were identified (DiMarzo, 2006). Anandamide is a low efficacy agonist (Breivogel and Childers, 2000) and 2-AG is a high efficacy agonist (Gonsiorek et al., 2000). Cannabinoid endogenous ligands are present in central as well as peripheral tissues. A combination of uptake and hydrolysis terminate the action of the endogenous ligands. The endogenous cannabinoid system is a locally active signaling system that, to help restore homeostasis, is activated “on demand” in response to changes to the local homeostasis (Petrocellis and Di Marzo, 2009). The endogenous cannabinoid system, including the endogenous cannabinoids and the cannabinoid receptors, demonstrate substantial plasticity in response to several physiological and pathological stimuli (Petrocellis and Di Marzo, 2009). This plasticity is particularly evident in the central nervous system.

Delta 9 – THC and cannabidiol (CBD) are two abundant cannabinoids present in marijuana. Marijuana’s major psychoactive cannabinoid is delta 9-THC (Wachtel et al., 2002). In 1964, Gaoni and Mechoulam first described delta 9 -THC’s structure and function. In 1963, Mechoulam and Shvo first described CBD’s structure. The pharmacological actions of CBD have not been fully studied in humans.

Delta 9 – THC and CBD have varying affinity and effects at the cannabinoid receptors. Delta 9 – THC displays similar affinity for CB 1 and CB2 receptors, but behaves as a weak agonist for  CB2 receptors. The identification of synthetic cannabinoid ligands that selectively bind to

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CB2 receptors but do not have the typical delta 9-THC-like psychoactive properties suggests that the activation of CB1 – receptors mediates cannabinoids’ psychotropic effects (Hanus et

al., 1999). CBD has low affinity for both CB 1 and CB 2 receptors (Mechoulam et al., 2007). According to Mechoulam et al. (2007), CBD has antagonistic effects at CB 1 receptors and some inverse agonistic properties at CB 2 receptors. When cannabinoids are given subacutely to rats, CB1, receptors down-regulate and the binding of the second messenger system coupled to

CB1 receptors, GTPgammaS, decreases (Breivogel et al., 2001).

Animal Behavioral Effects

Self-Administration

Self-administration is a method that assesses the ability of a drug to produce rewarding effects. The presence of rewarding effects increases the likelihood of behavioral responses to obtain additional drug. Animal self-administration of a drug is often useful in predicting rewarding effects in humans, and is indicative of abuse liability. A good correlation is often observed between those drugs that rhesus monkeys self-administer and those drugs that humans abuse (Balster and Bigelow,2003). Initially, researchers could not establish self­ administration of cannabinoids, including delta 9 -THC, in animal models. However, self-. administration of delta 9 THC can now be established in a variety of animal models under specific training paradigms (Justinova et al., 2003, 2004, 2005).

Squirrel monkeys, with and without prior exposure to other drugs of abuse, self-administer delta 9 – THC under specific conditions. For instance, Tanda et al. (2000) observed that when squirrel monkeys are initially trained to self-administer intravenous cocaine, they will continue to bar-press delta 9 –THC at the same rate as they would with cocaine. The doses were notably comparable to those doses used by humans who smoke marijuana. SR141716, a CB 1 cannabinoid receptor agonist-antagonist, can block this rewarding effect. Other studies show that naive squirrel monkeys can be successfully trained to self-administer delta 9 – THC intravenously (Justinova et al.,2003). The maximal responding rate is 4 ug/kg per injection, which is 2-3 times greater than observed in previous studies using cocaine­ experienced monkeys. Naltrexone, a mu-opioid antagonist, partially antagonizes these rewarding effects of delta 9 – -THC (Justinova et al., 2004).

Additionally, data demonstrate that under specific conditions, rodents self-administer

cannabinoids. Rats will self-administer delta 9- THC when applied intracerebroventricularly

(i.c.v.), but only at the lowest doses tested (0.01-0.02 ug /infusion) (Braida et al., 2004). SR141716 and the opioid antagonist naloxone can antagonize this effect. However, most studies involve rodents self-administrating the synthetic cannabinoid WIN 55212, a CB1 receptor agonist with a non-cannabinoid structure (Deiana et al., 2007; Fattore et al., 2007; Martellotta et al., 1998; Mendizabal et al., 2006).

Aversive effects, rather than reinforcing effects, occur in rats that received high doses of 9

WIN 55212 (Chaperon et al., 1998) or delta 9 – THC (Sanudo-Pena et al., 1997), indicating a possible critical dose – dependent effect. In both studies, SR 141716 reversed these aversive effects.

