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Notices - 2001

Additional Scientific Data Considered by the Drug Enforcement Administration in Evaluating Jon Gettman's Petition To Initiate Rulemaking Proceedings To Reschedule Marijuana

Drug and Chemical Evaluation Section, Office of Diversion Control, Drug Enforcement Administration, March 2001

Introduction

On July 10, 1995, Jon Gettman petitioned the Drug Enforcement Administration (DEA) to initiate rulemaking proceedings to reschedule marijuana. Marijuana is currently listed in schedule I of the Controlled Substances Act (CSA).

Mr. Gettman proposed that DEA promulgate a rule stating that "there is no scientific evidence that [marijuana has] sufficient abuse potential to warrant schedule I or II status under the [CSA]."

In accordance with the CSA, DEA gathered the necessary data and, on December 17, 1997, forwarded that information along with Mr. Gettman's petition to the Department of Health and Human Services (HHS) for a scientific and medical evaluation and scheduling recommendation. On January 17, 2001, HHS forwarded to DEA its scientific and medical evaluation and scheduling recommendation. The CSA requires DEA to determine whether the HHS scientific and medical evaluation and scheduling recommendation and "all other relevant data" constitute substantial evidence that the drug should be rescheduled as proposed in the petition. 21 U.S.C. 811(b). This document contains an explanation of the "other relevant data" that DEA considered. In deciding whether to grant a petition to initiate rulemaking proceedings, DEA must consider eight factors specified in 21 U.S.C. 811(c). The information contained in this document is organized according to these eight factors.

(1) Its Actual or Relative Potential for Abuse

Evaluation of the abuse potential of a drug is obtained, in part, from studies in the scientific and medical literature. There are many preclinical indicators of a drug's behavioral and psychological effects that, when taken together, provide an accurate prediction of the human abuse liability. Specifically, these include assessments of the discriminative stimulus effects, reinforcing effects, conditioned stimulus effect, effects on operant response rates, locomotor activity, effects on food intake and other behaviors, and the development of tolerance and dependence (cf., Brady et al., 1990; Preston et al., 1997). Clinical studies of the subjective and reinforcing effects in substance abusers, interviews with substance abusers, clinical interviews with medical professionals, and epidemiological studies provide quantitative data on abuse liability in humans and some indication of actual abuse trends (cf., deWit and Griffiths, 1991).

Evidence of actual abuse and patterns of abuse are obtained from a number of substance abuse databases, and reports of diversion and trafficking. Specifically, data from Drug Abuse Warning Network (DAWN), Poison

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Control Centers, System To Retrieve Investigational Drug Evidence (STRIDE), seizures and declarations from U.S. Customs, DEA Drug Theft Reports and other diversion and trafficking data bases are indicators of the pattern, scope, duration and significance of abuse. 

Reinforcing Effects in Animals

As described by the petitioner, the preponderance of preclinical studies using animal models had, to recently, shown that D9-THC had minimal activity in behavioral paradigms predictive of reinforcing efficacy (i.e., self-administration paradigms; Harris et al., 1974; Pickens et al., 1973; Deneau and Kaymakcalan, 1971). In general, D9-THC had been shown to be relatively ineffective in maintaining self-administration behavior by either the intravenous or oral routes (Kaymakcalan, 1973; Harris et al., 1974; Carney et al., 1977; Mansbach et al., 1994). Under limited experimental parameters, D9-THC self-administration was demonstrated after animals were either first trained to self-administer PCP, after a chronic cannabinoid history was established or when maintained at 80% reduced body weight (Pickens et al., 1973; Deneau and Kaymakcalan, 1971; Takahashi and Singer, 1979). However, Tanda, Munzar and Goldberg of the Intramural Preclinical Pharmacology Section of the NIDA (2000) have clearly demonstrated that THC can act as a strong reinforcer of drug-taking behavior in an experimental animal model, the squirrel monkey, as it does in humans. The self-administration behavior was comparable in intensity to that maintained by cocaine under identical conditions and was obtained using a range of doses similar to those self-administered by humans smoking a single marijuana cigarette.

Although the neuropharmacological actions of D9-THC suggest a powerful brain substrate underlying its rewarding and euphorigenic effects, behavioral studies of D9-THC's rewarding effects had been inconclusive. Several reasons for the previous inability by a number of laboratories to demonstrate self-administration of D9-THC in animals may be its relatively slow-onset, its long-lasting behavioral effects and its insolubility in physiological saline or water for injection (Mansbach et al., 1994). Similar findings have been found in the animal literature with nicotine--an avid reinforcer in humans. The strength of THC, like nicotine, as a reinforcer in animals may be more dependent on supplementary strengthening by ancillary stimuli than is the case for other drugs (cf. Henningfield, 1984).

