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Quit Marijuana The Complete Guide

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Quit Marijuana The Complete Guide Summary

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Patterns of cannabis use

Cannabis has been tried by many young adults in Europe, the United States, and Australia. (3) Most cannabis users in the United States stop in their middle to late twenties, and very few engage in daily cannabis use over a period of years.(3,.4) In the United States and Australian surveys, about 10 per cent of those who ever use cannabis become daily users, and another 20 to 30 per cent use weekly.(3) This pattern of use in developed countries differs from that in traditional cannabis-using countries, such as Egypt and India, where recreational cannabis use is uncommon and heavy cannabis use is confined to small and marginalized groups in the population 3) Because of uncertainties about THC content, 'heavy' cannabis use is usually defined as daily or near-daily use. (5) This pattern of use over years places users at the greatest risk of experiencing adverse psychological consequences. Daily cannabis users are more likely to use alcohol and tobacco regularly and to use amphetamines,...

Acute psychological effects of cannabis use

Cannabis produces euphoria and relaxation, perceptual alterations (including time distortion, and impaired short-term memory and attention), and intensification of ordinary sensory experiences, such as eating and listening to music.(2) The most common unpleasant psychological effects are anxiety and panic reactions.(2) These may be reported by naive users and they are a common reason for discontinuing use.(2) Cannabis produces dose-related impairments in cognitive and behavioural functions that may potentially impair driving an automobile or operating machinery. (6) Chronic psychological effects of cannabis use Cannabis dependence For much of the 1970s cannabis was not regarded as a drug of dependence because of the apparent absence of tolerance and withdrawal symptoms, and a lack of persons seeking help to stop their cannabis use. There is now evidence that animals and humans develop tolerance to the effects of THC, (1) with some heavy users experiencing withdrawal symptoms on the...

Cannabis and schizophrenia

There is good clinical and epidemiological evidence of an association between schizophrenia and cannabis use, which suggests that cannabis use can precipitate schizophrenia or exacerbate its symptoms. But this is not the only explanation of the association. Persons with schizophrenia may use cannabis as a form of self-medication, or there may be other variables that explain both for example, cannabis use is a marker of other psychotogenic drug use, or of vulnerability to schizophrenia 2) There is clinical and epidemiological evidence that cannabis use exacerbates the symptoms of schizophrenia in affected individuals. This includes the findings of a number of prospective studies that have controlled for confounding variables. (12) It is also a biologically plausible relationship. Psychotic disorders involve disturbances in the dopamine neurotransmitter systems, since drugs that increase dopamine release produce psychotic symptoms when given in large doses, and neuroleptic drugs that...

Differences Between the Pharmacology of Exoand Endocannabinoids in the Central Nervous System

In vivo activity of cannabinoids is assessed in mice based on a battery of four assays designed by Martin and colleagues (motor activity, catalepsy, body temperature, and analgesia) (41). Overall, anandamide displayed similar pharmacologocal effects compared to tetrahydrocannabinol (THC) (42). Anandamide's shorter duration of action in vivo compared to that of the plant-derived and synthetic cannabinoids (by 1 h, compared to several hours at least) has been attributed to anandamide's facile degradation (23,43) by FAAH (28).

Effects of Cannabinoids on Endogenous Opioid Peptides

Biochemical studies have revealed that cannabinoid administration can increase the release of several endogenous peptides, which can contribute to the acute and chronic pharmacological responses induced by these compounds. Thus, acute intrathecal administration of THC and other cannabinoid agonists has been reported to enhance in vivo the extracellular levels of endogenous dynorphins in the spinal cord (48,61,62,70,101,). These dynorphins seem to play an important role in the antinociception induced by cannabinoids at the spinal level (48,62). Different dynorphins seem to be released by the administration of several cannabinoid agonists. Thus, an increase of the extracellular levels of dynorphin A has been observed after THC administration, whereas CP-55,940, another cannabinoid agonist, has been reported to enhance the release of dynorphin B (48). However, the administration of the endogenous cannabinoid ligand anandamide did not modify the extracellular concentration of dynorphins...

Overview of Cannabinoids and Cannabinoid Receptors

Cannabinoids are a group of approx 60 terpinophenolic 21-carbon-containing compounds present in plants of the Cannabis genus, particularly C. sativa and C. indica. Although cannabis preparations have been used for centuries for medicinal, recreational, or religious purposes, it was not until the mid-1960s that the primary psychoac- tive ingredient was determined to be (-)-irans-D9-tetrahydrocannabinol (THC) (18,19). Subsequently, highly potent and selective synthetic cannabinoid agonists, including HU-210, CP-55,940, and the aminoalkylindole WIN 55,212-2, were developed. The study of the biological effects of these and other cannabimimetic compounds led to the hypothesis that the pharmacological actions of cannabinoids are mediated by the activation of specific receptors. Direct evidence for this hypothesis was obtained in the mid-1980s, when cannabinoid agonists were shown to inhibit the enzymatic synthesis of cyclic adenosine monophosphate (cAMP) in neuroblastoma cells in a manner...

Implications for Addiction to Cannabinoids 81 Tolerance

Tolerance to cannabinoids developed in all species studied, with varying duration and onset, depending, for example, on the parameter studied (72,180-184). In humans, development of tolerance to the psychoactive effects of marijuana is clearly seen with heavy (daily) use, but usually not with casual or moderate use (72,185). Tolerance to ANA has been shown in animal studies (50,51).

Cannabis the drug

Cannabis is derived from the female plant of Cannabis sativa. Its primary psychoactive constituent is delta-9-tetrahydrocannabinol ( THC).(1) The THC content is highest in the flowering tops of the plant. Marijuana (THC content 0.5-5 per cent) is prepared from the dried flowering tops and leaves of the plant. Hashish (THC content 2-20 per cent) consists of dried cannabis resin and compressed flowers.(1 Cannabis is usually smoked in a 'joint', like a tobacco cigarette, or in a water pipe, often mixed with tobacco. Although marijuana and hashish may be eaten, cannabis is usually smoked because this is the most efficient way to achieve the desired level of intoxication. (2)

