REVIEW OF AVAILABLE INFORMATION ON DIBENZOPYRANS: DIMETHYLHEPTYLPYRAN AND RELATED COMPOUNDS

Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants (1984)

CHEMISTRY

The structure of the active principle of the cannabis plant (Cannabis sativa), Δ-9-tetrahydrocannabinol, or THC (Figure 3-2), was elucidated in the mid-1960s.11,22,42 However, Adams and Baker2 and Todd and co-workers12 in 1940 independently synthesized à Δ-6à,10à congener that differed from the natural material by the position of the cyclic double bond. A series of homologues of that congener was prepared in which the alkyl side chain on the aromatic ring was varied, and the compounds were tested for their capacity to produce ataxia in dogs.3,5 The most active compound was dimethylheptylpyran (DMHP), the 1,2-dimethylheptyl analogue (EA 1476). Table 3-5 shows the relative potencies of several natural and synthetic dibenzopyrans.3,5

TABLE 3-5

Relative Potencies of Several Dibenzopyrans4

Compound Potency (Capacity to Compound Produce Ataxia in Dogs)

Synthetic Ñ5Í11

1.00 (standart)

Acetate (natural THC acetate)

14.6

Natural THC by hydrolysis of acetate

7.8

Natural THC from cannabidiol

7,3

(DMHP)

512

Because DMHP contains three asymmetric carbon atoms, it can exist as four diastereoisomeric racemates, each consisting of a (+) and a (-) isomer. These isomers, synthesized by Aaron and Ferguson1 - and isolated as the acetates, have been assigned the designations EA 2233-1 through EA 2233-8; the racemic mixture was designated EA 2233 (Figure 3-2). A mixture of isomers 2 and 4 was designated EA 2233-24. Table 3-6 lists the optical rotations of the isomers. DMHP is a colorless or pale yellow viscous oil that readily undergoes autoxidation. It is insoluble in water, but soluble in alcohols, benzene, and nonpolar solvents. Because the acetate form (EA 2233) retains the atactlc potency of the parent compound in dogs and is more stable, it and its stereoisomers were a focus of attention at Edgewood and were tested on human volunteers.

The DMHP used in these tests was procured from Shell Development Corporation or made at Edgewood. Analytic information on the test material is not available, but some Edgewood-prepared samples were reported to have a purity of 98%.

EA 2233 was produced at Edgewood, but no specific analytic information on the material used is available.

The eight optical isomers of EA 2233 were synthesized at Edgewood and analyzed by gas-liquid chromatography. Each of the eight products exhibited three peaks; a primary product in the first peak represents about 85% of the total mixture, a second peak represents about 10-22%, and a third peak represents 3-5%. The impurities were not identified, but they were not isomers.

ABSORPTION. FATE AND ELIMINATION

Absorption

Early research on effects of DMHP and its acetate ester (DMHP acetate) was conducted in a variety of animals (mice, rats, rabbits, cats, dogs, and monkeys) with intravenous administration.44 Rapid onset of such signs as ataxia, mydriasis, generalized weakness, nystagmus, and ptosis was seen with this route. With oral administration, fatigue, thirst, headache, postural hypotension, temporary blurring or loss of vision, and pronounced psychomotor activity were observed in humans.44 These results indicate that both drugs are well absorbed when administered orally. Efficacies of the drugs when administered parenterally and orally have been confirmed by additional studies In cats,8 rats and rabbits,32 mice,29 and man.28,31,35,36,38,40

I
Δ-9-tetrahydrocannabinol

II
Congener of I

III
Δ-6a,10a-Dimethylheptylpyran (DMHP) EA 1476

IV
EA 2233, Acetate form of EA 1476

TABLE 3-6l
Optical Rotation of Isomers of DMHP Acetatea
Isomer [α]D, deg (MeOH)
1 +65
2 -130
3 +133
4 -70
5 +94
6 -110
7 +105
8 -93

aIsomers 1 and 4,2 and 3, 5 and 8, and 6 and 7 are enantiomorphic pairs.

DISTRIBUTION

Tissue concentrations were measured in rats and rabbits sacrificed at selected times after intravenous administration of [14C]DMHP.32 Radioactivity (from DMHP and its metabolites) in rats at 1 h after administration was highest in lung and liver. Concentrations decreased to approximately 10% of initial values in 24 h and gradually diminished during the next 48 h. Radioactivity was lower in brain than in other tissues assayed. Plasma concentrations of [14C]DMHP decreased from an initial value of approximately 5,000 dpm/ml to about 50 dpm/ml at 72 h. Disappearance was in two phases; the initial one was attributed to tissue distribution (breakpoint, 6 h), and the second to elimination. Rabbit spleen, liver, and lung exhibited their highest radioactivity 3 h after injection; radioactivity in all tissues diminished with time. In this species, initial disappearance from plasma (and, presumably, distribution to other tissues) was more rapid, and the secondary phase slower. The investigators concluded that the tissue distribution of total radioactivity (from both DMHP and its metabolites) is similar to that of THC. The octanol-water partition coefficient was 7,500, compared with 6,000 for THC.