In other behavioral and pharmacological tests used to assess reinforcing efficacy, D9-THC produced significant effects. Specifically, D9-THC augments responding for intracranial self-stimulation by decreasing the reinforcing threshold for brain stimulation reward. It also dose-dependently enhances dopamine efflux in forebrain nuclei associated with reward and this enhanced efflux occurs locally in the terminal fields within brain reward pathways (Gardner and Lowinson, 1991; Gardner, 1992; Chen et al., 1993, 1994). In conditioned place preference procedures, D9-THC (2.0 and 4.0 mg/kg, i.p.) produced significant dose-dependent increases in preference for the drug paired chamber, the magnitude of which was similar to that seen with 5.0 mg/kg cocaine and 4.0 mg/kg morphine (Leprore et al., 1995). However, D 9-THC also produced a conditioned place aversion and conditioned taste aversion (Leprore et al., 1995; Parker and Gillies, 1995). The development of taste aversions with drug administrations that also produce place preferences have been described as somewhat of a "drug paradox" by Goudie; however, this has been found to occur within the "therapeutic window" of all known drugs of abuse (cf Goudie, 1987). Goudie has concluded that drugs can possess both reinforcing and aversive properties at the same doses. This fact may underlie the reciprocal relationship between the behavioral effects of THC, CBD, and THC+CBD combinations, discussed below.

Drug Discrimination in Animals

Preclinical drug discrimination studies with D9-THC are predictive of the subjective effects of cannabinoid drugs in humans and serve as animal models of marijuana and THC intoxication in humans (Balster and Prescott, 1992; Wiley et al., 1993b, 1995). In a variety of species it has been found that D9-THC shares discriminative stimulus effects with cannabinoids that bind to CNS cannabinoid receptors with high affinity (Compton et al., 1993; Jarbe et al., 1989; Gold et al., 1992; Wiley et al., 1993b, 1995b; Jarbe and Mathis, 1992) and that are psychoactive in humans (Balster and Prescott, 1992). Furthermore, recent studies show that the discriminative stimulus effects of D9-THC are mediated via the CB1 receptor subtype (Perio et al., 1996). 

Chronic D9-THC administration to rats produced tolerance to the discriminative stimulus effects of D9-THC, but not to its response rate disruptions. Specifically, tolerance to the stimulus effects of D9-THC increased 40-fold when supplemental doses of up to 120 mg/kg/day D9-THC were administered under conditions of suspended training (Wiley et al., 1993a). 

The discriminative stimulus effects of D9-THC appear to be pharmacologically specific as non-cannabinoid drugs typically do not elicit cannabimimetic effects in drug discrimination studies (Browne and Weissman, 1981; Balster and Prescott, 1992, Gold et al., 1992; Barrett et al., 1995; Wiley et al., 1995a). Furthermore, these studies show that high doses of D9-THC produce marked response rate disruption, immobility, ataxia, sedation and ptosis in rhesus monkeys and rats (Wiley et al., 1993b; Gold et al., 1992; Martin et al., 1995).

Clinical Abuse Potential

Both marijuana and THC can serve as positive reinforcers in humans. Marijuana and D9-THC produced profiles of behavioral and subjective effects that were similar regardless of whether the marijuana was smoked or taken orally, as marijuana in brownies, or orally as THC-containing capsules, although the time course of effects differed substantially. There is a large clinical literature documenting the subjective, reinforcing, discriminative stimulus, and physiological effects of marijuana and THC and relating these effects to the abuse potential of marijuana and THC (e.g., Chait et al., 1988; Lukas et al., 1995; Kamien et al., 1994; Chait and Burke, 1994; Chait and Pierri, 1992; Foltin et al., 1990; Azorlosa et al., 1992; Kelly et al., 1993, 1994; Chait and Zacny, 1992; Cone et al., 1988; Mendelson and Mello, 1984).

