We previously assessed rCBF following smoking of marijuana and placebo as subjects repeatedly performed the same cognitive task. The task provided a stable cognitive baseline but did not allow assessment of direct vs task-related effects of marijuana. The present doubly-blinded study used PET with [O-15]water to measure rCBF in 12 volunteers who smoked marijuana or placebo cigarettes on 2 occasions at least a week apart. On each occasion subjects were imaged after smoking a marijuana (~20 mg THC) or placebo cigarette while performing 3 auditory tasks; a baseline RT task (also presented before smoking), and dichotic listening tasks with attend-right and attend-left ear instructions. As in our previous studies, smoking marijuana resulted in intoxication (self report), increased rCBF in orbital frontal cortex, anterior cingulate, temporal pole, insula, and cerebellum, and reduced rCBF in auditory and visual cortices. These changes occurred in all 3 tasks and appear to be direct effects of marijuana on rCBF. T...

Brain serotonin has been implicated in the action of many psychoactive drugs. One agent of particular social and medical interest is Δ9-THC, the major active constituent in marijuana. Although a number of studies have characterized the effect of Δ9-THC on various neurochemical indices of serotonergic function, none has directly examined the effect of this compound on the electrophysiological activity of serotonergic neurons. To determine whether Δ9-THC alters serotonergic neuronal activity, we monitored the firing rate of serotonergic dorsal raphe neurons in behaving animals acutely treated with this agent. Serotonergic neurons were identified and recorded as described previously (Fornal et al., 2001). Systemic administration of Δ9-THC (5 mg/kg, i.p.) produced clear signs of sedation and impaired motor function, which are established characteristics of THC's action. These behavioral effects were evident within 15-30 min after injection and persisted for several hours. During periods when the cats were clea...

Several pharmacological effects of delta-9-tetrahydrocannabinol (THC) are reduced or blocked by administration of opioid antagonists and rewarding or aversive properties of THC are modified in mice lacking opioid receptors. In this study, rats learned to discriminate a 3 mg/kg i.p. injection of THC from an injection of vehicle under a two-lever choice procedure with food reinforcement. We then investigated whether the subjective effects of THC could be blocked or reduced by administration of opioid antagonists and whether opioid agonists could mimic or potentiate THC’s subjective effects. The opioid antagonist naloxone (1 mg/kg, i.p.) produced a small decrease in the discriminative effects of the training dose of 3 mg/kg THC and significantly shifted the THC dose-response curve to the right. When the opioid agonist morphine (1-10 mg/kg, i.p.) was substituted for THC, it did not produce THC-like discriminative effects. However, a 1 mg/kg dose of morphine potentiated the discriminative effects of THC, shifti...

A characteristic pattern of behavioral and physiological effects is produced by marijuana and its principal psychoactive component, THC, in humans. However, THC’s sites of action in the human brain and their relationships to the drug’s actions are not well described. We have now studied in frequent marijuana users, the effects of two doses of THC (1 and 3 mg iv over 1 min) that produce effects similar to those seen with marijuana use in a social situation, on regional brain activity using BOLD fMRI. The subjects reported that the intensity of the “high” produced by the 3 mg dose was twice that of the lower dose (8/10 vs. 4.5/10). A modest dose-related tachycardia was also observed.Both increases and decreases in brain activity as measured by BOLD fMRI were seen in discrete brain regions. The 3 mg dose of THC produced time-related decreases in fMRI signal in the cerebellum including the region of the dentate nucleus, the middle temporal gyrus and the orbitofrontal region. Decreases were also seen in several...

Altered time perception is one of the most frequently-reported subjective experiences associated with the “high” induced by marijuana (MJ). Intoxicated subjects typically experience time as passing more quickly relative to real time i.e., MJ increases the subjective time rate. We assessed the acute and chronic effects of smoking MJ or placebo cigarettes (provided by NIDA) on a self-paced finger tapping task using a double-blind, placebo-control design. Volunteers (n = 10) who smoked marijuana recreationally an average of 3 times a month (low-use group) were compared with chronic users (n = 15) who smoked marijuana daily for an average duration of 5 years. A tone was presented for 50s with a beat to beat interval of 730ms, and was then turned off. Subjects were instructed to tap in time with the tone and to continue tapping at the same pace for 50s after it terminated. Tone-paced tapping did not change in either group after smoking placebo or MJ, indicating that MJ did not cause sensory-motor impairment on ...