[14C]DMHP was injected intravenously into adult male albino Tuck strain No. 1 mice;29 20 min after administration, the blood:brain concentration ratio was 3.7:1. Brain concentration of the drug, on the basis of radioactivity, was approximately 2.5 picograms/gram (pg/g) 15 min after injection and about 1.7 pg/g at 90 min; it slowly decreased to nearly 1.2 pg/g after 16 h.

In three young men who received 200 μg of a racemic mixture of DMHP containing [14C]DMHP,31 radioactivity disappeared from plasma in a multiphasic manner. The rapid initial disappearance was attributed to uptake and distribution into tissues, and the later disappearance to metabolism and excretion.

METABOLISM

Cannabinoids may be metabolized to both hydroxy and dihydroxy metabolites.14 The hydroxylated compounds are not taken up in the circulation after metabolism by the liver, but are predominantly excreted in bile. It is unlikely, but not known, whether the dihy-droxylated compound can be further metabolized or activated to form more reactive compounds.

Metabolism of [14C]DMHP was studied in vitro with 9000 g liver supernatant fractions obtained from rabbits, mice, rats, guinea pigs, or dogs and in vivo in rats and rabbits.32 Incubation for 1 h with the supernatant fractions in the presence of an NADPH-generating system resulted in metabolism of the following percentages of the total amount of DMHP: rabbit, 68; mouse, 63; rat, 44; guinea pig, 41; and dog, 34. Thus, of the species studied, the rabbit preparation was the most active, and that of the dog the least active. The rabbit preparation gave rise to three radioactive metabolites; one of these appeared to be further metabolized to one of the other metabolites. All seemed to be more polar than the parent drug, according to their behavior in thin-layer chromatographic systems.

When [14C]DMHP was administered intravenously to rats or rabbits, it appeared that DMHP was hydroxylated and then further oxidized to at least one acidic compound, which was recovered from urine. No nonmetabolized DMHP was found in the urine of either species.

A similar in vitro system used [3H]Δ-9-DMHP (This DMHP is a Δ-9 form, in contrast with the DMHP used at Edgewood and by Lemberger, which was à Δ-6à,10à DMHP).; mass spectra of incubation extracts were silylated and subjected to gas chromato-graphy/mass spectrometry. Strong evidence was accumulated that the major metabolite was 11-hydroxy-DMHP. Overall recovery of the metabolite was only 4.7%; this low yield was insufficient for confirmatory analyses by other methods, such as nuclear magnetic resonance. The low recovery indicated to the investigators that DMHP and Its metabolites are much more strongly bound to tissue components than are THC and its metabolites. Sixteen hours after injection of [3H]DMHP into mice, their brains were extracted. Gas chromatography of the extracts indicated retention times identical with those of synthetic 11-hydroxy-DMHP, which accounted for 90% of the radioactivity; two other fractions were noted, which the investigators referred to as "non-extractable material" and "polar metabolite."

Lemberger et al,30 used gas chromatography/mass spectrometry and reported that the hydroxymethyl metabolite represents only two minor metabolites produced by rat liver microsomes; this suggests that with DMHP the methyl group at C-11 is not active and therefore that the 11-hydroxy DMHP would not be a major metabolite, Lemberger et al. have given evidence that the hydroxylation occurs primarily on one of the methyl groups of the side chain.

ELIMINATION

Kinetic data on the cannabinoids are limited, but it appears that they are eliminated slowly from the body. Reported THC half-lives in human plasma have ranged from 19 to 57 h. Because of their high lipid solubility, cannabinoids and their metabolites can be sequestered in fatty tissues, and traces may be detectable for over a week. The pharmacologic significance of these persistent cannabinoids and their metabolites is unknown.26

Very slow elimination (or at least displacement or metabolism at bioactive sites) was suspected in early studies of the effects of DMHP and DMHP acetate on human volunteers, because such signs and symptoms as sluggishness, inability to concentrate, dimness and blurring of vision, and orthostatic hypotension occurred up to 48 h after drug administration.44 At high doses of DMHP, cats "lay in plastic-like poses for hours or days against the side of the container in which they were placed."8

DMHP in plasma appears to have a half-life of 20 h in both rat and rabbit;32 the half-life of total radioactivity ([14C]DMHP plus C-labeled metabolites) in the slower phase of elimination was approximately 24 h. In the rat, 70% of the total radioactivity of the intravenous dose was recovered in urine and feces during 72 h; 4% was excreted in urine and 66% was found in feces. A 7-d collection of urine and feces of rabbits given [14C]DMHP resulted in recovery of 87% of the total radioactivity - 24% in urine and 63% in feces. In mouse brain,29 the half-life of [3H]Δ-9-DMHP appeared to be about 20 h, whereas 11-hydroxy-DMHP and the "polar metabolite" seem to have (by extrapolation) half-lives in excess of 48 h. All three values were calculated on the basis of the slower phase of elimination.

Studies on human volunteers given DMHP intravenously indicated a half-life of the terminal phase of [14C]DMHP elimination of 39 h; 58% of radioactivity was excreted in the feces and 11% in the urine during a 7-d collection period.31 The investigators concluded that the plasma disappearance curve in humans obtained with DMHP is similar to that obtained with THC.
In summary, both DMHP and DMHP acetate are well absorbed after oral and parenteral administration, have a relatively long half-life, are extensively metabolized, and are excreted mainly via the feces.