These listed studies represent a fraction of the studies performed to evaluate the abuse potential of marijuana and THC. In general, these studies demonstrate that marijuana and THC dose-dependently increases heart rate and ratings of "high" and "drug liking", and alters behavioral performance measures (e.g., Azorlosa et al., 1992; Kelly et al., 1993, 1994; Chait and Zacny, 1992; Kamien et al., 1994; Chait and Burke, 1994; Chait and Pierri, 1992; Foltin et al., 1990; Cone et al., 1988; Mendelson and Mello, 1984). Marijuana also serves as a discriminative stimulus in humans and produces euphoria and alterations in mood. These subjective changes were used by the subjects as the basis for the discrimination from placebo (Chait et al., 1988).

In addition, smoked marijuana administration resulted in multiple brief episodes of euphoria that were paralleled by rapid transient increases in EEG alpha power (Lukas et al., 1995);

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these EEG changes are thought to be related to CNS processes of reinforcement (Mello, 1983).

To help elucidate the relationship between the rise and fall of plasma THC and the self-reported psychotropic effects, Harder & Rietbrock (1997) measured both the plasma levels of THC and the psychological "high" obtained from smoking a marijuana cigarette containing 1% THC. As can be seen from these data, a rise in plasma THC concentrations results in a corresponding increase in the subjectively reported feelings of being "high". However, as THC levels drop the subjectively reported feelings of "high" remain elevated. The subjective effects seem to lag behind plasma THC levels. Similarly, Harder and Rietbrock compared lower doses of 0.3% THC-containing and 0.1% THC-containing cigarettes in human subjects.

As can be clearly seen by these data, even low doses of marijuana, containing 1%, 0.3% and even 0.1% THC, typically referred to as "non-active", are capable of producing subjective reports and physiological markers of being "high'. THC and its major metabolite, 11-OH-THC, have similar psychoactive and pharmacokinetic profiles in man ( Wall et al., 1976; DiMarzo et al., 1998; Lemberger et al., 1972). Perez-Reyes et al. (1972) reported that THC and 11-OH-THC were equipotent in generating a "high" in human volunteers. However, the metabolite, 11-OH-THC, crosses the blood-brain barrier faster than the parent THC compound (Ho et al., 1973; Perez-Reyes et al., 1976). Therefore, the changes in THC plasma concentrations in humans may not be the best predictive marker for the subjective and physiological effects of marijuana in humans. Cocchetto et al. (1981) have used hysteresis plots to clearly demonstrate that plasma THC concentration is a poor predictor of simultaneous occurring physiological (heart rate) and psychological ("high") pharmacological effects. Cocchetto et al. demonstrated that the time course of tachycardia and psychological responses lagged behind the plasma THC concentration-time profile. As recently summarized by Martin & Hall (1997, 1998)

There is no linear relationship between blood [THC] levels and pharmacological effects with respect to time, a situation that hampers the prediction of cannabis-induced impairment based on THC blood levels (p90).

Physical Dependence in Animals

There are reports that abrupt withdrawal from D9-THC can produce a mild spontaneous withdrawal syndrome in animals, including increased motor activity and grooming in rats, decreased seizure threshold in mice, increased aggressiveness, irritability and altered operant performance in rhesus monkeys (cf., Pertwee, 1991). The failure to observe profound withdrawal signs following abrupt discontinuation of the drug may be due to D9-THC's long half-life in plasma and slowly waning levels of drug that continue to permit receptor adaptation.

Recently the discovery of a cannabinoid receptor antagonist demonstrates that a profound precipitated withdrawal syndrome can be produced in D9-THC tolerant animals after twice daily injections (Tsou et al., 1995) or continuous infusion (Aceto et al., 1995, 1996).

Physical Dependence in Humans

Signs of withdrawal in humans have been demonstrated after studies with marijuana and D9-THC. Although the intensity of the withdrawal syndrome is related to the daily dose and frequency of administration, in general, the signs of D9-THC withdrawal have been relatively mild (cf., Pertwee, 1991). This withdrawal syndrome has been compared to that of short-term, low dose treatment with opioids, sedatives, or ethanol, and includes changes in mood, sleep, heart rate, body temperature, and appetite. Other signs such as irritability, restlessness, tremor, mild nausea, hot flashes and sweating have also been noted (cf., Jones, 1980, 1983).