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Conditioned Place Preference [CPP]

Conditioned place preference (CPP) is a less rigorous method than self-administration for determining whether or not a drug has rewarding properties. In this behavioral test, animals spend time in two distinct environments: one where they previously received a drug and one where they received a placebo. If the drug is reinforcing, animals will choose to spend more time in the environment paired with the drug, rather than with the placebo, when presented with both options simultaneously.

Animals show CPP to delta 9 -THC, but only at the lowest doses tested (0.075-1.0 mg/kg, Intraperitoneal (i.p.)) (Braida et al .,2004). SR141716 and naloxone antagonize this effect

(Braida et al., 2004). As a partial agonist, SR141716 can induce CPP at doses of 0.25,0.5, 2

and 3 mg/kg (Cheer et al., 2000). In knockout mice, those without mice, u-opioid receptors do not develop CPP to de1ta 9 – -THC (Ghozland et al., 2002).

Drug Discrimination Studies

Drug discrimination is a method where animals indicate whether a test drug produces physical or psychic perceptions similar to those produced by a known drug of abuse. In this test, an animal learns to press one bar when it receives the known drug of abuse and another bar when it receives placebo. To determine whether the test drug is like the known drug of abuse, a challenge session with the test drug demonstrates which of the two bars the animal presses more often.

In addition to humans (Lile et al., 2009; Lile et al., 2011 ), it has been noted that animals, including monkeys (McMahon, 2009), mice (McMahon et al., 2008), and rats (Gold et al., 1992), are able to discriminate cannabinoids from other drugs or placebo. More over, the major active metabolite of delta 9-THC, 11-hydroxy-delta 9-THC, also generalizes (following

oral administration) to the stimulus cues elicited by delta 9 -THC (Browne and Weissman,

1981). Twenty-two other cannabinoids found in marijuana also fully substitute for delta 9-THC. However, CBD does not substitute for delta 9 -THC in rats (Vann et al., 2008).

Discriminative stimulus effects of delta 9-THC are pharmacologically specific for marijuana­ containing cannabinoids (Balster and Prescott, 1992; Browne and Weissman, 1981 ; Wiley et al.,1993,I995). The discriminative stimulus effects of the cannabinoid group appear to provide unique effects because stimulants, halIucinogens, opioids, benzodiazepines, barbiturates, NMDA antagonists, and antipsychotics do not fully substitute for delta 9 – THC.

Central Nervous System Effects

Human Psychological and Behavioral Effects

Psychoactive Effects

Below is a list of the common subjective responses to cannabinoids (Adams and Martin, 1996; Gonzalez, 2007; Hollister 1986, 1988; Institute of Medicine, 1982). According to Maldonado (2002), these responses to marijuana are pleasurable to many humans and are

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often associated-with drug-seeking and drug-taking. High levels of positive psychoactive effects are associated with increased marijuana use, abuse, and dependence (Scherrer et al., 2009; Zeiger et al., 2010).

1) Disinhibition, relaxation, increased sociability, and talkativeness.
2) Increased merriment and appetite, and even exhilaration at high doses.
3) Enhanced sensory perception, which can generate an increased appreciation of music, art, and touch.

4) Heightened imagination, which can lead to a subjective sense of increased creativity.

5) Initial dizziness, nausea, tachycardia, facial flushing, dry mouth, and tremor.
6) Disorganized thinking, inability to converse logically, time distortions, and short-term memory impairment.

7) Ataxia and impaired judgment, which can impede driving ability or lead to an increase in risk-tasking behavior.
8) Illusions, delusions, and hallucinations that intensify with higher doses.
9) Emotional liability, incongruity of affect, dysphoria, agitation, paranoia, confusion, drowsiness, and panic attacks, which are more common in inexperienced or high-dosed users.

As with many psychoactive drugs, a person’s medical, psychiatric, and drug-taking history · can influence the individual’s response to marijuana. Dose preferences to marijuana occur in that marijuana users prefer higher concentrations of the principal psychoactive substance (1.95 percent delta 9-THC) over lower concentrations (0.63 percent delta 9 -THC) (Chait and Burke, 1994). Nonetheless, frequent marijuana users (> [greater than] 100 times of use) were able to identify a drug effect from low-dose delta 9 -THC better than occasional users·(<10 times of use) while also experiencing fewer sedative effects from marijuana (Kirk and deWit, 1999).