ANIMAL TOXICOLOGY

The animal-toxicity data in this section, taken from several sources,18,20,35,36,40,44 show that the compounds most studied in animals and humans were DMHP and DMHP acetate (more light- and air-stable than DMHP). Although eight optical isomers of the acetate were tested in humans, no specific toxicology data were found.

Route of Administration and Vehicle

The intravenous route of administration was usually used for testing these compounds in animals. Because they are insoluble in aqueous solvents, they were dissolved in small amounts of alcohol or emulsified with an oil-lecithin mixture or polyethylene glycol.

Toxicity of DMHP

DMHP was chosen as the prototype of the various cannabinol test compounds used at Edgewood and was studied more thoroughly than its congeners.

Acute toxicity studies have been performed in various animals: mice, rats, rabbits, cats, dogs, and macaques.18,20,35,36,40,44 Lethal doses of DMHP are extremely high, in comparison with the small doses required to produce its pharmacodynamic effects. For instance, the intravenous LD50 in mice is 63 mg/kg, whereas the minimal effective dose in 50% of the animals (MED50) is 0.075 mg/kg, for a safety factor of 840. The dose required to produce tranquilization in the unanesthetized dog is 0.05 mg/kg, and the minimal lethal dose is 10 mg/kg by the same route. The margin of safety in the dog is about 200. By comparison, the margin of safety of reserpine is 5.0.

The major signs of toxicity are ataxla, analgesia, mydriasis (less prominent in monkeys at lower doses), and profound central nervous system (CNS) depression lasting from several hours to several days, depending on dose. At higher doses, the CNS depression may be preceded by CNS stimulation and convulsions. Marked hypothermia at an intravenous dose of 1 mg/kg, hypotension, and respiratory depression are other significant effects of this compound. DMHP produces a marked decrease in mean arterial pressure in the anesthetized dog. This effect occurs slowly at small doses, but the latent period is considerably shortened at large doses. In the monkey, the minimal effective intravenous dose to produce ptosis and to decrease activity was 0.0316 mg/kg, whereas the minimal lethal dose was 10 mg/kg by the same route, for a safety factor of about 300,

Death after intravenous administration of DMHP in dogs is preceded by ventricular fibrillation, which may be secondary to hypothermia. However, there are no fatalities if the animals' rectal temperature is kept from falling.

Studies of the interaction of DMHP with other drugs were performed with dogs. If such compounds as cocaine, caffeine, d-amphetamine, and nalorphine are used to antagonize the CNS depression produced by DMHP, they also can produce a marked increase in toxicity and death. Death occurred during the depressed state that followed the stimulation induced by these agents.

Subchronic toxicity was studied in rats and dogs by administering DMHP intravenously over a period of a month.18 DMHP at 0.1, 1.0, and 10 mg/kg-d was given intravenously to male albino rats (10 per dosage) for 20 daily injections over a 4-wk period. No effects were seen at 0.1 mg/kg. However, rats at both 1.0 and 10 mg/kg-d showed the following effects: gross signs of toxicity, decreased body weight gain, decreased liver and kidney weights, and decreased ratios of liver and kidney weights to body weight. In addition, the high-dosage group showed decreased food consumption and histologic lesions of the lungs. Histologic examination revealed of mild to severe pneumonitis, fatty metamorphosis of the liver, arrest of spermato-genesis, and cellular alterations of the ovaries among all dogs. No hematologic changes occurred at any dosage. In dogs, repeated intravenous doses at 0.1 and 1.0 mg/kg-d were given to mongrel dogs (three per dosage) for 10 daily injections during a 2-wk period. Transient signs of effect at 0.1 mg/kg-d consisted of moderate hyperpnea and a slight decrease in activity, which were noted after each injection. Similar signs of toxicity were seen at 1 mg/kg-d, and these generally persisted throughout the course of the study. Terminal body weights were significantly lower in all high-dosage dogs, and significant changes in ratios of organ weights to body weight occurred among both groups. Although hematuria had been observed in earlier studies In mice and cats, it was not observed in these long-term studies.
Studies with dogs and monkeys have shown that tolerance to the toxic effects of DMHP develops.20,35,36,40,44

Toxiclty of DMHP Acetate (ÅA 2233)

The same types of toxicity data were gathered on DMHP acetate as on DMHP.18

In mice, the intravenous LD50 was greater than 25 mg/kg, and the MED50 (median effective dose) was 0.1 mg/kg, for a safety margin greater than 250. In the dog, slight hypertension was seen at 0.1 and 1 mg/kg. In monkeys trained on a visual discrimination test, minimal behavioral effects were seen at 0.316 mg/kg, and moderate to marked effects at 1.0 mg/kg.

Repeated intravenous administrations of DMHP acetate at 0.01, 0.1, and 1.0 mg/kg-d to male albino rats (10 per dosage) were carried out for 20 daily injections during a 4-wk period. Miosis was observed at the intermediate and high dosages, and lacrimation only at the high dosage. The high-dosage animals exhibited significantly lower food consumption, growth rates, liver and kidney weights, and ratios of liver to body weight and significantly higher ratios of adrenal to body weight. No changes attributable to the compound were seen in blood chemical tests or in gross or microscopic pathologic tests.