Chait, Fischman, & Schuster (1985) have demonstrated an acute withdrawal syndrome or "hangover" occurring approximately 9 hours after a single marijuana smoking episode. Significant changes occurred on two subjective measures and on a time production task. In 1973, Cousens & DiMascio reported a similar "hangover" effect from acute administrations of D9-THC. The hangover phenomenon or continued "high", in the Cousens & DiMascio study, occurred 9 hrs after drug administration and was associated with some residual temporal disorganization, as well. These residual or hangover effects may mimic the withdrawal syndrome, both qualitatively and quantitatively, which is expressed after chronic marijuana exposure. This acute hangover may reflect a true acute withdrawal syndrome similar to that experienced from high acute alcohol intake. The presence of an acute withdrawal syndrome after drug administration has been suggested to represent a physiological compensatory rebound by which chronic administration of the drug will eventually potentiate and produce dependence and the potential for continued abuse (Gauvin, Cheng & Holloway, 1993).

Crowley et al. (1998) screened marijuana users for DSM-IIIR dependence criteria. Of the 165 males and 64 female patients that met the criteria, 82.1% were found to have co-morbid conduct disorders; 17.5% had major depression; and 14.8% had a diagnosis of attention- deficit/hyperactivity disorder. These results also showed that most patients claimed to have "serious problems" from cannabis use. The data also indicated that for adolescents with conduct problems, cannabis use was not benign, and that the drug served as a potent reinforcer for further cannabis usage, producing dependence and withdrawal.

Kelly & Jones (1992) quantified concentrations of THC and its metabolites in both plasma and urine after a 5 mg intravenous dose of THC was administered to frequent and infrequent marijuana smokers. The frequent smokers were users who smoked marijuana almost daily for at least two years. The infrequent smokers were users who smoked marijuana no more than two to three times per month but had done so for at least two years. Pharmacokinetic parameters after intravenously administered THC revealed no significant differences between frequent and infrequent marijuana users on area under the time-effect curve (AUC), volume of distribution, elimination half-lives of parent THC and metabolites in plasma and urine. There were also no group differences in metabolic or renal clearances. The authors concluded that there was no evidence for metabolic or dispositional tolerance between the two groups of subjects. Kelly and Jones also reported that tolerance was not evident in heart rate, diastolic blood pressure, skin temperature, and the degree of psychological "high" from the i.v. administration of THC.

In two separate reports, Haney et al. have recently described abstinence symptoms of an acute withdrawal syndrome following high (30 mg q.i.d.) and low (20 mg q.i.d) dose administrations of oral THC (Haney et al., 1999a) and following 5 puffs of high (3.1%) and low (1.8%) THC-containing smoked marijuana cigarettes (Haney et al., 1999b). Abstinence from oral THC increased ratings of "anxious", "depressed", and "irritable", and decreased the reported quantity and quality of sleep and decreased food intake by 20-30% compared to baseline. Abstinence from as low as 5 controlled puffs of active marijuana smoking increased ratings of "anxious", "irritable" and "stomach pain", and

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significantly decreased food intake. The 5 controlled puffs of 5 second duration each were drawn from 2 separate marijuana cigarettes (3 puffs from one, 2 puffs from the other. The smoke was held for 40 seconds and then exhaled. All subjects reported significant increases on subjective measures of "high", "good drug effect", and "stimulated", as well as "mellow", "content", and "friendly" as a result of this limited and controlled draw of THC. Both of these studies have delineated a withdrawal syndrome from concentrations of THC significantly lower than those reported in any other previous study and, for the first time, clearly identified a marijuana withdrawal syndrome detected at low levels of THC exposure that do not produce tolerance. The abstinence syndrome was not limited to subjective state changes but was also quantified using a cognitive/memory test battery.

In a related study, Khouri et al (1999) found that long-term heavy marijuana users became more aggressive during abstinence from marijuana than did former or infrequent users. Previous dependence studies have relied largely on patients' subjective reports of a range of symptoms. Khouri et al. examined a single symptom--aggression. The authors concluded that marijuana abstinence is associated with unpleasant behavioral symptoms that may contribute to continued marijuana use.

Kouri & Pope (2000) examined three groups of marijuana users during a 28-day supervised abstinence period. Current marijuana users experienced significant increases in anxiety, irritability, physical tension, and physical symptoms and decreases in mood and appetite during marijuana withdrawal. These symptoms were most pronounced during the initial 10 days of abstinence, bust some were present for the entire 28-day withdrawal period. The findings from this study reveal that chronic heavy users of marijuana experience a number of withdrawal symptoms during abstinence and clearly demonstrate a "marijuana dependence syndrome" in humans.