Cannabis psychosis

High doses of THC have been reported to produce visual and auditory hallucinations, delusional ideas, and thought disorder in normal volunteers. (2) In traditional cannabis-using cultures, such as India, a 'cannabis psychosis' has been reported in which the symptoms are preceded by heavy cannabis use and remit after abstinence.(1,12) The existence of a 'cannabis psychosis' in Western cultures is still a matter for debate. In its favour are case series of 'cannabis psychoses', and a small number of controlled studies that compare the characteristics of 'cannabis psychoses' with those of psychoses in individuals who were not using cannabis at the time of hospital admission 13) Critics of the hypothesis emphasize the fallibility of clinical judgements about aetiology, the poorly specified criteria used in diagnosing these psychoses, the dearth of controlled studies, and the striking variations in the clinical features of 'cannabis psychoses'. (14)

Brigitte L Kieffer and Frdric Simonin 1 Introduction

Opioids have been classified as narcotic drugs (from the Greek word for stupor), due to their pharmacological profile very distinct from that of other drugs of abuse, such as pyschostimulants (cocaine, amphetamine), cannabinoids, nicotine, or alcohol (3). As for other substances of abuse, though, opioid addiction typically develops in four stages (4) (a) the initiation phase, in which drug exposure produces positive subjective effects (euphoria) (b) the maintenance phase, in which drug-taking becomes compulsive, indicating that dependence has developed (c) withdrawal, which develops when drug levels decrease in the body and is recurrently experienced by drug abusers and (d) craving or the intense desire to use the drug and relapse, which are most critical from a therapeutic standpoint. Not every individual exposed to opioids will develop addiction, depending on social, contextual, or perhaps genetic factors (5). However, opioids are considered strongly addictive, and it has been...

Effects of psychoactive drugs

Drugs of abuse, particularly alcohol, have adverse effects on various aspects of immunity and susceptibility to infectious diseases. (3 35) Fetal alcohol exposure can permanently affect endocrine and immune responses. Alcohol inhibits production of proinflammatory cytokines, reduces NK cell activity and suppresses B- and T-cell immunity. Alcoholics are infection prone. Although HIV-seronegative heroin addicts generally have reduced immune functions, persons maintained on methadone in a state of steady tolerance have normal immunity. Marijuana suppresses production of a- and b-interferon and the cytolytic activity of macrophages. Other psychoative drugs often have immune effects. Benzodiazepines antagonize suppression of NK cell activity by corticotrophin-releasing factor and thus may modify stress effects on immunity 36)

Commonly Abused Substances

There are five groups of drugs that are commonly abused in the United States and in other developed countries. These are heroin, cocaine, cannabis, hallucinogens, and inhalants. Heroin is a Schedule I drug (see Chapter 1) that has no accepted medical use in the United States. Cocaine stimulates the central nervous system (see Chapter on CNS). Cannabis includes drugs such as marijuana and hashish.

Who uses drugs and why

Sixteen-year-olds from the United States and the United Kingdom topped the league in lifetime experience of any illicit drug in a comparison of 23 countries. (5) Forty-one per cent of British school students admitted using cannabis in comparison with 34 per cent of North American, 19 per cent of Italian, 15 per cent of Spanish, 12 per cent of French, and 2 per cent of Greek students. Overall, around one in four of the British population have tried an illegal drug at some time. Peak use occurs in the late teens and early twenties. Cannabis accounts for 85 per cent of this and most cannabis smokers never use any other illegal drug. Polydrug use is the norm on the club scene. Among a sample of Scottish clubbers,(6) individuals had consumed a lifetime average of 11 different drugs. Drug use within the past year included alcohol (96 per cent), cannabis (96 per cent), ecstasy (87 per cent), tobacco (86 per cent), LSD (79 per cent), amphetamine (77 per cent), cocaine (59 per cent), 'poppers'...

Do school prevention programmes work

Outcome research of prevention programmes in the United States has been the subject of a comprehensive review.(21) Programmes should be guided by awareness that the average age of trying alcohol, cigarettes, solvents, or cannabis for the first time is between 11 and 13 years, and that exposure to drugs is now the norm for older teenagers.(22) The two distinct aims are to delay experimentation in younger children and to minimize harm in those over 13, many of whom can be assumed to be dabbling already or to have friends who are doing so. Only those programmes that actively involve students in discussion and debate, and provide relevant skills training such as assertiveness, ways of resisting social pressure, problem solving, stress management, and confidence boosting, have any measurable benefit. Improvement in knowledge without this practical dimension has no effect on behaviour, and scaremongering or moralizing can be actively counterproductive.

Chapter References

Interpreting Dutch cannabis policy reasoning by analagy in the legalization debate. Science, 278, 47-51. 3. McGeorge, J. and Aitken, C.K. (1997). Effects of cannabis decriminalisation in the Australian Capital Territory on university students' patterns of use. Journal of Drug Issues, 27, 785-93.

Prevalence of volatile substance use

Volatile substances are used throughout the world. A World Health Organization report gives an overview of the issue, (6) and a National Institute on Drug Abuse (NIDA) report presents prevalence studies worldwide.(7) A Pompidou Group report(8) indicated that VSA was a pan-European problem. In the United Kingdom, up to 20 per cent of young people have tried sniffing volatile substances. (9) In continental Europe, while prevalence is lower, experimental volatile substance use among teenagers comes second only to cannabis, and in Greece and Sweden it is higher than cannabis use. (10)

Other disorders Cognitive impairment

The fact that cannabis use acutely impairs cognitive functioning has raised the reasonable concern that chronic use may produce chronic cognitive impairment. The available evidence, however, suggests that even the long-term heavy use of cannabis does not produce any severe or grossly debilitating impairment of cognitive function 18) There is no evidence, for example, that it produces anything comparable to the cognitive impairments found in chronic heavy alcohol drinkers if it did, it should have been detected by research to date.(2) However, there is some clinical and experimental evidence that the long-term use of cannabis may produce more subtle cognitive impairment in the higher cognitive functions of memory, attention and organization, and the integration of complex information.(18) The evidence suggests that the longer the period of heavy cannabis use, the more pronounced is the cognitive impairment 18) None the less, the impairments in performance are subtle, and so it remains...

Behavioural effects in adolescence

There has been understandable societal concern about the effects of adolescent cannabis use on school performance, mental health and adjustment, and the use of other more hazardous drugs. There is a strong cross-sectional association between heavy cannabis use in adolescence and the risk of discontinuing a high-school education and experiencing job instability in young adulthood. (22> However, the strength of this association is reduced in longitudinal studies when adjustments are made for the fact that heavy cannabis users have lower academic aspirations and poorer high-school performance prior to using cannabis than their peers. (22,,23) There is some evidence that heavy cannabis use has adverse effects upon family formation, mental health, and involvement in drug-related crime. (22) In each case, the strong associations in cross-sectional studies are more modest in longitudinal studies after statistically controlling for associations between cannabis use and other pre-existing...