The petitioners contend that many of marijuana’s naturally occurring cannabinoids mitigate the psychoactive effects of delta 9 -THC, and therefore that marijuana lacks sufficient abuse potential to warrant Schedule I placement, because Marinol, which is in Schedule III, contains only delta 9- THC.

[Ed. Petitioners included Governors Chafee of Rhode Island and Gregoire of Washington, who asked the DEA to repeal rules placing Marijuana in Schedule I of the Controlled Substance Act, contending it was accepted for medical use, safe, and with low abuse potential. The DEA, in turn, received scientific and medical information with recommendations from the Secretary HHS, FDA, Controlled Substance Staff, Center for Drug Evaluation and Research, in 2015.]

This theory has not been demonstrated in controlled studies.  Moreover, the concept of abuse potential encompasses all properties of a substance, including its chemistry, pharmacology, and pharmacokinetics, as well as usage patterns and diversion history. The abuse potential of a substance is associated with the repeated or sporadic use of a substance in nonmedical situations for the psychoactive effects the substance produces. These psychoactive effects include euphoria, perceptual and other cognitive distortions, hallucinations, and mood changes. However, as stated above, the abuse potential not only includes the psychoactive effects, but also includes other aspects related to a substance.

DEA’s final published rule entitled “Rescheduling of the Food and Drug Administration Approved Product Containing Synthetic Dronabinol[(-)-delta 9 (trans)­ Tetrahydrocannabinol] in Sesame Oil and Encapsulated in Soft Gelatin Capsules From Schedule II to Schedule III” (64 FR 35928, July 2, 1999) rescheduled Marinol from Schedule II to Schedule III. The HHS assessment of the abuse potential and subsequent scheduling recommendation compared Marinol to marijuana on different aspects related to abuse

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potential. Major differences in formulation, availability, and usage between marijuana and the drug product, Marinol, contribute to their differing abuse potentials.

Hollister and Gillespie (1973) estimated that delta 9-THC by smoking is 2.6 to 3 times more potent than delta 9-THC ingested orally. The intense psychoactive drug effect achieved rapidly by smoking is generally considered to produce the effect desired by the abuser. This effect explains why abusers often prefer to administer certain drugs by inhalation, intravenously, or intranasally rather than orally. Such is the case with cocaine, opium, heroin, phencyclidine, methamphetamine, and delta 9 -THC from marijuana (0.1-9.5 percent delta 9-THC range) or hashish (10-30 percent delta 9-THC range) (Wesson and Washburn, I990). Thus, the delayed onset and longer duration of action for Marinol may be contributing factors limiting the abuse or appeal of Marinol as a drug of abuse relative to marijuana.

The formulation of Marinol is a factor that contributes to differential scheduling of Marinol and marijuana. For example, extraction and purification of dronabinol from the encapsulated sesame oil mixture of Marinol is highly complex and difficult. Additionally, the presence of sesame oil mixture in the formulation may preclude the smoking of Marinol-Iaced cigarettes.

Additionally, there is a dramatic difference between actual abuse and illicit trafficking of Marinol and marijuana. Despite Marinol’s availability in the United States, there have been no significant reports of abuse, diversion, or public health problems due to Marinol. By comparison, 18.9 million American adults report currently using marijuana (SAMHSA, 2013).

In addition, FDA [FOOD AND DRUG ADMINISTRATION]’s approval of an [NEW DRUG APPLICATION] NDAfor Marinol allowed for Marinol to be rescheduled to Schedule II, and subsequently to Schedule III of the CSA. In conclusion, marijuana and Marinol differ on a wide variety of factors that contribute to each substance’s abuse potential. These differences are major reasons distinguishing the higher abuse potential for marijuana and the different scheduling determinations of marijuana and Marinol.

In terms of the petitioners’ claim that different cannabinoids present in marijuana mitigate

the psychoactive effects of delta 9 -THC, only three of the cannabinoids present in marijuana

were simultaneously administered with delta 9-THC to examine how the combinations of

these cannabinoids such as CBD, cannabichromene (CBC) and cannabinol (CBN) influence
delta 9-THC’s psychoactive effects.

[Ed. Petitioners included Governors Chafee of Rhode Island and Gregoire of Washington, who asked the DEA to repeal rules placing Marijuana in Schedule I of the Controlled Substance Act, contending it was accepted for medical use, safe, and with low abuse potential. The DEA, in turn, received scientific and medical information with recommendations from the Secretary HHS, FDA, Controlled Substance Staff, Center for Drug Evaluation and Research, in 2015.]