When dogs were treated with DMHP acetate at 0.01 or 0.1 mg/kg-d for 10 dally injections, no significant effect was seen at the low dosage. Marked defensive hostility developed at the high dosage— perhaps a sign of a cumulative effect. A.t this dosage, there was histologic evidence of glycogen storage in the liver.

MECHANISM OF ACTION

The mechanism of action of cannabinoids is not understood. Gill and Lawrence13 have shown that some active cannabinoid derivatives produce disordering of artificial lipid membranes, whereas inactive compounds either do not have this action or actually increase membrane ordering, as determined by electron spin resonance. This suggests that the cannabinoids resemble anesthetics in their mode of action. Cannabinoids do, however, appear to exhibit selectivity. Thus, DMHP, which is active in animals and produces marked vasomotor changes in humans, does not Induce subjective effects;31 but nabilone, which is structurally related to DMHP, causes both subjective and vasomotor changes. Burstein and Hunter7 have suggested that cannabinoids exhibit specificity In Interacting with such enzymes as phosphollpase A2 and cholesterol esterase, which may mediate some of their actions.

NEUROPHARMACOLOGY

Little is known about the pharmacology of DMHP and DMHP acetate, but the reference compound, THC, has been extensively described both in humans and in animals. Many reviews and symposia have discussed marijuana and the canuabinoids.6,10,19,26,39 The National Institute on Drug Abuse has reported to the Congress annually on research on marijuana. And the National Research Council34 and the Institute of Medicine23 issued recent reports on marijuana. Thus, we will briefly describe marijuana before commenting on the two compounds tested at Edgewood.

The pharmacology of THC in humans has been carefully explored. THC Intake at 50 µg/kg by smoking produces feelings of giddiness and changes in time sense and the perception of visual and auditory stimuli. At this dose, subjects may behave in a "silly" manner. Higher doses (over 200 µg/kg orally) may produce nausea, marked visual and auditory distortions, feelings of unreality and depersonalization, and auditory and visual hallucinations. The perceptual changes may be associated with panic reactions. Pulse rate is increased in a dose-related manner; blood pressure decreases, particularly on standing (orthostatic hypotension); and conjunctival injection (reddening) is observed.24 Although some subjects liken marijuana and THC to LSD, the effects of these drugs can be clearly differentiated by subjects In double-blind comparisons.25 The cannabinoids may also Increase blood pressure, particularly diastolic pressure.15 Hepler and Frank2l have shown that smoking marijuana reduces intraocular pressure, and Adams at al.4 demonstrated that this property was shared by THC. This effect is thought to be due to vasoconstriction of the afferent blood vessels to the ciliary body, which causes a decrease in perfusion pressure.14 THC also has an antiemetlc action.37 Marijuana and THC also produce bronchodilatation.41

The effects of THC and other cannabinoids on psychomotor performance are not easily summarized. There is clear impairment in most psychomotor tasks at high doses. The major conclusions that can be drawn are probably that moderate doses of THC have little effect on attention or on performance of very simple and well-practiced tasks. Furthermore, performance of complex tasks and tasks requiring complex processing of information is significantly impaired by THC and other centrally active cannabinoids.

Of the specific cannabinoids studied at Edgewood, pharmacologic data are available on DMHP. It was effective in producing sedation in animals at oral doses lower than 0.5 mg/kg. Several doses and routes of administration were studied, up to 1 mg/kg given Intravenously. In rats, sedation occurred without initial stimulation; in dogs and monkeys, hyperactivity was followed by depression and then, at higher doses, by coma. Motor effects were dramatic, in that animals developed spastic ataxia and showed extremely active deep tendon reflexes. If the animals were handled while sedated by the drug, extensor seizures often occurred. In contrast with these results in intact animals, animals subjected to spinal transection showed mild depression of deep tendon reflexes.17

Autonomic changes were quite prominent in DMHP-treated animals - hypothermia, mydriasis, hypersalivation, bradycardia, and reduced respiratory rate. Several experimental manipulations were undertaken to determine the mechanism of these autonomic changes. The tentative conclusion was that the drug was acting centrally to reduce sympathetic tone.

DMHP was also found to have anticonvulsant properties. Studies conducted in mice showed that it was 8 times as potent as THC.27

DMHP was found to be 20 times as potent as THC in prolonging hexobarbital sleep time in mice. The drug produced EEC changes similar to those produced by morphine. In an experiment that light link some of DMHP's effects to opiate receptors, DMHP-induced sedation, ataxia, and analgesia were significantly reversed by the mixed-opioid antagonist nalorphlne.16

DMHP appeared to have a wide margin of safety for acute toxic effects. One investigator calculated the therapeutic ratio for producing tranqullization in nonanesthetized dogs.l6 The ratio of LD50 to ED50 was 2,000:1, compared with only 5:1 for reserpine, a clinically approved drug. No long-term effects in animals after single doses were looked for, and no repeated-dose or chronic-toxicity studies of DMHP were reported. DMHP has more potent and more prolonged hypotensive effects than THC, but far fewer psychologic effects.