Size and nature of the problem

In the United Kingdom there have been no representative national population surveys focusing exclusively on drug use. However, the latest British Crime Survey of almost 11 000 participants aged 16 to 59 in England and Wales has provided valuable data on the prevalence of illicit drug use. (5) Lifetime prevalence estimates from the British Crime Survey are as follows cannabis, 22 per cent amphetamines, 9 per cent cocaine hydrochloride, 3 per cent crack cocaine and heroin, 1 per cent. Six per cent of the sample were defined as current users of any drug (having used in the month prior to interview), with the majority reporting cannabis use. Prevalence rates for drug use vary considerably by age grouping and other factors such as unemployment. For example, approximately 50 per cent of young people sampled between the ages of 16 and 24 years have tried an illicit drug on at least one occasion. (56) Figures for lifetime cocaine use are 2 per cent for 16- to 19-year-olds and 6 per cent for...

Risk factors age of onset and outcome

Schizophrenic patients with an early age at onset of psychosis are also more likely than patients with later onset to have had a history of exposure to obstetric complications 59) while those schizophrenic individuals who showed childhood deficits such as low IQ also tend to have an early onset. Schizophrenic patients who abuse cannabis have also recently been shown to have an earlier onset than those who do not. (58)

The risk factor model Geneenvironment interaction

Similarly, there is evidence that individuals with a family loading for schizophrenia may be more susceptible to psychosis following abuse of cannabis. (61) The latter situation may be complicated by the possibility that individuals who inherit a schizotypal personality may be more likely to take drugs such as cannabis to try to alter an unhappy internal mood state, i.e. their genotype renders them more liable to expose themselves to a factor to which they are genetically susceptible.

General and History Aspects

A particular member of eicosanoids is anandamide. Anandamide binds to specific receptors in brain tissue and the effects of anandamide are comparable to those of the cannabinoids. Since anadamide is a potent neuromodulator, a separate section is dedicated to this eicosanoid (Section 4.2).

Mental disorders and suicide

Attempted suicide, which carries about 40 times the expected value (Tab e 3). In anorexia nervosa and major depression the risk is about 20-fold, and in other mood disorders and psychoses about 10 to 15 times higher than expected. In anxiety, personality, and substance use disorders the suicide risk is at lower levels, but about five to 10 times higher than the expected value. In subtance disorders the risk is dependent on the type of disorder, being clearly lowest in alcohol, cannabis, and nicotine abusers.(23)

Low Doses of Anandamide

Much less is known about the in vivo pharmacology of 2-AG compared to anandamide. However, being deactivated by similar mechanisms as anandamide (see previous section), it is not surprising that 2-AG also has a short duration of action compared to plant-derived or synthetic cannabinoids, while partial agonist properties are also apparent for 2-AG (5,56).

Pharmacokinetic Aspects

A9-THC is readily absorbed when marijuana is smoked. Pharmacological effects are produced rapidly and generally peak within 30 minutes of the onset of smoking. The dynamics of smoking (number of puffs, spacing, hold time, and lung capacity) substantially influence how much drug is absorbed. Although oral ingestion of marijuana produces similar pharmacological effects, A9-THC is absorbed more slowly than by smoking. Impairment on various performance measures related to driving skills has been demonstrated immediately following marijuana smoking and up to 24 hours thereafter. Generally, behavioral and physiological effects return to baseline levels 4 to 6 hours after usage. Blood concentrations of A9-THC peak prior to drug-induced effects. This time discordance between blood concentrations of A9-THC and effects has made it difficult to establish a meaningful relationship between blood concentrations and effects.

Mechanism of Action

Of the most abundant receptors in the CNS, and its distribution within the brain reflects the pharmacological effects produced by A9-THC. High receptor densities in the extrapyramidal motor system and the cerebellum are consistent with the actions of cannabinoids on many forms of movement. The effects of cannabinoids on cognition and memory may be due to the relatively dense receptor populations in the hippocampus and cortex. The presence of cannabinoid receptors in the ventro-medial striatum and nucleus accumbens suggests an association with dopamine neurons hypothesized to mediate brain reward.

Pharmacological Actions Central Nervous System

Marijuana produces a distinctive behavioral syndrome that is easily distinguished from that of most other drugs. The most prominent feature is the initial period of euphoria, or high, which has been described as a sense of well-being and happiness. Euphoria is frequently followed by a period of drowsiness or sedation. Perception of time is altered, along with distortions in both hearing and vision. However, illusions and hallucinations occur infrequently. The subjective effects also include dissociation of ideas. The subjective effects of marijuana vary from individual to individual as a function of dose, route of administration, the experience and expectation of the subjects, and individual vulnerability to certain psychoactive substances. Motor coordination also may decrease, especially in situations requiring highly complex motor skills, such as flying an airplane and driving an automobile. Increased appetite is frequently attributed to smoking marijuana. Cannabinoids are effective...

Other Organ Systems

The most consistent pharmacological effect produced by marijuana is tachycardia, which is closely associated with the blood levels of A9-THC. There is relatively little effect on blood pressure unless large quantities of marijuana are smoked, in which case there can be marked orthostatic hypotension. Cannabinoids are also vasodilatory, which results in the characteristic conjunc-tival reddening following marijuana smoking. They also reduce intraocular pressure and are capable of producing bronchodilation.

Receptor Mediated Mechanisms for Endocannabinoid Activities in the Central Nervous System

Fan (92) has shown that cannabinoids including anandamide, inhibit 5-HT3 receptor-mediated currents. These data indicated that the 5-HT3 receptor ion channel is a site of action of cannabinoids and endocannabinoids. The direction of the effect is compatible with the antiemetic potential of cannabinoid agonists (93), since 5-HT3 receptor antagonist are well-established antiemetic medicinal drugs. Fan's observation went largely unchallenged but was also not supported further by experimental evidence. However, we have observed that the 5-HT3 antagonists MDL72222 and granisetron show cannabinoid-like profiles in the mouse tetrad (73). In assays for synaptosomal receptor binding, MDL72222 did not bind CB1 receptors, and vice versa, neither anandamide nor HU210 bound to 5-HT3 receptors (Fride et al., in preparation). Thus, the nature of the interaction between CB1 and 5-HT3 receptors needs to be clarified further. The current state of knowledge is complex. Mice injected with the 5-HT2...

