Psychoactive effects Of all the immediate actions of cannabis, its psychoactive effects are undoubtedly those that give the greatest concern in considering its medical uses (7R, 8RS, 10ER). All of the CNS effects of THC, both the desired medical actions and the undesired psychological effects, appear to be mediated through a single type of brain receptor, the CB1 cannabi-noid receptor. This was illustrated, for example, by a well-controlled study in 63 healthy cannabis users, who received either the CB1 receptor antagonist rimonabant (SR141716A) or placebo and smoked either a THC-containing or a placebo marijuana cigarette (12C ). Rimon-abant blocked the acute psychological effects of the active cigarettes, but when given alone (with placebo cigarettes) produced no significant psychological effects. In many of the medical applications that have been assessed to date, unwanted psychological adverse effects have been blamed as the main cause of patients' rejection of the drug as unacceptable. Patients who have had no prior experience with cannabis often find its intoxicant effects disturbing, and it can cause panic/anxiety attacks in such people. Others may simply not want to be "high" when they go about their daily work. The deleterious effects of cannabis on short-term memory and other aspects of cognition make it especially unacceptable for those whose occupation depends on an ability to remain alert and capable of handling and processing complex information.
The medicinal use of cannabis often involves oral administration, but absorption is slow and erratic, leading to the risks of overdosage or underdosage. For this reason smoking is the preferred route of administration, but it carries its own hazards (see below). If improved delivery systems could be devised, it is likely that patients could titrate optimum doses of the drug to avoid some of these unwanted effects, but the therapeutic window between a medically effective dose and an intoxicant one is narrow. A possible acceptable alternative to smoking may be to give cannabis by means of a sublingual spray, and this is currently being tested in clinical trials (13S).
Psychomotor impairment CB1 receptors are expressed in particularly high densities in the basal ganglia and cerebellum, so it is not surprising that cannabinoids have complex effects on psychomotor function (14R). One of the earliest reports of the effects of cannabis extracts in experimental animals described an awkward swaying and rolling gait in dogs, with periods of intense activity provoked by tactile or auditory stimuli, and followed eventually by catalepsy and sleep (15E). In mice a "popcorn effect" was described: the animals are sedated by THC but will jump in response to auditory or tactile stimuli; as they fall into other animals these in turn jump, resembling popping corn (16R).
These effects of cannabinoids may be due in part to actions at cerebellar or striatal receptors. Tests of specific cerebellar functions have shown that cannabinoids increased gait width and the number of slips on a bar cross test (17E). Rotorod impairments were also reported in mice after direct injection of synthetic cannabinoids into the cerebellum, but not in animals pretreated with cerebellar injections of an antisense oligonucleotide directed at a sequence in the CB1 receptor (18E).
In humans cannabis caused impaired performance in tests of balance (19E) or tests that require fine psychomotor control, for example tracking a moving point of light on a screen (20e). Human cannabis users may also seek isolation and remain immobile for long periods (21R).
Because psychomotor skills are impaired by cannabis intoxication, it is inadvisable for users to drive for some hours after taking the drug, and the ability to carry out any tasks that require manual dexterity is likely to be impaired. Drug-induced impairment of balance could also make elderly patients more likely to fall. A comparison of 452 marijuana smokers with a similar number of non-smokers attending the Kaiser Permanente Health Group in California showed that the marijuana smokers had an increased risk of attending out-patient clinics with injuries of various types, perhaps as a result of the acute intoxicant effects of the drug (22C ).
Effects on memory One of the well-established effects of acute intoxication with cannabis in man is impairment of short-term memory (21R, 23R-25R). Many studies have shown significant effects on short-term memory, particularly when tests were used that depend heavily on attention (26E, 27R). In animals THC, synthetic cannabinoids, and anan-damide cause deficits in short-term memory in spatial learning tasks (28ER). These include delayed matching or non-matching tests in rodents (29e, 30e), performance in a maze (31E,
32E ), and a fixed-ratio food acquisition task in squirrel monkeys (33E). The effects of both cannabinoids (32E) and anandamide (30E) were reversed by rimonabant, showing that they are mediated by the CB1 receptor.
A likely site for these effects is the hippocampus: the effects of cannabinoids on short-term memory in rats were the same as the effects seen after surgical removal of the hippocampus (29E). In each case the animals were unable to segregate information between trials in the task because of disruptions to the processing of sensory information in hippocam-pal circuits. CB1 receptors are expressed in high density in the hippocampus (34E, 35E) and the mechanisms underlying synaptic plasticity have been studied more intensely in the hippocampus than in any other brain region. In particular the electrophysiological phenomena of long-term potentiation and long-term depression are thought to be involved in memory formation at glutamatergic synapses in the hippocampus. Several studies have shown that cannabinoids inhibit the induction of both long-term potentia-tion and depression (36R). Cannabinoids appear to work by reducing glutamate release below the level needed to activate NMDA receptors, a requirement for long-term potentiation and depression (37E, 38E).
Effects on other cognitive functions Like other intoxicant drugs, cannabis causes profound changes in a variety of higher brain functions (9R, 21R, 23R, 25R). The distribution of CB1 receptors in the neocortex has been described in detail (39E, 40E). The earlier literature contained several reports of the effects of acute and chronic cannabis use on EEG activity, both in animals (16R) and man (25R ). Most studies in man have shown EEG changes consistent with a state of drowsiness, with increases in relative and absolute alpha power, particularly in the frontal cortex. In contrast, the CB1 antagonist rimonabant caused EEG changes characteristic of arousal in rats and increased the time spent in wakefulness as opposed to sleep (41E).
There have been many studies of the acute and chronic effects of cannabis on human cognitive function (21R, 23R, 25R). Performance in a variety of tests is impaired, but by comparison with alcohol the effects of cannabis are subtle. Whereas even moderate doses of alcohol impair reaction time, most studies of cannabis have failed to show consistent effects. Therefore, abnormal cognitive function due to cannabis cannot be due to an inability to respond promptly. Among the types of impairment of cognitive function that have been observed in many, but not all, human studies are: a reduced ability to inhibit responses, impaired vigilance, especially for long and boring tasks, reduced ability to perform complex mental arithmetic, and impairment in tests of complex reaction times. On the other hand, intoxicated subjects can perform simple arithmetic, learn simple lists of words, and recall memories laid down earlier (21R ).
Cardiovascular effects Cannabis has profound effects on the cardiovascular system. In inexperienced users it can cause a large increase in heart rate (up to a doubling) and this could be harmful to someone with a previous history of coronary artery disease or heart failure (3R, 4r, 9r). Such patients should therefore be excluded from clinical trials of cannabis-based medicines. The postural hypotension that can be caused by cannabis could also be distressing or possibly dangerous. These cardiovascular effects usually show rapid tolerance on repeated exposure to cannabis, so for healthy subjects they are not of concern.
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