The nonpsychoactive phytocannabinoid cannabidiol (CBD) has been shown to have analgesic effects in animal studies but little is known about its mechanism of action. We examined the effects of CBD on intrinsic excitability of primary pain-sensing neurons. Studying acutely dissociated capsaicin-sensitive mouse DRG neurons at 37°C, we found that CBD effectively inhibited repetitive action potential firing, from 15–20 action potentials evoked by 1 s current injections in control to 1–3 action potentials with 2 μm CBD. Reduction of repetitive firing was accompanied by a reduction of action potential height, widening of action potentials, reduction of the afterhyperpolarization, and increased propensity to enter depolarization block. Voltage-clamp experiments showed that CBD inhibited both TTX-sensitive and TTX-resistant (TTX-R) sodium currents in a use-dependent manner. CBD showed strong state-dependent inhibition of TTX-R channels, with fast binding to inactivated channels during depolarizations and slow unbin...

Excitotoxicity is a paradigm used to explain the biochemical events in both acute neuronal damage and in slowly progressive, neurodegenerative diseases. Here, we show in a longitudinal magnetic resonance imaging study that Δ9-tetrahydrocannabinol (Δ9-THC), the main active compound in marijuana, reduces neuronal injury in neonatal rats injected intracerebrally with the Na+/K+-ATPase inhibitor ouabain to elicit excitotoxicity. In the acute phase Δ9-THC reduced the volume of cytotoxic edema by 22%. After 7 d, 36% less neuronal damage was observed in treated rats compared with control animals. Coadministration of the CB1 cannabinoid receptor antagonist SR141716 prevented the neuroprotective actions of Δ9-THC, indicating that Δ9-THC afforded protection to neurons via the CB1 receptor. In Δ9-THC-treated rats the volume of astrogliotic tissue was 36% smaller. The CB1 receptor antagonist did not block this effect. These results provide evidence that the cannabinoid system can serve to protect the brain against neu...

The abuse of Δ-9-tetrahydrocannabinol (THC), the principal psychoactive constituent of marijuana, is associated with persistent cognitive dysfunction. We therefore studied the effects of chronic administration of THC (10 mg/kg) on cognitive function in the rat. THC administration, twice daily for 14 days, resulted in a persistent attentional impairment that is reminiscent of cognitive deficits observed following excitotoxic lesions of the dorsomedial frontal cortex. Specifically, rats chronically administered THC showed subsequent impairments in a self-paced version of the classic 5-choice serial reaction time task, which persisted 14 days after the final drug administration. Longer time points have yet to be examined. These attentional impairments were temporarily reversible by an acute amphetamine (0.5 mg/kg) challenge. Importantly, the attentional deficit was observed after withdrawal from THC, suggesting that the behavioral effects were drug-induced changes in the brain rather than a direct effect of T...

Marijuana remains the most commonly abused illicit substance in the United States, however, the effects of cannabis on cerebral blood volume (CBV) have not been fully examined. Given reported changes in frontal BOLD activation in marijuana smokers the objective of the present study was to examine both cerebral (frontal and temporal areas) and cerebellar blood volume during a period of supervised abstinence. Dynamic susceptibility contrast (DSC) MRI data were collected on eleven current, long-term marijuana users (MJ) between 6 hours and 36 hours after the subject's last reported cannabis use. Resting state CBV images were also acquired in 11 healthy comparison subjects (NCs). Data were acquired in the axial plane following a bolus of gadolinium contrast agent with a 1.5-Tesla GE Signa scanner. MJ smokers demonstrated significantly increased blood volumes in the left temporal area (p= 0.018) and in the cerebellum (p= 0.023) relative to control subjects. A regression analysis revealed that age was not signif...

We have previously shown that cannabinoid agonists, including delta-9-tetrahydrocannabinol (THC), are more potent and in some cases more efficacious in female than in male rats, in terms of their antinociceptive and motoric effects (Tseng & Craft, Eur J Pharmacol 430:41, 2001). In the present study, we manipulated gonadal steroid hormone state in adulthood, to determine to what extent activational effects of gonadal steroids are responsible for sex differences in sensitivity to the behavioral effects of THC. Adult Sprague-Dawley rats were gonadectomized; half of the females were implanted s.c. with estradiol (1-mm capsule/rat), and half of the males were implanted with testosterone (10-mm capsule/100 g body weight), and the rest of the rats were implanted with blank capsules of comparable length and number. Three weeks later, rats were injected with THC (5 mg/kg i.p.) or vehicle (1:1:18 emulphor:ethanol:saline) and tested for antinociception (tail withdrawal and paw pressure tests) and motor behaviors (hor...