MUTAGENICITY, TERATOGENICITY, AND CARCINOGENICITY

Although the literature on cannabinolds is large, no information Is available with regard to the capacity of DMHP and the eight acetate isomers to produce mutagenesis, teratogenesis, or carcinogenesis in animals or man.

DELAYED AND LONG-TERM EFFECTS

DMHP and a series of optical isomers of DMHP acetate, studied at Edgewood in humans, produce similar symptoms, but vary greatly in potency. The more potent isomers appear to produce postural hypotension and fewer psychologic effects than equivalent doses of THC. However, they all evoke redness of the eyes, dryness of the mouth, sense of hunger, tachycardia, and drowsiness. 31,38 Postural hypotension is immediately reversed and blood pressure returned to normal by lying down.

Death due to inhalation or ingestion of marijuana has not been reported. Nor are there lasting ill effects from the acute use of marijuana,45 except that the acute or chronic use of marijuana occasionally precipitates or exacerbates a schizophrenic state.43 Isomer 2 is the most potent of the DMHP acetate isomers, being active at intravenous doses of 0.5-2.8 μg/kg. Postural hypotension was regularly noted, but euphoric responses were infrequent. DMHP has been the most extensively studied of these analogues.44 At toxic doses of 50 μg/kg or more, postural hypotension, tachycardia, hypothermia, and lethargy were noted. Fatigue, thirst, and headaches were associated symptoms. Prolonged or delayed effects of a small number of acute doses were not mentioned in the literature.

The literature on THC is much more voluminous and may be used in this evaluation, because DMHP and the DMHP acetate isomers and THC are related chemically and pharmacologically. This cannabinoid also produces no known long-term or delayed effects, except when administered chronically in large doses.33

The doses of the dibenzopyrans used at Edgewood were similar to those used by other investigators. Lemberger et al.30 used DMHP at 200μg per 70 kg intravenously, for example. The severe postural hypotension that occurs when the drug is taken intravenously, intramuscularly, or orally is a limiting factor in giving hallucinogenic amounts of DMHP isomers.

Two long-term effects are theoretical considerations. One is that exposure to the cannabinoids may somehow have caused a chronic or delayed posttraumatic stress disorder. In the dosage and frequency used, this is unlikely. The postexperimental effect that was most undesirable was postural hypotension. This resulted in dizziness and faintness, from which all subjects recovered. Such a stress is insufficient to provoke a delayed or chronic posttraumatic stress syndrome, nor is there any evidence that any such syndrome occurred. A second consideration is that exposure to DMHP at Edgewood may have produced a tendency toward abuse of cannabinoids in later years. This is not possible to assess.

The target organs that may be involved in prolonged or delayed effects are the brain and the cardiovascular system. The mental effect consists of a transient or reversible psychosis, which may in rare instances result in activation of a schizophrenic process. The cardiovascular effects are postural hypotension and tachycardia. These are transitory and leave no permanent residua.

Given the absence of follow up information on the effects of DMHP, the Committee cannot evaluate the possibility that the exposures at Edgewood produced delayed or long-term effects. However, information on THC suggests that such effects are unlikely to be associated with the exposures tested. In addition, clinical evaluations immediately after test administration did not indicate any acute effects likely to presage future complications or long-term sequelae.

A review of the epidemiologic aspects of DMHP is in Appendix C.

EFFECTS ON VOLUNTEERS

This review of acute effects on volunteers is based on clinical records at Edgewood. When the cannabinoid studies began at Edgewood in November 1958, much less was known about the pharmacology of DMHP than about the pharmacology of phencyclidine (SNA). The studies of the DMHP series in humans spanned the period from 1958 through 1968, with concentration in 1963-1966.

Although they are generally more potent, the DMHP derivatives had effects in the normal volunteers at Edgewood that were very similar to those later described over the last 15 yr by many research laboratories working with cannabis and THC. After administration of DMHP, there was more orthostatic hypotension than with THC or cannabis and possibly fewer subjective and mood effects. The time course appeared more variable, and DMHP's effects were often slower or more erratic in onset, particularly when it was given orally, than were those of THC. DMHP's effects also persisted longer.

In some of the earliest studies, beginning about November 1958, racemic mixtures of DMHP were given to approximately 35 volunteers at 0.5-4 mg per 70 kg of body weight. At 0.5 mg per 70 kg, fatigue, drowsiness, mild headache, and occasionally increased thirst developed. At 1 and 2.5 mg per 70 kg, postural hypotension was common, and faintness on standing was observed often. Blood pressure in a supine or prone position was normal or slightly increased. Weakness, ataxia, a feeling of giddiness, and general slowing of motor activity were common. At the highest doses, the subjects often showed marked psychomotor retardation, sluggishness, difficulty in concentrating, and blurred vision lasting for as long as 48 h after a single dose. Fewer comments were made about postural hypotension, probably because at this dose volunteers were unwilling or unable to get out of bed. Volunteers given over 2 mg of DMHP were judged to be incapable of performing their regular military duties. The intensity and duration of the hypotension, tachycardia, decrease in oral temperature, visual disturbance, subjective symptoms of thirst and dry mouth, and decreases in motor performance were generally dose-related, but their intensity varied among subjects. Thus, many of the signs and symptoms of DMHP intoxication were similar to those reported in recent years In many cannabis and THC studies of volunteers, except that DMHP was more potent and probably had more effects on the cardiovascular system.