Dalton et al. (1976) observed that smoked administration of placebo marijuana cigarettes containing injections of 0.15 mg/kg CBD combined with 0.025 mg/kg of delta 9 – THC, in a 7:1 ratio of CBD to delta 9-THC, significantly decreased ratings of acute subjective effects and “high” when compared to smoking delta 9-THC alone. In contrast, Ilan et al. (2005) calculated the naturally occurring concentrations of CBC and CBD in a batch of marijuana cigarettes with either 1.8 percent or 3.6 percent delta 9-THC concentration by weight. For each strength of delta 9-THC in marijuana cigarettes, the concentrations of CBC and CBD were classified in groups of either low or high. The study varied the amount of CBC and CBD within each strength of delta9-THC marijuana cigarettes, with administrations consisting of either low CBC (between 0.1-0.2 percent CBC concentration by weight) and low CBD (between 0.1-0.4 percent CBD concentration by

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weight), high CBC (> [greater than] 0.5 percent CBC concentration by weight) and low CBD, or low CBC and high CBD (> 1.0 percent CBD concentration by weight). Overall, all combinations scored significantly greater than placebo on ratings of subjective effects, and there was no significant difference between any combinations.

The oral administration of a combination of either 15, 30, or 60 mg CBD with 30 mg delta 9-THE dissolved in liquid (in a ratio of at least 1;2 CBD to delta 9-T H C ) reduced the subjective effects produced by delta 9-THC alone (Karniol et al., 1974). Additionally, orally administering a liquid mixture combining 1 mg/kg CBD with 0.5 mg/kg of delta 9–THC (ratio of 2:I CBD to delta 9-THC) decreased scores of anxiety and marijuana drug effect on the Addiction Research Center Inventory (ARCI) compared to delta 9 -THC alone (Zuardi et al., 1982). Lastly, oral administration of either 12.5, 25, or 50 mg CBN combined with 25 mg delta 9-THC dissolved in liquid (ratio of at least I :2 CBN to delta 9 -THC) significantly increased subjective ratings of “drugged,” “drowsy,” “dizzy,” and “drunk,” compared to delta 9-THC alone (Karniol et al., 1975).

Even though some studies suggest that CBD may decrease some of delta 9-THC’s psychoactive effects, the ratios of CBD to delta 9-THC administered in these studies are not present in marijuana used by most people. For example, in one study, researchers used smoked marijuana with ratios of CBD to delta 9-THC naturally present in marijuana plant material and they found out that varying the amount of CBD actually had no effect on delta 9-THC’s psychoactive effects (llan et al., 2005). Because most marijuana currently available on the street has high amounts of delta 9-THC with low amounts of CBD and other cannabinoids, most individuals use marijuana with low levels of CBD present (Mehmedic et al., 2010). Thus, any possible mitigation of delta 9-THC’s psychoactive effects by CBD will not occur for most marijuana users. In contrast, one study indicated that another cannabinoid present in marijuana, CBN, may enhance delta 9-THC’s psychoactive effects (Kamiol et al., I 975).

Behavioral Impairment

Marijuana induces various psychoactive effects that can lead to behavioral impairment. Marijuana’s acute effects can significantly interfere with a person’s ability to learn in the classroom or to operate motor vehicles. Acute administration of smoked marijuana impairs performance on learning, associative processes, and psychomotor behavioral tests (Block et al., 1992). Ramaekers et al. (2006a) showed that acute administration of 250 ug/kg and 500 ug/kg of delta 9-THC in smoked marijuana dose-dependently impairs cognition and motor control, including motor impulsivity and tracking impairments (Ramaekers et al., 2006b). Similarly, administration of 290 delta 9-THC in a smoked marijuana cigarette resulted in impaired perceptual motor speed and accuracy: two skills which are critical to driving ability (Kurzthaler et al., 1999). Lastly, administration of 3.95 percent delta 9-THC in a smoked marijuana cigarette not only increased disequilibrium measures, but also increased the latency in a task of simulated vehicle braking at a rate comparable to an increase in  stopping distance of five feet at 60 mph (Liguori et al., 1998). However, acute administration of marijuana containing 2.1 percent delta 9-THC does not produce “hangover effects” (Chait, 1990).

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In addition to measuring the acute effects immediately following marijuana administration, researchers have conducted studies to determine how long behavioral impairments last after abstinence. Some of marijuana’s acute effects may not fully resolve until at least one day after the acute psychoactive effects have subsided. Heishman et al. (1990) showed that impairment on memory tasks persists for 24 hours after smoking marijuana cigarettes containing 2.57 percent delta 9-THC. However, Fant et al. (1998) showed that the morning after exposure to 1.8 percent or 3.6 percent smoked delta 9 – THC, subjects had minimal residual alterations in subjective or performance measures.