Motor Functions and Schizophrenia

CB1 receptors are richly distributed in the basal ganglia and cerebral cortex, regions that play a pivotal role in motor control (119,120). Cannabinoids and endocannabinoids affect motor behavior in a bi- or even triphasic fashion (52,121). An intimate interactivity between the dopamine system and the endocannabinoids has been uncovered. Thus, earlier studies include cannabinoid-induced increases in dopamine release in the frontal brain regions (122), while chronic treatment with dopamine D2 receptor antagonists resulted in increased CB1 receptor expression in the striatum (123). Furthermore, localized application of cannabinoids into the nigrostriatal system in the rat counteracted the motor response to dopamine D2 receptor agonists (124,125). Direct studies on the endocannabinoid system indicated that stimulation of D2 receptors enhances anandamide in the rat striatum (126), while the anandamide transport blocker

The Controversy Over Cannabinoid Dependence

The acute behavioral and pharmacological effects of cannabis (marijuana) have been well characterized and are in relatively little dispute. On the other hand, there is less agreement regarding the consequences of repetitive exposure to cannabis, particularly when it comes to development of dependence. Two events that typically occur con-comitantly following chronic exposure to many psychoactive drugs are tolerance and dependence. Although these two events are likely to be mediated through distinct mechanisms, they both demonstrate that some form of adaptation has occurred. As for development of tolerance to cannabis and its main psychoactive constituent, -tetrahydrocannabinol (THC), there is ample evidence for its occurrence in both laboratory animals and humans. Actually, animal studies are in good agreement on the development of tolerance to the effects of THC following repeated exposure (1). There is also evidence that chronic heavy cannabis smokers develop tolerance to its...

Animal Models for Measuring Cannabinoid Dependence

Two general procedures that elicit withdrawal responses are abrupt cessation of chronic drug administration and antagonist challenge in animals during chronic drug administration. Adaptation that occurs during chronic drug administration rebounds either to a mild or severe extent and is manifested by a withdrawal syndrome. Most dependence-inducing drugs produce numerous somatic signs that can be quantified. Interestingly, the same somatic signs can be used to characterize the withdrawal syndrome for several different drugs. Typically, a withdrawal syndrome is characterized by hyperactivity, increased grooming, tremors, shaking activity, piloerection, diarrhea, and so on. The withdrawal signs reported for several cannabinoids are presented in Table 1. Given the appearance of some common withdrawal signs for several different drug classes and the apparent ease of quantifying these signs, it is surprising that there can be considerable discrepancy between similar studies carried out in...

Precipitated Cannabinoid Withdrawal

The development of the selective CB1 cannabinoid receptor antagonist, SR 141716A, represented a major breakthrough for cannabinoid research (57). This antagonist has been found to block most pharmacological effects of cannabinoids in different animal species. SR 141716A has been particularly useful for characterizing cannabinoid withdrawal in laboratory animals. In contrast to studies confined to employing abrupt withdrawal techniques, SR 141716A has been demonstrated to elicit reproducible and quantifiable withdrawal reactions following repeated cannabinoid administration in a variety of laboratory animals including mice, rats, and dogs (Table 1). A challenge in quantifying withdrawal is that the syndrome appears in rapidly alternating sequences of different behaviors (58). Moreover, specific withdrawal responses are also affected by methodological procedures employed by different investigators relating to differences in species, strain, agonist, dosing regimen, and aspects of the...

S Evidence statements

Four placebo-controlled crossover trials examined the efficacy of different cannabis derivatives for spasticity. The first randomised crossover trial compared Delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), and a combination of THC and CBD to placebo. The results indicated that THC and the combination of THC and CBD showed beneficial effects on four of the seven outcome measures assessed, whilst CBD alone showed positive effects on three when compared to placebo.360 The second trial assessing Delta-9-THC reported no overall significant effects at lower doses, with a significant reduction in symptoms being noted only at high doses of the drug which was intolerable due to the number of side effects reported.361 The third trial assessed the effect of active smoked marijuana on postural stability and reported negative effects on both outcome measures recorded.362 The last randomised crossover trial compared THC and cannabis sativa plant extract to placebo. The results showed no...

Cannabinoid Self Administration

The other important characteristic of a dependence-producing substance is that typically animals can be trained to self-administer such compounds. Contrary to the majority of drugs abused by humans, it has been quite difficult to train animals to self-administer cannabinoids. Although the physical characteristics of cannabinoids probably contributed to this difficulty, the general opinion persisted that cannabinoids lack rewarding effects and therefore are devoid of dependence liability. However, a recent study (70) demonstrated that the synthetic cannabinoid agonist WIN 55,212-2 was intravenously self-administered by mice in a concentration-dependent manner according to an inverted U-shaped curve. Therefore, it is possible that WIN 55,212-2 may elicit both rewarding and aversive effects depending on the concentration used. It may well be that these dual properties have hindered the development of a THC model of self-administration. Alternatively, decreased response rates at higher...

S From evidence to recommendations

In formulating its recommendations, the guideline developers noted the relatively low level of evidence available for most of the commonly used drugs, that comparative studies were very rare, the absence of evidence for most of the commonly used physical therapies, and the difficulty in defining and measuring the benefits of treating spasticity in formal trials. Further, we recognise that cannabis derivative and extracts are currently being researched with several large studies to be published and that NICE is undertaking a review of cannabis drugs. It also recognized that the management of spasticity was an important topic, and hence derived a series of recommendations that drew on clinical consensus as well as the limited evidence.

Other Parental Factors

Limited data have been published on diet as a risk factor for childhood leukemia. One study reported an association between parental or child consumption of hot dogs and ALL.39 One very preliminary study suggested a positive association between maternal consumption of foods that inhibit DNA topoisomerase II and infant AML.40 Other reported associations include maternal marijuana use during pregnancy,41 birth order (first born at higher risk) and advanced maternal age,13 and certain medications used either by the mother41 or the child.42 By and large, however, these associations have been either inconsistent, or evaluated in only one study.

Effects of Targeted Gene Disruption on the Expression of Cannabinoid Dependence

Although the CB1 receptor has been presumed to mediate the dependence-inducing effects of cannabinoids based on the fact that CB1 is the major cannabinoid receptor in the CNS and that withdrawal symptoms are precipitated by the CB1 antagonist SR141716A, the use of CB1 knockout mice has provided confirmation of this hypothesis. Ledent et al. (61) reported that cannabinoid dependence and self-administration were absent in a CB1 receptor knockout mouse line on a CD1 background. Five days of twice-daily intraperitoneal injections of THC produced significant dependence as gauged by SR141716A-precipitated withdrawal signs in the CB1 + + mice. Most withdrawal signs were absent or significantly reduced in CB1 - - compared to CB1 + + mice, including rearing, sniffing, wet-dog shakes, paw tremor, piloerection, penile licking, mastication, hunched posture, and body tremor. Although an acute vehicle-injection group was not included to control for the effects of SR141716A in nondependent mice,...