The most extensive experiments at Edgewood were done in 1963-1966 with DMHP acetate. Approximately 100 volunteers were given doses of a DMHP acetate racemlc mixture during this period. Oral, intramuscular, and intravenous routes of administration were used. Oral doses ranged from 3 to about 60 μg/kg. Intravenous doses ranged from 0.5 μg/kg to (in a few subjects) 5 μg/kg. Intramuscular doses were between 0.5 and 5 μg/kg. Most subjects received only one drug exposure, and a few had multiple exposures, but rarely more than two.

Cardiovascular effects were most notable. Tachycardia and orthostatic hypotension were seen in some subjects at almost all doses. ECGs occasionally showed such nonspecific changes as inverted Ò waves. ECGs documented the 6- to 10-s lag In heart-rate increase caused by DMHP acetate after standing. Many subjects felt lightheaded and faint on standing. As the studies progressed and the relationship between dose and orthostatic hypotension was better appreciated, this effect was less likely to occur. In general, oral doses produced changes in heart rate and blood pressure at 1 or 2 h and peak effects at 6-10 h. Major effects on the cardiovascular system disappeared in most subjects after 24 h, but persisted for several days in a few subjects in whom hypotension and increased heart rate occurred.

As is often observed with cannabis, conjunctival blood vessel injection was common. Body temperatures decreased, sometimes by 3-4ºF. These changes were generally dose-dependent. Dryness of the mouth and throat, nasal stuffiness, apathy, and nausea were common, and their intensity was dose-related.

Psychomotor impairments were measured by such test batteries as the numerical facility, speed of closure, Purdue pegboard, and Strom-berg manual dexterity tests. Anecdotal reports, both by subjects and by staff, of changes in behavior and mood generally paralleled the other symptoms. The spectrum of the effects and their intensity is similar to that commonly reported in the recent literature on cannabis studies in other volunteer populations. However, DMHP acetate seemed to elicit more orthostatic hypotension, and cannabis, a greater degree of mental effects.
The lack of evidence of severe mental or emotional disturbances, even in volunteers who were observed to experience intense and persistent cardiovascular effects, is noteworthy. Although DMHP acetate elicits far greater cardiovascular consequences than other cannabinoids, it appears to induce less severe mental impairment. It is possible that careful screening and a supportive test milieu tend to minimize the occurrence of adverse mental effects.

The acute effects of eight optical isomers of DMHP acetate given singly or in combination were assessed in about 125 volunteers. Several of these subjects had participated or were participating concurrently in other DMHP experiments. The isomers were given intramuscularly or intravenously. Some of the intravenous injections were given with the isomer diluted in propylene glycol and others with alcohol as the vehicle. Isomers 1, 3, 5, 6, 7, and 8 appeared to have little biologic activity (generally at about 0.5-10 μg/kg). Apart from nonspecific symptoms, such as pain at the injection site, subjects appeared unaffected subjectively and objectively. In one sense, this series of experiments provides some index of placebo responsiveness - minimal. Many subjects commented (as recorded in the charts) that they generally enjoyed the experiments, thought well of the staff support, and, in general, had few complaints other than about the food.

Isomers 2 and 4 and mixtures thereof had significant biologic activity. Intravenous doses of 1-2 mg of isomer 2 produced fairly intense tachycardia and orthostatic hypotension in the volunteers, as already described. The postural hypotension was marked, increases in heart rate were present but less intense, and feelings of impaired cognition and concentration and altered mood were present and dose-dependent. The volunteers seemed able to function reasonably well - if they were able to get out of bed and walk around. However, during the first few hours of intoxication, this was virtually impossible in many cases, because of hypotension. Dryness of the mouth, increased thirst and hunger, mild sleepiness, Injected conjunctivas, and mild to severe hypotension are consistent with the effects of cannabis. Some\charts contain comments about such observations as skin pallor on standing. These are understandable in the light of the circumstances.

During the DMHP studies, hepatic function and renal function were assessed. Although occasional borderline-abnormal results were noted after exposure, these were generally followed up and did not appear to be clinically significant. Some attention was given to EEG and ECG assessments to follow the intensity and duration of any drug-induced changes in cardiovascular and brain functions. In no instances of followup, did the effects appear to be particularly specific or clinically significant for acute or long-term toxicity.

In summary, DMHP and some of its acetate isomers produced various degrees of physical incapacitation due largely to the moderate to marked and prolonged orthostatic hypotension. Blood pressure was normal in the supine position. Mental effects of DMHP were much less severe than those of THC or cannabis at doses that produced similar degrees of orthostatic hypotension. Individual differences in intensity of response were considerable: some subjects showed little or no response at doses that produced intense symptoms in other subjects.

This pattern of variability has been commented on in the extensive civilian literature on cannabinoid research. Duration of effects also varied. With most doses and subjects, the majority of measurable effects disappeared in 24 h, although in a few instances they persisted for 2 or 3 d. DMHP and biologically active isomers of its acetate cause greater and longer-lasting orthostatic hypotension and fewer psychologic effects than THC; otherwise, they are very similar on the measures recorded during these experiments. The potencies of DMHP acetate and DMHP itself seemed relatively similar. The eight isomers of DMHP acetate varied greatly in potency. Those with biologic activity seemed similar to DMHP in their effects.