A number of factors may influence marijuana’s behavioral effects including the duration of use (chronic or short term), frequency of use (daily, weekly, or occasionally), and amount of use (heavy or moderate). Researchers also have examined how long behavioral impairments last following chronic marijuana use. These studies used self-reported histories of past duration, frequency, and amount of past marijuana use, and administered a variety of performance and cognitive measures at different time points following marijuana abstinence. In chronic marijuana users, behavioral impairments may persist for up to 28 days of abstinence. Solowij et al.(2002) demonstrated that after 17 hours of abstinence, 51 adult heavy chronic marijuana users performed worse on memory and attention tasks than 33 non­ using controls or 51 heavy, short-term users. Another study noted that heavy, frequent marijuana users, abstinent for at least 24 hours, performed significantly worse than the controls on verbal memory and psychomotor speed tests (Messinis et al., 2006).

Additionally, after at least 1 week of abstinence, young adult frequent marijuana users, aged 18-28, showed deficits in psychomotor speed, sustained attention, and cognitive inhibition (Lisdahl and Price, 2012). Adult heavy, chronic marijuana users showed deficits on memory tests after ? days of supervised abstinence (Pope et al., 2002). However, when these same individuals were again tested after 28 days of abstinence, they did not show significant memory deficits. The authors concluded, “cannabis-associated cognitive deficits are reversible and related to recent cannabis exposure, rather than irreversible and related to cumulative lifetime use.”

[footnote 3 – In this quotation the term Cannabis is used interchangeably for marijuana.]

However, other researchers reported neuropsychological deficits in memory, executive functioning, psychomotor speed and manual dexterity in heavy marijuana users abstinent for 28 days (Bolla et al., 2002). Furthermore, a follow-up study of heavy marijuana users noted decision-making deficits after 25 days of supervised abstinence. (Bolla et al., 2005). However, moderate marijuana users did not show decision-making deficits after 25 days of abstinence, suggesting the amount of marijuana use may impact the duration of residual impairment.

The effects of chronic marijuana use do not seem to persist after more than 1 to 3 months of abstinence. After 3 months of abstinence, any deficits observed in IQ, immediate memory, delayed memory, and information-processing speeds following heavy marijuana use compared to pre-drug use scores were no longer apparent (Fried et al., 2005). Marijuana did not appear to have lasting effects on performance of a comprehensive neuropsychological battery when 54 monozygotic male twins (one of) whom used marijuana, one of whom did not) were compared 1-20 years after cessation of marijuana use (Lyons et al., 2004). Similarly, following abstinence for a year or more, both light and heavy adult marijuana

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Users did not show deficits on scores of verbal memory compared to non-using controls (Tait et al., 2011). According to a recent meta-analysis looking at non-acute and long-lasting effects of marijuana use on neurocognitive performance, any deficits seen within the first month following abstinence are generally not present after about 1 month of abstinence (Schreiner and Dunn, 2012).

Another aspect that may be a critical factor in the intensity and persistence of impairment resulting from chronic marijuana use is the age of first use. Individuals with a diagnosis of marijuana misuse or dependence who were seeking treatment for substance use, who initiated marijuana use before the age of 15 years, showed deficits in performance on tasks assessing sustained attention, impulse control, and general executive functioning compared to non­ using controls. These deficits were not seen in individuals who initiated marijuana use after the age of 15 years (Fontes et al., 2011). Similarly, heavy, chronic marijuana users who began using marijuana before the age of 16 years had greater decrements in executive functioning tasks than heavy, chronic marijuana users who started using after the age of 16 years and non-using controls (Gruber et al., 2012). Additionally, in a prospective longitudinal birth cohort study of 1,037 individuals, marijuana dependence or chronic marijuana use was associated with a decrease in IQ and general neuropsychological performance compared to pre-marijuana exposure levels in adolescent onset users (Meier et al., 2012). The decline in adolescent-onset user’s IQ persisted even after reduction or abstinence of marijuana use for at least 1 year. In contrast, the adult-on set chronic marijuana users showed no significant changes in IQ compared to pre-exposure levels whether they were current users or abstinent for at least 1 year (Meier et al., 2012).