Summary and Conclusions

Although marijuana has been used for centuries and the occurrence of psychological dependence in humans has been widely accepted, until recently there was little direct evidence of physiological dependence and no animal models of cannabinoid withdrawal. The establishment of reliable measures of cannabinoid withdrawal was for years hampered by the lack of a specific high-affinity cannabinoid antagonist. The discovery that cannabinoids act through G-protein-coupled receptors and the subsequent cloning of the CB1 and CB2 receptors aided in the development of a selective antagonist of CB1 cannabinoid receptors. Once the antagonist became available, it was possible to use established in vivo pharmacological approaches to define antagonist-precipitated withdrawal behaviors indicative of cannabinoid dependence. Perhaps not surprisingly, the cannabinoid withdrawal syndrome includes many of the same somatic withdrawal signs that are observed with other dependence-inducing psychoactive drugs....

Participation of Opioid Mechanisms in the Development of Cannabinoid Tolerance

Different pharmacokinetic mechanisms have been suggested to be involved on can-nabinoid tolerance, such as changes in drug absorption, distribution, biotransformation, and excretion. However, the role of such pharmacokinetic mechanisms, if any, seems minor (108,119,124). In contrast, pharmacodynamic events play a crucial role in cannabinoid tolerance. Indeed, a significant decrease in the total number of CBl-bind-ing sites (125-130) and the levels of mRNA coding for the CB1 cannabinoid receptor have been reported in several brain areas during chronic administration of cannabinoid agonists (131,132). A widespread decrease in mRNA levels of Gai and Gas proteins has also been reported in rats treated chronically with cannabinoids (133). Changes in G-protein expression have been postulated to be related to desensitization of CB1 can-nabinoid receptors. Accordingly, a strong reduction of cannabinoid agonist-stimulated 35S GTPYS binding has been obtained in most brain regions of rats...

Participation of Opioid Mechanisms in Cannabinoid Induced Dependence

Molecular studies have reported a significant decrease in the severity of morphine withdrawal syndrome in knockout mice deficient in CB1 cannabinoid receptors (44). In addition, acute administration of several cannabinoid agonists (158-162), including anandamide (163), has been reported to attenuate the severity of naloxone-precipitated morphine withdrawal. A similar effect was observed when THC was administered for a long period of time before starting opioid dependence. Thus, chronic pretreatment with THC (10 mg kg once daily during 3 wk) before starting chronic opioid administration decreased the somatic manifestations of naloxone-precipitated morphine withdrawal and did not modify morphine rewarding effects (67). Therefore, long term preexposure to cannabinoids does not seem to modify motivational responses of opio-ids related to their addictive properties.

Activation of TRPV4 by Thermal Stress and Lipids

Following a search for the true physiological lipid agonist of TRPV4, this group made the striking observation that the endogenous cannabinoid anandamide activated the channel.18 Although cannabinoids were known to be potent agonists of TRPV1 (reviewed in Ref. 17), their role in TRPV4 activation had not been explored. Classically, cannabinoids exert their myriad physiological effects via interaction with specific G-protein-coupled receptors,19 but this effect of anandamide did not require the participation of cannabinoid receptors. Through the use of pharmacological inhibitors and agonists, Watanabe et al. suggested that anandamide is not a direct activator of TRPV4. Rather, anandamide is likely metabolized to arachidonic acid and then, via the action of cytochrome P450 epoxygenase, is metabolized further to one of several epoxyeicosatrienoic acid (EET) compounds. These lipids, particularly 5',6'-epoxyeicosatrienoic acid, then activate TRPV4. Whether activation of TRPV4 by these lipid...

Place Conditioning Paradigm

Recent studies have used the place-conditioning paradigm in knockout mice to evaluate the involvement of the endogenous opioid system in the rewarding and aversive properties of cannabinoids. The motivational responses induced by THC have been investigated in knockout mice lacking < x-, -, or D-opioid receptor (144). The rewarding effects induced by 1 mg kg of THC, avoiding the possible dysphoric consequences of the first drug exposure, were abolished in < x-opioid receptor knockout mice but were not modified in mice lacking - or D-opioid receptor. The dysphoric effects induced by a high dose of THC (5 mg kg) were not modified in -opioid receptor knockout mice, slightly attenuated in < x-knockout animals, and completely abolished in mice lacking -opioid receptor. These D-opioid receptor knockout mice also showed place preference to THC (1 mg kg) in animals that had not received any priming exposure, revealing the crucial role of this opioid receptor in THC-induced dysphoria....

Self Administration Studies

The procedure by which animals are permitted to intravenously self-administered drugs has provided a reliable method to evaluate directly the reinforcing properties of a psychoactive compound, and is probably the clearest indication in animals of its addictive potential in humans (187). Numerous studies have shown that THC is unable to induce a self-administration behavior in any of the animal species studied (148,149, 188-192). Animals that have already learned to self-administer other drugs of abuse did not self-infuse THC (148,191,192). THC pharmacokinetic properties seem to be crucial for the behavioral responses on the self-administration paradigm. Indeed, WIN 55,212-2, a synthetic cannabinoid agonist that has a shorter half-life than THC, was intravenously self-administered in mice in a concentration-dependent manner, according to a two-phase bell-shaped curve (193). Another synthetic cannabinoid agonist, CP 55,940 has been reported to sustain intracerebroventricular...

Biochemical and Electrophysiological Studies

Dose-dependent increase in the spontaneous firing rate of ventral tegmental area dopamine neurons (202,203). The biochemical (201) and electrophysiological effects (202,203) of cannabinoids on in vivo dopamine transmission in the nucleus accumbens were prevented by the administration of SR 141716A, indicating the selective involvement of CB1 cannabinoid receptors.The endogenous opioid system has also been reported to be involved in the effects of cannabinoids on mesolimbic dopamine activity. Thus, administration of opioid antagonists was reported to block the increase in extracellular efflux of dopamine in the nucleus accumbens induced by the acute administration of cannabinoid agonists (176,201). However, other studies have reported that naloxone did not modify THC-induced increase of the firing rate of dopaminergic neurons projecting to the nucleus accumbens (203,204) and neostriatum (202).

