Antinociceptive, subjective and behavioral effects of smoked marijuana in humans

Abstract

The purpose of this study was to determine whether marijuana produced dose-dependent antinociception in humans and, if so, whether endogenous opiates modulate this effect. A total of five male regular marijuana users participated in three test sessions during which they smoked cigarettes containing 0% (placebo) and 3.55% Δ⁹-tetrahydrocannabinol (Δ⁹-THC) (active). Each of four controlled smoking bouts per session, spaced at 40-min intervals, consisted of nine puffs from active and placebo cigarettes (three cigarettes, three puffs per cigarette, one puff per min). During successive bouts, participants smoked 0, 3, 6 and 9 (0, 3, 9 and 18 cumulative) puffs from active marijuana cigarettes, with the remainder of puffs from placebo cigarettes. Test sessions were identical, except for naltrexone 0, 50 or 200 mg p.o. (randomized, double-blind) administration 1 h before the first smoking bout on the different days. Before smoking, between smoking bouts and postsmoking, participants completed an assessment battery that included antinociceptive (finger withdrawal from radiant heat stimulation), biological, subjective, observer-rated signs and performance measures. Marijuana produced significant dose-dependent antinociception (increased finger withdrawal latency) and biobehavioral effects. Naltrexone did not significantly influence marijuana dose-effect curves, suggesting no role of endogenous opiates in marijuana-induced antinociception under these conditions.

Introduction

Cannabinoid receptor agonists generally produce antinociception in animals; however, the test compound, assay, species, dose and route of administration used can modulate this effect (Harris, 1971, Dewey, 1986, Adams and Martin, 1996, Martin and Lichtman, 1998). Neuropharmacological studies, most using the tail-flick assay, have begun to characterize the mechanisms of cannabinoid antinociception. Two cannabinoid receptor subtypes have been identified; CB₁ receptors (nervous system) account for most of marijuana’s effects, whereas CB₂ receptors (spleen) mediate immune response (Adams and Martin, 1996). The primary brain site of tetrahydrocannabinol (THC) antinociceptive action is at CB₁ receptors in the periacqueductal gray (Lichtman et al., 1996), also a principal site of opioid antinociception (Basbaum and Fields, 1984). Cannabinoid antinociception in this region is blocked by the CB₁ antagonist SR-141716A (Lichtman and Martin, 1997, Welch et al., 1998) but not systemically administered opioid antagonists (Welch et al., 1995, Vivian et al., 1998), indicating a centrally mediated, opioid-independent mode of action. Recent studies also implicate brainstem circuitry that mediates THC, but not morphine, analgesia (Martin et al., 1998, Meng et al., 1999).

Early studies using opioid antagonists, at high doses that presumably blocked mu, kappa and delta receptors, demonstrated partial attenuation of THC-induced antinociception (Wilson and May, 1975, Tulunay et al., 1981, Ferri et al., 1986). These results suggested that endogenous opiates might partly mediate this effect. Subsequently, a second site of cannabinoid antinociception was identified in the spinal cord (Yaksh, 1981, Lichtman and Martin, 1991, Smith and Martin, 1992), where this effect is blocked by i.t. administration of kappa-opioid antagonists (Welch, 1993a, Welch, 1993b, Smith et al., 1994, Reche et al., 1996) but only partially attenuated by SR-141716A (Welch et al., 1995).

Effects of THC on clinical pain have been infrequently studied in humans, with mixed results (Noyes et al., 1975, Noyes et al., 1976, Raft et al., 1977). Analgesic effects of THC are usually overshadowed by side-effects, e.g. sedation. Cannabinoid effects on human pain sensitivity have been studied in double-blind, placebo-controlled laboratory situations, again with conflicting findings. Single doses of oral THC did not increase pain threshold using cold pressor (25 mg; Karniol et al., 1975) or electrocutaneous stimuli (12 mg; Hill et al., 1974), whereas i.v. THC (0.022 and 0.044 mg/kg) increased pain detection but not tolerance threshold using pressure and electrocutaneous stimulation (Raft et al., 1977). Acute marijuana (cigarettes with ≈1.0% THC) versus placebo smoking did not affect radiant heat (thermode on the forearm) sensitivity in either cannabis-experienced or non-experienced volunteers (Milstein et al., 1974). These negative results may be due to the use of a single low THC dose, smoking procedures that were less well-controlled, a response criterion that was closer to a sensory than a pain threshold, and short mean reaction times (i.e. possibly indicating a ceiling effect). In contrast, Milstein et al. (1975) found significant increases in pain tolerance following marijuana smoking, with slightly (but not significantly) greater effects for cannabis-experienced than non-experienced volunteers. Clark et al. (1981) found a hyperalgesic effect of chronic daily marijuana smoking, relative to a presmoking wash-out period, during a long-term residential study.

Contributing to this uncertain body of literature is the fact that procedures for measuring human pain sensitivity are often unreliable. Lee and Stitzer (1995) developed a procedure in humans that is comparable to the tail-flick assay. This procedure, which requires the participant to withdraw the finger from a radiant heat source under pain threshold instructions, was shown to have better reliability (within- and between-sessions) than an electrocutaneous method. This is also important because THC actually lowered pain threshold (produced hyperalgesia rather than antinociception) in healthy volunteers using electrocutaneous stimulation (Hill et al., 1974). Thermal stimulation has been the predominant laboratory model for evaluating cannabinoid antinociception in animals; we therefore used this method to probe pain sensitivity in marijuana-smoking human volunteers.

This study had three aims. The first aim was to determine whether marijuana smoking produced dose-dependent thermal antinociception in humans, similar to animals. These data were compared with biological, subjective effects, objective signs and performance measures for a complete profile. Psychomotor measures were used to evaluate whether marijuana produced motor deficits versus an inhibition of pain transmission. The second aim was to extend the method of Chait et al. (1988), in which participants smoked 0, 2, 4 and 8 cumulative active (and placebo) puffs across four smoking bouts from cigarettes with 1.4% THC. In the present study, participants smoked a wider range of doses — 0, 3, 9 and 18 cumulative active (and placebo) puffs from cigarettes with 3.55% THC across four bouts. In the Chait et al. study, smoking occurred at 20-min intervals; in the present study, bouts were scheduled every 40-min to collect a broader range of data (see first aim). The third aim was to assess whether endogenous opiates influence marijuana effects in humans, i.e. whether naltrexone pretreatment produced rightward shifts in marijuana dose-response curves. Based on evidence that kappa-opioid antagonists attenuate THC-induced spinal antinociception in animals, we tested high doses of naltrexone to block a higher fraction of kappa (and other opioid) receptors. Naltrexone was used because there are no kappa-selective antagonists presently available for human use, and it has a long duration of action (Verebey et al., 1976) to span the cumulative dosing period.