In addition to the age of onset of use, some evidence suggests that the amount of marijuana used may relate to the intensity of impairments. In the above study by Gruber et al. (2012), where early-onset users had greater deficits than late-onset users, the early-onset users reported using marijuana twice as often and using three times as much marijuana per week than the late-onset users. Meier et al.(2012) showed that the deficits in IQ seen in adolescent-onset users increased with the amount of marijuana used. Moreover, when comparing scores for measures of IQ, immediate memory, delayed memory, and information-processing speeds to pre-drug-use levels, the current, heavy, chronic marijuana users showed deficits in all three measures while current, occasional marijuana users did not(Fried et al., 2005).

Behavioral Effects of Prenatal Exposure

Studies with children at different stages of development are used to examine the impact of prenatal marijuana exposure on performance in a series of cognitive tasks. However, many pregnant women who reported marijuana use were more likely to also report use of alcohol, tobacco, and cocaine (Goldschmidt et al., 2008). Thus, with potential exposure to multiple drugs, it is difficult to determine the specific impact of prenatal marijuana exposure.

Most studies assessing the behavioral effects of prenatal marijuana exposure included women who, in addition to using marijuana, also reported using alcohol and tobacco. However, some evidence suggests an association between heavy prenatal marijuana exposure and deficits in some cognitive domains. In both 4-year-old and 6-year-old children, heavy

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prenatal marijuana use is negatively associated with performance op tasks assessing memory, verbal reasoning, and quantitative reasoning (Fried and Watkinson, 1987; Goldschmidt et al., 2008). Additionally, heavy prenatal marijuana use is associated with deficits in measures of sustained attention in children at the ages of 6 years and 13-16 years (Fried et al., 1992; Fried, 2002). In 9- to 12-year-old children, prenatal marijuana exposure is negatively associated with executive functioning tasks that require impulse control, visual analysis, and hypothesis (Fried et al., 1998).

Association of Marijuana Use with Psychosis

This analysis evaluates only the evidence for a direct link between prior marijuana use and the subsequent development of psychosis. Thus, this discussion does not consider issues such as whether marijuana’s transient effects are similar to psychotic symptoms in healthy individuals or exacerbate psychotic symptoms in individuals already diagnosed with schizophrenia.

Extensive research has been conducted to investigate whether exposure to marijuana is associated with the development of schizophrenia or other psychoses. Although many studies are small and inferential, other studies in the literature use hundreds to thousands of subjects. At present, the available data do not suggest a causative link between marijuana use and the development of psychosis (Minozzi et al., 201 0). Numerous large, longitudinal studies show that subjects who used marijuana do not have a greater incidence of psychotic diagnoses compared to those who do not use marijuana (Fergusson et al., 2005; Kuepper et al., 2011; Van Os et al., 2002).

When analyzing the available evidence of the connection between psychosis and marijuana, it is critical to determine whether the subjects in the studies are patients who are already diagnosed with psychosis or individuals who demonstrate a limited number of symptoms associated with psychosis without qualifying for a diagnosis of the disorder. For example, instead of using a diagnosis of psychosis, some researchers relied on non-standard methods of representing symptoms of psychosis including “schizophrenic cluster” (Maremmani et al., 2004), “subclinical psychotic symptoms” (Van Gastel et al., 2012), “pre-psychotic clinical high risk” (VanderMeer et al., 2012), and symptoms related to “psychosis vulnerability” (Griffith-Lendering et al., 2012). These groupings do not conform to the criteria in the Diagnostic and Statistical Manual (DSM-5) or the International Classification of Diseases (ICD-10) for a diagnosis of psychosis. Thus, these groupings are not appropriate for use in evaluating marijuana’s impact on the development of actual psychosis. Accordingly, this analysis includes only those studies that use subjects diagnosed with a psychotic disorder.

In the largest study evaluating the link between psychosis and drug use, 274 of the approximately 45,500 Swedish conscripts in the study population (< [less than] 0.01 percent) received a diagnosis of schizophrenia within the 14-year period following military induction from 1969 to 1983 (Andreasson et al., 1987). Of the conscripts diagnosed with psychosis, 7.7 percent (21 of the 274 conscripts with psychosis) had used marijuana more than 50 times at induction, while 72 percent (197 of the 274 conscripts with psychosis) had never used marijuana. Although high marijuana use increased the relative risk for schizophrenia to 6.0,

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the authors note that substantial marijuana use history “accounts for only a minority of all cases” of psychosis (Andreassen et al., 1987). Instead, the best predictor for whether a conscript would develop psychosis was a non-psychotic psychiatric diagnosis upon induction. The authors concluded that marijuana use increased the risk for psychosis only among individuals predisposed to develop the disorder. In addition, a 35-year follow up to this study reported very similar results (Manrique- Garcia et al., 2012). In this follow up study, 354 conscripts developed schizophrenia; of these 354 conscripts, 32 used marijuana more than 50 times at induction (9 percent, an odds ratio of 6.3), while 255 had never used marijuana (72 percent).