REFERENCES


1. Aaron, H.S., and Ferguson, C.P. Synthesis of the eight stereo-isomers of a tetrahydrocannabinol congener. J. Org. Chem. 33:684-689, 1968.
2. Adams, R., amd Baker, B.R. Structure of cannabidiol. VII. A method of synthesis of a tetrahydrocannabinol which possesses marihuana activity. J. Am. Chem. Soc. 62:2405-2408, 1940.
3. Adams, R,, Chen, K.H., and Loewe, S. Tetrahydrocannabinol homologs with a s-alkyl group in the 3-position. XVI. J. Am. Chem. Soc. 67:1534-1537, 1945.
4. Adams, A.J., Flom, M.C., and Jones, R.T. Influence of marijuana on intraocular pressure. Am. J. Optom. Arch. Am. Acad. Optom. 49:880-881 (abst.), 1972.
5. Adams, R., MacKenzie, S., Jr., and Loewe, S. Tetrahydrocannabinol homologs with doubly branched alkyl groups in the 3-position. XVIII. J. Am. Chem. Soc. 70:664-668, 1948.
6. Braude, M.C., and Szara, S., editors. Pharmacology of Marihuana. Volumes 1 and 2. A Monograph of the National Institute on Drug Abuse. New York: Raven Press. 1976. 865 p.
7. Burstein, S. and Hunter, S.A. The biochemistry of the cannabinoids. Rev. Pure Appl. Pharmacol. Sci. 2:155-226, 1981.
8. Dagirmanjian, R., and Boyd, E.S. Some pharmacological effects of two tetrahydrocannabinols. J. Pharmacol. Exp. Ther. 135:25-33, 1962.
9. Domino, E.F. Neurobiology of phencyclidine—An update. In Petersen, R.C., and Stillman, R.C., editors. Phencyclidine (PCP) Abuse: An Appraisal. Rockville, Md.: U.S. National Institute on Drug Abuse. NIDA Research Monograph 21, 1978. p. 18-43.
10. Dornbush, R.L., Freedman, A.M., and Fink, M. eds. Chronic Cannabis Use. Ann. N.Y. Acad. Sci. 282:1-430, 1976.
11. Gaoni, Y., and Mechoulam, R. Isolation, structure, and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc. 86:1646-1647, 1964.
12. Ghosh, R., Todd, A.R., and Wilkinson, S. Cannabis indica. Part IV. The synthesis of some tetrahydrodibenzopyran derivatives. J. Chem. Soc., Part 11:1121-1125, 1940.
13. Gill, E.W., and Lawrence, O.K. The physicochemical mode of action of tetrahydrocannabinol on cell membranes. In Braude, M.C., and Szara, S., editors. The Pharmacology of Marihuana. New York: Raven Press. 1:147-155, 1976.
14. Green, K., and Bowman, K. Effects of marihuana and derivatives on aqueous humor dynamics in the rabbit. In Braude, M.C., and Szara, S., editors. The Pharmacology of Marihuana. New York: Raven Press. 2:803-813, 1976.
15. Hardman, H.F., and Hosko, M.J. Autonomic effects: An overview of the cardiovascular-autonomic actions of cannabis. In Braude, M.C., and Szara, S., editors. The Pharmacology of Marihuana. New York: Raven Press. 1:231-238, 1976.
16. Hardman, H.F., Domino, E.F., and Seevers, M.H. General pharmacological actions of some synthetic tetrahydrocannabinol derivatives. Pharmacol. Rev. 23:295-315, 1971.
17. Hardman, H.F., Domino, E.F., and Seevers, M.H. The Chemistry and Pharmacology of EA 1476. Terminal Report on Contract No. DA 18-108-CML-5663. U.S. Army, Chemical Warfare Laboratories, Army Chemical Center, Md. 1959. [17] p.
18. Hardman, H.F., Domino, E.F., and Seevers, M.H. The Chemistry and Pharmacology of EA 1476 and The Chemistry and Pharmacology of Certain Compounds Affecting the Central Nervous System of Animals and Man. Reports issued under Contract No. DA-18-108-CML 5663 between 1956 and 1959. U.S. Department of the Army, Chemical Warfare Laboratories, Army Chemical Center, Md.
19. Harris, L.S., Dewey, W.L., and Razdan, R.K. Cannabis: Its chemistry, pharmacology, and toxicology. Handb. Exp. Pharmakol. 45/11:371-429, 1977.
20. Hazleton Laboratories, Inc., Falls Church, Va. Reports issued under Contract No. DA-18-108-405-CML-826 between 1960 and 1963.
U.S. Army Chemical Research and Development Laboratories, Army Chemical Center, Md.
21. Hepler, R.S., and Frank, I.R. Marihuana smoking and intraocular pressure. J. Am. Med. Assoc. 217:1392, 1971.
22. Hively, R.L., Mosher, W.A., and Hoffmann, F.W. Isolation of trans-Δ6-tetrahydrocannabinol from marijuana. J. Am. Chem. Soc. 88:1832-1833, 1966.