These data suggest that dependence on THC may in fact be an important consequence of repeated, daily exposure to cannabinoids and that daily marijuana use may be maintained, at least in part, by the alleviation of abstinence symptoms. Relevant to the present petition, the Haney et al. study is the first report demonstrating this syndrome with extremely low concentrations of THC.

Results of THC Dose Comparison Studies

There are reports in the scientific literature that evaluated dose-related subjective and reinforcing effects of Cannabis sativa in humans. These studies have assessed the subjective and reinforcing effects of cannabis cigarettes containing different potencies of THC and/or which have manipulated the THC dose by varying the volume of THC smoke inhaled (Azorlosa et al., 1992; Lukas et al., 1995; Chait et al., 1988; Chait and Burke, 1994; Kelly et al., 1993).

Chait et al. (1988) studied the discriminative stimulus effects of smoked marijuana cigarettes containing THC contents of 0%, 0.9%, 1.4%, 2.7%. Marijuana smokers were trained to discriminate smoked marijuana from placebo using 4 puffs of a 2.7%-THC cigarettes. Subjective ratings of "high", and physiological measures (i.e., heart rate) were significantly and dose-dependently increased after smoking the 0.9%, 1.4%, 2.7%.

Marijuana cigarettes containing 1.4% THC completely substituted for 2.7%-THC on drug identification tasks, however, 0.9%-THC did not. The authors found that the onset of discriminative stimulus effects was within 90 seconds after smoking began (after the first two puffs). Since the 1.4%-THC cigarette substituted for 2-puffs of the 2.7%-THC cigarette, the authors estimate that an inhaled dose of THC as low as 3 mg can produce discriminable subjective effects.

Similarly, Lukas et al. (1995) reported that marijuana cigarettes containing either 1.26% or 2.53% THC produced significant and dose-dependent increases in level of intoxication and euphoria in male occasional marijuana smokers. Four of the six subjects that smoked the 1.26%-THC cigarette reported marijuana effects and 75% of these subjects reported euphoria. All six of the subjects that smoked 2.53% THC reported marijuana effects and euphoria. Peak levels of self-reported intoxication occurred at 15 and 30 minutes after smoking and returned to control levels by 90-105 minutes. There was no difference between latency to or duration of euphoria after smoking either the 1.26% or 2.53% THC cigarettes. The higher dose-marijuana cigarette produced a more rapid onset and longer duration of action than the lower dose marijuana cigarette (1.26% THC). Plasma THC levels peaked 5-10 minutes after smoking began; the average peak level attained after the low- and high-dose marijuana cigarette was 36 and 69 ng/ml respectively.

In order to determine marijuana dose-effects on subjective and performance measures over a wide dose range, Azorlosa et al. (1992) evaluated the effects of 4, 10, or 25 puffs from marijuana cigarettes containing 1.75 or 3.55% THC in seven male moderate users of marijuana. Orderly dose-response curves were produced for subjective drug effects, heart rate, and plasma concentration, as a function of THC content and number of puffs. After smoking the 1.75% THC cigarette, maximal plasma THC levels were 57 ng/ml immediately after smoking, 18.3 ng/ml 15 minutes after smoking, 10.3 ng/ml 30 minutes after smoking, and 7.7 ng/ ml 45 minutes after smoking.

The study also showed that subjects could smoke more of the low THC cigarette to produce effects that were similar to the high THC dose cigarette (Azorlosa et al., 1992). There were nearly identical THC levels produced by 10-puff low-THC cigarette (98.6 ng/ml) and 4-puff high THC cigarette (89.4 ng/ml). Similarly, the subjective effects ratings, including high, stoned, impaired, confused, clear-headed and sluggish, produced under the 10 puff low- and high-THC and 25 puff low-THC conditions did not differ significantly from each other.

As with most drugs of abuse, higher doses of marijuana are preferred over lower dose. Although not preferred, these lower doses still produce cannabimimetic effects. Twelve regular marijuana smokers participated in a study designed to determine the preference of a low potency (0.64%-THC) vs. a high potency (1.95%-THC) marijuana cigarette (Chait and Burke, 1994). The subjects first sampled the marijuana of two different potencies in one session, then chose which potency and how much to smoke. During sampling sessions, there were significant dose-dependent increases in heart rate and subjective effects, including ratings of peak "high", strength of drug effects, stimulated, and drug liking. During choice sessions, the higher dose marijuana was chosen over the lower dose marijuana on 87.5% of occasions. Not surprising, there was a significant positive correlation between the total number of cigarettes smoked and the ratings of subjective effects, strength of drug effect, drug "liking", expired air carbon monoxide, and heart rate increases. The authors state it is not necessary valid to assume that the preference observed in the present study for the high-potency marijuana was due to greater CNS effects from its higher THC content. The present study found that the low- and high-potency marijuana cigarettes also differ on

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several sensory dimensions; the high-potency THC was found to be reported as "fresher" and "hotter". Other studies found that marijuana cigarettes containing different THC contents varied in sensory dimensions (cf., Chait et al., 1988; Nemeth-Coslett et al., 1986).