Additionally, the conclusion that the impact of marijuana may manifest only in individuals likely to develop psychotic disorders has been shown in many other types of studies. For example, although evidence shows that marijuana use may precede the presentation of symptoms in individuals later diagnosed with psychosis (Schimmelmann et al., 2011), most reports conclude that prodromal symptoms of schizophrenia appear prior to marijuana use (Schiffman et al., 2005). Similarly, a review of the gene-environment interaction model for marijuana and psychosis concluded that some evidence supports marijuana use as a factor that may influence the development, but only in those individuals with psychotic liability (Pelayo-Teran et al., 20 12).

A similar conclusion was drawn when the prevalence of schizophrenia was modeled against marijuana use across eight birth cohorts in Australia in individuals born between the years 1940 to 1979 (Degenhardt et al., 2003). Although marijuana use increased overtime in adults born during the four-decade period, there was not a corresponding increase in diagnoses for psychosis in these individuals. The authors conclude that marijuana may precipitate schizophrenic disorders only in those individuals who are vulnerable to developing psychosis. Thus, marijuana per se does not appear to induce schizophrenia in the majority of individuals who have tried or continue to use marijuana. However, in individuals with a genetic vulnerability for psychosis, marijuana use may influence the development of psychosis.

Cardiovascular and Autonomic Effects

Single smoked or oral doses of delta9-THC produce tachycardia and may increase blood pressure (Capriotti et al., 1988; Benowitz and Jones, 1975). Some evidence associates the tachycardia produced by delta9-THC with excitation of the sympathetic and depression of the parasympathetic nervous systems (Malinowska et al., 2012). During chronic marijuana. ingestion, a tolerance to tachycardia develops (Malinowska et al., 2012).

However, prolonged delta 9- THC ingestion produces bradycardia and hypotension (Benowitz and Jones, 1975). Plant-derived cannabinoids and endocannabinoids elicit hypotension and bradycardia via activation of   peripherally-located CB1 receptors (Wagner et al., 1998). Specifically, the mechanism of this effect is through presynaptic CB1 receptor-mediated inhibition of norepinephrine release from peripheral sympathetic nerve terminals, with possible additional direct vasodilation via activation of vascular cannabinoid receptors (Pacher et al., 2006). In humans, tolerance can develop to orthostatic hypotension (Jones,

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2002; Sidney, 2002) possibly related to plasma volume expansion, but tolerance does not develop to the supine hypotensive effects (Benowitz and Jones, 1975). Additionally, electrocardiographic changes are minimal, even after large cumulative doses of delta9-THC are administered. (Benowitz and Jones, 1975)

Marijuana smoking by individuals, particularly those with some degree of coronary artery or cerebrovascular disease, poses risks such as increased cardiac work, catecholamines and carboxyhemoglobin, myocardial infarction, and postural hypotension (Benowitz and Jones, 1981; Hollister, 1988; Mittleman et al., 2001; Malinowska et al., 2012).

Respiratory Effects

After acute exposure to marijuana, transient bronchodilation is the most typical respiratory effect (Gong et al., 1984). A recent 20-year longitudinal study with over 5,000 individuals collected information on the amount of marijuana use and pulmonary function data at years 0, 2, 5, 10, and 20 (Pletcher et al., 2012). Among the more than 5,000 individuals who participated in the study, almost 800 of them reported current marijuana use but not tobacco use at the time of assessment. Pletcher et al. (2012) found that the occasional use of marijuana is not associated with decreased pulmonary function. However, some preliminary evidence suggests that heavy marijuana use may be associated with negative   pulmonary effects (Pletcher et al., 2012). Long-term use of marijuana can lead to chronic cough and increased sputum, as well as an increased frequency of chronic bronchitis and pharyngitis. In addition, pulmonary function tests reveal that large-airway obstruction can occur with chronic marijuana smoking, as can cellular inflammatory histopathological abnormalities in bronchial epithelium (Adams and Martin 1996; Hollister 1986).