Non Related Neurotransmitters

Cannabinoids are compounds of the plant Cannabis sativa, of which the 89-tetrahydrocannabinol is the most psychoactive substance upon intake. The two cannabinoid receptors CB1-R and CB2-R have been identified in 1988 177 , and 1993 178 , respectively, and the natural ligand for the CB-Rs, termed anandamide from the Sanskrit word 'ananda' for bliss and the amide-containing structure, has been isolated in 1992 by the same group, which has identified the CB1-R before 179 . Anandamide is a derivate of the arachidonic acid and binds to CB2-R with higher affinity than to CB1-R 180 . The CB2-R was initially identified in macrophages in the margin zone of the spleen 178 . Since then, both CB-Rs have been found in several lymph organs and leukocyte subpopulations, and cannabinoids are modulators for the immune response, especially with regard to the balance between T helper1 and T helper2 lymphocytes 181, 182 . The migration of CTLs is inhibited by CB2-R engagement, whereas the migration of SW...

Pathways to service utilization

While language can be a major obstacle in mental state assessment, for many people from minority ethnic groups who speak English the problem is one of communication rather than language. Both missed diagnoses and misdiagnosis may result and a lack of recognition of the personal, social, and cultural problems which influence the presenting patterns of symptoms in different ethnic groups can contribute to the tendency of clinicians to make assumptions and listen out for stereotypical triggers which then prompt a particular therapeutic response. Such triggers include religious euphoria, use of cannabis in African-Caribbeans, and the 'fatalistic attitude' attributed to Asian patients. For example, the diagnosis of cannabis-induced psychosis effectively blames the patient for causing his own illness. This may both provide a convenient expression of racist attitudes as well as deprive the patient of correct treatment.

Abnormal intrathoracic air collections

Many patients in the surgical ICU receive ventilatory support that includes positive end-expiratory pressure and are at increased risk of developing barotrauma. Abnormal intrathoracic air may also be the result of penetrating or non-penetrating injury, asthma, or illicit drug use (particularly crack cocaine and marijuana), as well as iatrogenic etiologies such as esophageal dilatation or neck surgery. The basic radiographic sign of a pneumothorax is the thin white line of visceral pleura as it is separated from the parietal pleura which is often seen in the lung apices. In the supine patient, the abnormal air may collect in the lateral costophrenic sulci (giving a deep sulcus sign) or anteromedially, causing abnormal lucencies near the cardiophrenic angle or superior mediastinum. The size of the pneumothorax is only poorly estimated by the supine chest radiograph, and its significance should be interpreted in the light of the clinical circumstances, particularly when a tension...

Environment beyond the family

Many of the risk factors that lead to alcohol and drug abuse are similar to those for antisocial behaviour. However, the relationship is more than just a passive overlap. Antisocial behaviour increases the chances of substance abuse, and vice versa. Longitudinal surveys show that antisocial behaviour in childhood and adolescence increases the risk of later alcohol- and drug-related problems, which peak in the twenties. ('Problems' refers to regular use of hard drugs or heavy drinking, with psychosocial impairment or medical complications as a result. This differs from the occasional or 'recreational' use of marijuana or hallucinogens, which is far more widespread, or alcohol use without impairment.) With alcohol, heavy drinking increases the chance of crime as it causes disinhibition and is associated with a range of disorderly and violent offences. With drugs, there is an increase in theft and non-violent offences to get money to buy drugs those who deal in drugs may use violent...

Behavioral Profiles of Drug Effects

Another way of determining whether the behaviors contained in the NCTR OTB are independent of each other is to determine whether experimental manipulations can preferentially affect specific behaviors. Toward this end, a series of experiments have been conducted in monkeys in which the behavioral effects of psychoactive compounds have been determined. In these studies, a variety of doses of each compound were given and the relative sensitivities of each task to these treatments were determined. In short, the profiles of behavioral effects obtained were specific for the particular compound tested. For example, time estimation behavior was significantly affected (disrupted) by low doses of delta-9-tetrahydrocannabinol (THC, the primary psychoactive ingredient in marijuana, MJ, smoke) that had no effect on the other OTB behaviors. Likewise for other compounds, behavioral profiles suggest that certain drugs preferentially affect different behaviors, again suggesting that these behaviors...

Participation of Opioid Mechanisms in Cannabinoid Antinociception

Of the paw (31), sciatic nerve (30), or tooth (32). Electrophysiological studies have largely confirmed these antinociceptive properties of cannabinoids (33). Cannabinoid agonists also induce antinociception in inflammatory models of pain, such as hyperalgesia induced by carrageenan (34), capsaicin (35), formalin (36-38), and Freund's adjuvant (39). Doses of cannabinoid agonists required to induce antinociception in inflammatory processes are usually lower than those required in other nociceptive models (35), in agreement with the anti-inflammatory properties of cannabinoid agonists (22). Cannabinoid agonists are also effective in visceral models of pain, such as the bladder wall inflammation induced by turpentine administration (38), and neuropathic models, such as the painful mono-neuropathy induced by loose ligation of sciatic nerve (40-42). In contrast with opioid responses, antinociceptive effects of cannabinoids in neuropathic pain are not decreased after repeated administration...

Other Supranuclear Oculomotor Disorders

Was superior to vigabatrin in a small series of patients 69 others have also reported an improvement due to gabapentin 70, 71 . Cannabis, which acts as a retrograde presynaptic inhibitory transmitter and in this way is similar to gabapentin, which also acts presynaptically, was recently reported to be equally effective 72, 73 . A bilateral retrobulbar botulinum toxin injection was successfully used in some patients to induce a complete external ophthalmoplegia, thereby diminishing the acquired pendular nystagmus 74, 75 however, it proved unsatisfactory in other patients 76 .

The NCTR Operant Test Battery OTB

Studies begun in the mid-1980s at the Food and Drug Administration's National Center for Toxicological Research (NCTR) incorporated a variety of behavioral tasks into an Operant Test Battery (OTB) for use with laboratory rhesus monkeys. (The term operant simply refers to the fact that subjects operate something in their environment, e.g., a response lever, in order to obtain reinforcers.) The initial studies were designed to assess the behavioral effects of delta-9-tetrahydrocannabinol (the primary psychoactive ingredient in marijuana smoke) and marijuana smoke. Initial OTB descriptions and drug effects can be found elsewhere.1-3 Since those earlier studies, the OTB has been used to study the acute effects of a variety of prototypic psychoactive compounds (see Table 16.1) as well as the effects of chronic exposure to a variety of agents, both in a developmental context4 and in adult subjects.5 The specific brain functions thought to be modeled by performance of the NCTR OTB and the...