As summarized by Martin & Hall for the United Nations only a small amount of cannabis (e.g. 2-3 mg of available THC) is required to produce a brief pleasurable high for the occasional user and a single joint may be sufficient for two or three individuals. Using these data and those of Harder & Reitbroch (1997, above), a one gram cigarette containing 1% THC containing cannabis, would contain 10 mg of THC--a dose well capable of producing a social high.

Carlini et al. (1974) examined 33 subjects who smoked marijuana cigarettes with different ratios of constituent cannabinoids. The plant containing 0.82% THC produced larger than expected results based on the estimates from the THC content.

Smoking a 250 mg cigarette containing 5.0 mg of D9-THC induced more reactions graded 3 and 4 than 10 or 20 mg of D9-THC. It was further observed that the psychological effects (subjective "high") started around 10 min after the end of the inhalation, and reached a maximum 20 to 30 min later, subsiding within 1 to 3 hrs. The peak of psychological disturbances, therefore, did not coincide in time with the peak of pulse rate effects. Carlini et al., suggested that other constituents of the marijuana were interacting synergistically with the THC to potentiate the subjective response induced by the smoking of the cigarette. Karniol and colleagues (1973, 1974) have clearly demonstrated that cannabidiol (CBD) blocks some of the effects induced by THC, such as increased pulse rates and disturbed time perception. More importantly, CBD blocked some of the psychological effects of THC, but not by altering the quantitative or intensity of the psychological reactions. CBD seemed better able to block the aversive effects of THC. CBD changed the symptoms reported by the subjects in such a way that the anxiety component produced by THC administration was actually reduced. The animal subjects of one study showed greater analgesia scores with a CBD+THC combination (1973) and the human subjects from the other study (1974) showed less anxiety and panic but reported more pleasurable effects. CBD may be best seen as an "entourage" compound (Mechoulam, Fride, DiMarzo, 1998) which is administered along with THC and results in a functional potentiation of THC's behavioral and subjective effects. This potentiation can be in both the intensity and/or duration of the high induced by marijuana. According to Paris & Nahas (1984) the CBD:THC ratio in industrial or fiber type hemp is 2:1. Relevant to the current petition, the CBD:THC ratio producing the greatest increase in euphoria in the Karniol, et al. studies was 2:1 (60:30 mg).

Jones & Pertwee (1972) were first to report that the presence of cannabidiol inhibited the metabolism of THC and its active metabolite. These data were soon replicated by Nilsson et al., (1973). Bronheim et al., (1995) examined the effects of CBD on the pharmacokinetic profile of THC content in both blood and brains of mice. CBD pretreatments produced a modest elevation in THC-blood levels; area under the kinetics curve of THC was increased by 50% as a function of decreased clearance. CBD pretreatments also modestly increased the Cmax, AUC, and half-life of the major THC metabolites in the blood. The THC kinetics function showed a 7- to 15-fold increase in the area under the curve, a 2- to 4-fold increase in the half-life, as well as the tmax. CBD pretreatments resulted in large increases in area under the curves and half-lives of all the THC metabolites in the mice brains. The inhibition of the metabolism of THC and its psychoactive metabolites by CBD may underlie the potentiation in the subjective effects of THC by CBD in humans.

In addition to THC, hemp material contains a variety of other substances (e.g., Hollister, 1974), including other cannabinoids such as cannabidiol (CBD) and cannabinol (CBN). One comprehensive review described the activities of 300 cannabinoid compound in preclinical models (Razdan, 1986). Since CBD is always present in preparations of cannabis, it may represent a high CBD:THC ratio in the case of low THC cannabis. Therefore, it is important to understand the interactions of cannabidiol and D9-THC.