Evidence regarding marijuana smoking leading to cancer is inconsistent, as some studies suggest a positive correlation while others do not (Lee and Hancox, 2011; Tashkin, 2005). Several lung cancer cases have been reported in young marijuana users with no tobacco smoking history or other significant risk factors (Fung et al., 1999). Marijuana use may dose-dependently interact with mutagenic sensitivity, cigarette smoking, and alcohol use to increase the risk of head and neck cancer (Zhang et al., 1999). However, in a large study with 1,650 subjects, a positive association was not found between marijuana and lung cancer (Tashkin et al., 2006). This finding remained true, regardless of the extent of marijuana use, when controlling for tobacco use and other potential confounding variables. Overall, new evidence suggests that the effects of marijuana smoking on respiratory function and carcinogenicity differ from those of tobacco smoking (Lee and Hancox, 2011).

Endocrine System

Experimental marijuana administration to humans does not consistently alter many endocrine parameters. In an early study, male subjects who experimentally received smoked marijuana showed a significant depression in luteinizing hormone and a significant increase in cortisol (Cone et al., 1986). However, two later studies showed no changes in hormones. Male subjects experimentally exposed to smoked delta 9-THC (18 mg/marijuana cigarette) or oral delta 9-THC (10 mg three times per day for 3 days and on the morning of the fourth day) showed no changes in plasma adrenocorticotropic hormone (ACTH), cortisol, prolactin,

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luteinizing hormone, or testosterone levels (Dax et al., 1989). Similarly, a study with 93 men and 56 women showed that chronic marijuana use did not significantly alter concentrations of testosterone, luteinizing hormone, follicle stimulating hormone, prolactin, or· cortisol (Block et al., 1991). Additionally, chronic marijuana use did not affect serum levels of thyrotropin, thyroxine, and triiodothyronine (Bonnet, 2013). However, in a double-blind, placebo-controlled, randomized clinical trial of HIV-positive men, smoking marijuana dose­ dependently increased plasma levels of ghrelin and leptin, and decreased plasma levels of peptide YY (Riggs et al., 2012).

The effects of marijuana on female reproductive system functionality differ between humans and animals. In monkeys, delta 9-THC administration suppressed ovulation (Asch et al., . 1981) and reduced progesterone levels (Almirez et al., 1983). However, in women, smoked marijuana did not alter hormone levels or the menstrual cycle (Mendelson and Mello, 1984).

Brown and Dobs (2002) suggest that the development of tolerance in humans may be the cause of the discrepancies between animal and human hormonal response to cannabinoids.

The presence of in vitro delta9-THC reduces binding of the corticosteroid, dexamethasone, in hippocampal tissue from adrenalectomized rats, suggesting an interaction with the glucocorticoid receptor (Eldridge et al.,1991). Although acute delta-9 -THC presence releases corticosterone, tolerance develops in rats with chronic administration (Eldridge et al., 1991).

Some studies support a possible association between frequent, long-term marijuana use and increased risk of testicular germ cell tumors (Trabert et al., 2011). On the other hand recent data suggest that cannabinoid agonists may have therapeutic value in the treatment of prostate cancer, a type of carcinoma in which growth is stimulated by androgens. Research with prostate cancer cells shows that the mixed CB 1 / CB 2 agonist, WIN-55212-2, induces apoptosis in prostate cancer cells, as well as decreases the expression of androgen receptors and prostate-specific antigens (Sarfaraz et al., 2005).

Immune System

Cannabinoids affect the immune system in many different ways. Synthetic, natural, and endogenous cannabinoids often cause different effects in a dose-dependent biphasic manner (Croxford and Yamamura, 2005; Tanasescu and Constantinescu, 2010).

Studies in humans and animals give conflicting results about cannabinoid effects on immune functioning in subjects with compromised immune systems. Abrams et al. (2003) investigated marijuana’s effect on immunological functioning in 62 AIDS patients taking· protease inhibitors. Subjects received one of the following three times a day: a smoked marijuana cigarette containing 3.95 percent delta 9- THC, an oral tablet containing delta 9- THC (2.5 mg oral dronabinol), or an oral placebo. The results showed no changes in CD4+ and CD8+ cell counts, HIVRNA levels, or protease inhibitor levels between groups. Thus, the use of cannabinoids showed no short-term adverse virologic effects in individuals with compromised immune systems. However, these human data contrast with data generated in
immunodeficient mice, which demonstrated that exposure to delta 9-THC in vivo suppresses

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immune function, increases HIV co-receptor expression, and acts as a cofactor to enhance HIV replication (Roth et al., 2005).

[Continued next Part 33]

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