Effects of Chronic Cannabinoid Administration on Molecular Signaling Pathways

Effects of Chronic Cannabinoids on Brain CB1 Receptor Expression receptor levels were detected by 3H CP55,940 autoradiography in the caudate-puta-men, nucleus accumbens, olfactory tubercle, and septum following induction of tolerance to THC or CP 55,940 by 2-wk treatment in rats, and this reduction was due to decreased receptor Bmax values (75). Similar results were subsequently reported in homogenates prepared from dissected rat brain regions 3H CP 55,940 Bmax values decreased in striatal membranes after several days of injection with THC but not with anandamide (76,77). Similarly, reduced expression of CB1 receptor mRNA in rat cau-date-putamen, but not other regions, was obtained using in situ hybridization methodology after 11 d of treatment with THC or CP 55,940 ( 78). Alternatively, a shorter treatment (1 wk) with a higher dose of CP 55,940 in mice produced tolerance in tests of hypoactivity, hypothermia, and catalepsy, as well as a significant reduction in the 3H CP...

Similar Neuroanatomical Sites are Involved in Cannabinoid and Opioid Antinociception

Supraspinal, spinal, and peripheral mechanisms seem to be involved in the antinociceptive properties of cannabinoid agonists. Thus, intracerebreventricular (29,49,50), intrathecal (29,39,75), and local peripheral administration of cannabinoids (37,75) are able to induce potent antinociceptive responses. Studies using local administration of cannabinoid agonists in various brain structures have identified the central areas involved specifically in cannabinoid antinociception. Thus, antinociceptive responses have been induced by local microinjection of cannabinoid agonists in the periaqueductal gray matter (39,76), rostral ventromedial medulla (77), submedius and lateral posterior nuclei of the thalamus (78), superior colliculus, central and basolateral nuclei of the amygdala, and A5 noradrenergic group in the brainstorm (39,77). Autoradiographic (79,80) and immunocytochemistry studies (10) have revealed that these brain areas contain CB1 cannabinoid receptors. These neuroanatomical...

Abrupt Cannabinoid Withdrawal

The sudden termination of chronic treatment with cannabinoids in several different laboratory animal models has not produced uniform results. Kaymakcalan treated rhesus monkeys for 36 d with THC and observed aggressiveness, hyperirritability, tremors, yawning, photophobia, hallucinatory behavior, and anorexia upon abrupt treatment termination (52). This syndrome appeared 12 h after THC was discontinued and lasted for 5 d. Another approach is to determine whether withdrawal can be measured by using a conditioned behavioral paradigm. Beardsley and co-workers were able to demonstrate marked response-time disruption of food-maintained operant behavior in rhesus monkeys. THC was given continuously for 10 d (53). Overt behavioral signs included aggressiveness, bruxism, and hyperactivity. ous withdrawal between these two drugs. Regardless of the reason for these differences, the results obtained with WIN 55,212-2 suggests that spontaneous withdrawal can occur with cannabinoids.

Neurological Disorders and Neurodegenerative Diseases

Cannabis has been historically used to relieve some of the symptoms associated with central nervous system disorders. Nowadays, there are anecdotal evidences for the use of cannabis in many patients suffering from multiple sclerosis or chronic pain. Considerable evidence indicates that the endocannabinoid system plays an essential role in pain regulation. For example, in vivo microdialysis experiments have shown that peripheral injections of the chemical irritant formalin are accompanied by increases in anandamide outflow within the periaque-ductal gray (PAG), a brain region involved in pain-processing. Since activation of CB1 receptors in the PAG causes profound analgesia, it is speculated that inhibitors of anandamide inactivation may be useful in the pharmacotherapy of pain, particularly in instances where opiates are ineffective. Recent research in animal models of multiple sclerosis has demonstrated the efficacy of cannabinoids in ameliorating symptoms such as spasticity and...

Craving and Reinforcement

Addictive potential of marijuana was long thought to be very weak or absent (72). However, although addictive behaviors such as compulsive drug seeking (due to craving) is rarely induced by marijuana use, preparations containing higher D9-THC concentrations, such as hashish, have been shown to induce addictive behaviors, especially in populations at risk (188-189). Hence one may speculate that marijuana, as obtained at the turn of the millenium, may be addictive as well, since it often contains much higher concentrations of D9-THC than in the 1960s and 1970s (185,190). From animal studies it has gradually become clear that cannabinoids interact with the same neural substrates that are thought to be responsible for the euphoriant and rewarding effects of other drugs of abuse such as cocaine, opiates, and alcohol (189,191). These neural substrates of addiction include the medial fore-brain bundle, containing the dopamine pathways, leading from the mesencepha-lic ventral tegmentum to the...

Generalized Anxiety Disorder

Pharmacologic causes of anxiety include salicylate intoxication, NSAI Ds antihistamine intoxication withdrawal, phenylpropanolamine pseudo-ephedrine, psychotropics (akathisia), stimulants, selective serotonin reuptake inhibitors. Caffeine, cocaine, amphetamines, theophylline, beta-agonists, over-the-counter decongestants, steroids, and marijuana can cause anxiety.

An amotivational syndrome

Anecdotal reports that chronic heavy cannabis use impairs motivation and social performance have been described in societies with a long history of cannabis use, such as Egypt, the Caribbean, and elsewhere.(2) Among young American adults who were heavy cannabis users in the early 1970s, there were clinical reports(2) of individuals who became apathetic, withdrawn, lethargic, and unmotivated, apparently as a result of chronic heavy cannabis use. This constellation of symptoms was described as an 'amotivational syndrome'. As these reports were uncontrolled it was not possible to disentangle the effects of chronic cannabis use from those of pre-existing personality and other psychiatric disorders.(2) Field studies of chronic heavy cannabis users in societies with a tradition of such use, for example Costa Rica and Jamaica, (2) have produced evidence that has usually been interpreted as failing to demonstrate the existence of the amotivational syndrome. Critics have argued that these...