Structure-activity studies of cannabinoid compounds characterized cannabidiol in relationship to D9-THC and other cannabinoids (Martin et al., 1981; Little et al., 1988). These and other studies have found that cannabidiol was inactive and did not produce neuropharmacological effects or discriminative stimulus, subjective effects and behavioral effects predictive of psychoactive subjective effects (Howlett, 1987; Howlett et al., 1992; c.f., Hiltunen and Jarbe, 1986; Perez-Reyes et al., 1973; Zuardi et al., 1982; Karniol et al., 1974).

Other studies have reported that cannabidiol has cannabinoid properties, including anticonvulsant effects in animal and human models (Consroe et al., 1981; Carlini & Cunha, 1981; Doyle and Spence, 1995), hypnotic effects (Monti, 1977), anxiolytic effects (Musty, 1984; Onaivi, Geen, & Martin, 1990; Guimarares et al., 1990; 1994) and rate-decreasing effects on operant behavior (Hiltunen et al., 1988).

Experiments with cannabidiol in combination with THC have found that certain behavioral responses induced by THC (i.e., operant, schedule-controlled responding) were attenuated by cannabidiol (Borgen and Davis, 1974; Brady and Balster, 1980; Consroe et al., 1977; Dalton et al., 1976; Kraniol and Carlini, 1973; Karniol et al., 1974; Welburn et al., 1976; Zuardi and Karniol, 1983; Zuardi et al., 1981, 1982; Hiltunen et al., 1988). However, other affects produced by THC are augmented or prolonged by the combined administration of CBD and THC or marijuana extract (Chesher and Jackson, 1974; Hine et al., 1975a,b; Fernandes et al., 1974; Karniol and Carlini, 1973; Musty and Sands, 1978; Zuardi and Karniol, 1983; Zuardi et al., 1984). Still other studies did not report any behavioral interaction between the CBD and THC (Bird et al., 1980; Browne and Weissman, 1981; Hollister and Gillespie, 1975; Jarbe and Henricksson, 1974; Jarbe et al., 1977; Mechoulam et al., 1970; Sanders et al., 1979; Ten Ham and DeLong, 1975).

A study to characterize the interaction between CBD and THC was conducted using preclinical drug discrimination procedures. Rats and pigeons trained to discriminate the presence or absence of THC, and tested with CBD administered alone and in combinations with THC (Hiltunen and Jarbe, 1986).

Specifically, in rats trained to discriminate 3.0 mg/kg, i.p. THC, CBD (30.0 mg/kg) was administered alone and in combination with THC (0.3 and 1.0 mg/kg, i.p.). In pigeons trained to discriminate 0.56 mg/kg, i.m. THC, CBD (17.5 mg/kg) was administered alone and in combination with THC (0.1, 0.3, and 0.56 mg/kg, i.m.). CBD prolonged the discriminative stimulus effects of THC in rats, but did not change the time-effect curve for THC in pigeons. In pigeons, the administration of CBD did not produce any differential effect under a fixed ratio schedule of reinforcement (Hiltunen and Jarbe, 1986).

These data suggest that CBD may somehow augment or prolong the actions of THC in rats and had no effect in pigeons. In the present study, the CBD/THC ratios ranged from 30:1 to 100:1 in rats and enhanced the stimulus

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effects of THC. However, similar CBD/THC ratios in pigeons (31:1, 58:1 and 175:1) did not result in any changes to THC's discriminative stimulus or response rate effects (Hiltunen and Jarbe, 1986).

It should be noted that cannabidiol can be easily converted to delta-9- and delta-8-tetrahydrocannabinol. Even industrial hemp plant material (leaves), containing high concentrations of CBD, can be treated in clandestine laboratories to convert the CBD to delta-9-tetrahydrocannabinol (Mechoulam, 1973) converting a supposedly innocuous weed into a potent smoke product.

In conclusion, the "entourage" compound, cannabidiol, does contribute to all of the effects ascribed to THC, however it also appears to lack cannabimimetic properties. However, there is no credible scientific evidence that CBD is a pharmacological antagonist at the cannabinoid receptor (Howlett, Evans, & Houston, 1992). There is clear evidence that CBD can functionally antagonize some of the aversive effects of THC (Dewey, 1986). The data from the scientific literature cited above, clearly demonstrate the ability of CBD to modify some very specific effects of THC. Most importantly, relative to the euphorigenic effects of THC (which contributes to its abuse liability), CBD appears to potentiate the psychological or subjective effects of THC by potentiating the blood and brain THC and 11-OH-THC levels and by functionally blocking the aversive (anxiety-like) properties of THC.

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