23. Institute of Medicine. Marijuana and Health. Washington, B.C.: National Academy Press. 1982. 188 p.
24. Isbell, H., Gorodetzsky, C.W., Jasinski, D., Claussen, U., Spulak, F., and Korte, F. Effects of (-)Δ9-tranc-tetrahydro-cannabinol in man. Psychopharmacologia 11:184-188, 1967.
25. Isbell, H., and Jasinski, D.R. A comparison of LSD-25 with (-)Δ9-trans-tetrahydrocannabinol (THC) and attempted cross tolerance between LSD and THC; Psychopharmacologia 14:115-123, 1969.
26. Jones, R.T. Cannabis and health. Ann. Rev. Med. 34:247-258, 1983.
27. Karler, R., Cely, W. and Turkanis, S.A. Anticonvulsant properties of Δ9-tetrahydrocannabinol and other cannabinoids. Life Sci. 15:931-947, 1974.
28. Klapper, J.A., McColloch, M.A., and Sidell, F.R. The effect on personality of reactivity to 1,2-dlmethyl-heptyl tetrahydrocannabinol. Arch. Gen. Psychiatry 26:483-485, 1972.
29. Lawrence, O.K., Pertwee, R.G., Gill, E.W., and Piper, J.M. Brain levels and relative potency of the 1,2-dimethylheptyl analogue of Δ1-tetrahydrocannabinol in mice. Biochem. Pharmacol. 23:3017-3027, 1974.
30. Lemberger, L., McMahon, R., and Archer, R. The role of metabolic conversion on the mechanism of action of cannabinoids. In Braude, M.C., and Szara, S., editors. The Pharmacology of Marihuana. New York: Raven Press. 1:125-132, 1976.
31. Lemberger, L., McMahon, R., Archer, R., Matsumoto, K., and Rowe, H. Pharmacologic effects and physiologic disposition of delta6a,10adimethyl heptyl tetrahydrocannabinol (DMHP) in man. Clin. Pharaacol. Ther. 15:380-386, 1974.
32. Lemberger, L., McMahon, R.E., Archer, R.A., Matsumoto, K., and Rowe. H. The in vitro and in vivo metabolism of delta6a,10adimethyl heptyl tetrahydrocannabinol (DMHP). J. Pharaacol. Exp. Ther. 187:169-175, 1973.
33. Mendelson, J.H., Babor, T.F., Kuehnle, J.C., Rossi, A.M., and Bernstein, J.G., Mello, N.K,, and Greenberg, I. Behavioral and biologic aspects of marijuana use. Ann. N.Y. Acad. Sci. 282:186-210, 1976.
34. National Research Council. Committee on Substance Abuse and Habitual Behavior. An Analysis of Marijuana Policy. Washington, D.C.: National Academy Press. 1982. 41 p.
35. Neitlich, H.W., and Pless, J.E. Effect on Man of Parenteral Administration of A Production-line Mixture of Isomers 2 and 4, EA 2233 (U) U.S. Army Edgewood Arsenal. Chemical Reserch and Development Laboratories. Edgewood Arsenal, Md. CRDL Technical Memorandum 2-36. 1965. 17 p.
36. Pless, J.E. The Effects of Isomer 2 of EA 2233 Administered Intravenously to Human Subjects (U), Medical Research Laboratory, Research Laboratories, Edgewood Arsenal, Md. Edgewood Arsenal Technical Memorandum EATM 114-5. 1966. 19 p.
37. Sallan, S.E., Zinberg, N.E., and Frei, E. Antiemetic effect of 9-tetrahydrocannablnol in patients receiving cancer chemotherapy. N. Engl. J. Med. 293:795-797, 1975.
38. Sidell, F.R., Pless, J.E., Neitlich, H., Sussman, P., Copelan, H.W., and Sim, V.M. Dimethylheptyl-delta 6a-10a-tetrahydro-cannabinol: Effects after parenteral administration to man. Proc. Soc. Exp. Biol. Med. 142:867-873, 1973.
39. Singer, A.J., ed. Marijuana: Chemistry, Pharmacology, and Patterns of Social use. Ann. N.Y. Acad. of Sci. 191:1-269, 1971.
40. Sussman, P. Effects of Intravenous Isomer 4, EA 2233 in Man (U), Department of the Army, Edgewood Arsenal, Research Laboratories, Medical Research Laboratory, Edgewood Arsenal, Md. Edgewood Arsenal Technical Memorandum EATM 114-10. 1967. 19 p.
41. Tashkin, D.P., Shapiro, B.J., and Frank, I.M. Acute pulmonary physiologic effects of smoked marijuana and oral Δ9-tetrahydrocannabinol in healthy young men. N. Engl. J. Med. 289:336-341, 1973.
42. Taylor, E.G., Lenard, K., and Shvo, Y. Active constituents of hashish. Synthesis of dl-Δ6-3,4-trans-tetrahydrocannabinol. J. Am. Chem. Soc. 88:367-369, 1966.
43. Treffert, D.A. Marijuana use in schizophrenia: A clear hazard. Amer. J. Psychiat. 135:1213-1215, 1978.

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