Acquisitive offending

It is frequently suggested that users of illicit drugs are forced to commit acquisitive crime through economic necessity. In an English study of police arrestees, (8) among those who reported using drugs, 46 per cent believed that their drug use and crime were connected. The most frequent reason given was the need for money to buy drugs. On urine testing, those arrestees who were positive for opiates, methadone, or cocaine reported two to three times the illegal income of those who had not taken these drugs. The offences involved were car theft, shoplifting, burglary, robbery, fraud or deception, handling stolen goods, and drugs supply. In general, those who tested positive for cannabis, amphetamines, benzodiazepines, or alcohol, did not report increased acquisitive offending. This work does not demonstrate a causal relationship between illicit drug use and acquisitive crime. A study of 151 Scottish prisoners and non-prisoners (9> found that heavy opiate use and polydrug use, was...

Why do people take drugs

Alcoholics will point to anxiety as their reason for drinking (1) indeed, social anxiety is one of the most common causes of alcoholism in young men.(2) If this can be treated (e.g. by selective serotonin reuptake inhibitors) then they are frequently able to become abstinent or even drink normally. Social anxiety is also a common reason for the use of stimulants by the young. Another psychiatric disorder associated with drug misuse is depression, which is particularly likely to lead to excess alcohol intake. A vicious cycle then develops because both alcohol and its withdrawal are depressogenic. Alcohol is also one of the most serious risk factors for suicide. There is increasing use of stimulants and cannabis by schizophrenic patients. In part this reflects the behaviour of their peer group but the use of stimulants may be in part due to the fact that they can offset some of the more negative aspects of neuroleptic treatment, especially the loss of drive and motivation. As both types...

Legal control of recreational drugs

Maintenance prescriptions of morphine or cocaine to addicts did not constitute acceptable medical practice, and a punitive response to addiction was established which lasted until the HIV epidemic in the 1980s forced a change in philosophy. This coercive approach to recreational drugs gathered momentum. A national prohibition of alcohol was enacted in 1919 and was only repealed in 1933 because of a desperate need by the Roosevelt administration for taxation income. Many states banned cannabis, and its use was effectively outlawed nationwide by the Marijuana Tax Act 1937. By the same year, the majority of states had adopted the Uniform Drug Act to standardize their approach to recreational drugs. In a further effort to overcome what was regarded as a fragmented approach to enforcement, the Comprehensive Drug Abuse Prevention and Control Act came into force in 1970. In Britain, the Establishment was startled out of its laissez-faire position during the First World War by the discovery...

Rafael Maldonado 1 Introduction

Derivatives of Cannabis sativa, such as marijuana and hashish, are the most widely consumed illicit drugs in humans. However, the potential ability of cannabis derivatives to produce dependence in humans is still a controversial issue. Several authors have reported that cannabis derivatives do not induce physical dependence in humans, whereas others describe some symptoms of abstinence in heavy users of strong cannabis preparations (1-3). The rarity of reports of these withdrawal reactions may reflect the fact that they are mild and seldom observed in cannabis users. However, cannabis derivatives produce clear subjective motivational responses in humans, leading to drug-seeking behavior and abuse. The endogenous opioid system has been reported to be a common neurobiological substrate involved in the development of dependence to several drugs of abuse, including cannabinoids. Neurons containing endogenous opioid peptides are largely distributed within the central nervous system, and...

Historical review

The hardy annual which Linnaeus labelled Cannabis sativa in 1753 was probably the first non-food crop. A detailed account of its medicinal powers appeared in China almost 5000 years ago, and it subsequently found its way into the pharmacopoeias of each succeeding civilization, including our own. The fibrous stem of the plant was used for rope-making and weaving, and the seeds were a source of oil for food and fuel. 'Indian hemp' reached Europe about 1000 years ago in the pouches of Moorish invaders of Spain and Portugal. It gradually gained a reputation as a rival panacea to opium, but it was not until the eighteenth century that it became a mainstream medicine in Britain and the United States. Recreational use was popular among European artists and intellectuals in the mid-nineteenth century, but in the United States its association in the public mind with the poorest immigrants from Mexico and elswhere demonized its image.

Other drug use

After being stimulated with amphetamine or cocaine, many individuals will use sedative drugs such as alcohol, benzodiazepines, or cannabis to 'come down' from their drug. Increasingly heroin is being used for this purpose, sometimes to the point of becoming dependent on the opiate, and even requiring methadone treatment. The use of cocaine in particular is commonly encountered as a secondary form of drug misuse in methadone patients, ( > with some individuals appearing to switch their preferred illicit drug from heroin to cocaine when treatment is established.

Prevalence

An association between drug use and musical subcultural preference has been recognized for many years cannabis and heroin with jazz and blues, LSD with the 'hippie' movement, and amphetamine sulphate with the punk era.(17> MDMA is associated with the 'dance and club scene'. The particular association between stimulant drugs and the 'dance scene' can be partly explained by the energetic and prolonged dancing that accompanies such music. Stimulants may enhance enjoyment and ability to perform to such music.(l8)

Flashbacks

There are a small number of case reports of cannabis 'flashbacks', i.e. experiencing symptoms of cannabis intoxication days or weeks after the individual last used cannabis 21) Because of their rarity and the fact that many affected individuals have also used other drugs, it is difficult to draw any conclusions about the relationship between these symptoms and cannabis use. It is often difficult to decide whether these are rare events that are coincidental with cannabis use, the effects of other drugs that are often taken together with cannabis, rare consequences of cannabis use that only occur at much higher doses than those used recreationally or that require unusual forms of personal vulnerability, or the results of interactions between cannabis and other drugs.

Shortterm predictors

There is good agreement between different studies on the factors that help predict a relapse of psychotic symptoms after a period of stabilization or remission. Stressful life events*6.7,) and a high expressed emotion index6) have attracted considerable interest in this regard but are technically difficult to assess. In addition, the expressed emotion measure is only applicable to patients interacting on a daily basis with family members or other persons in the household. In many settings, such patients would be a minority. By and large, the best predictor of relapse in the short term remains the withdrawal of antipsychotic medication, usually due to non-compliance.(68> Cannabis use on a daily basis has been shown to be associated with an increased risk of relapse in a dose-response relationship. (69) Short-term

List of Color Plates

Camellia sinensis (see full discussion in Chapter 1). Plate 2. Cannabis sativa (see full discussion in Chapter 2). Plate 3. Cocos nucifera (see full discussion in Chapter 3). Plate 4. Coffea arabica (see full discussion in Chapter 4). Plate 5. Daucus carota (see full discussion in Chapter 5). Plate 6. Ferula assafoetida (see full discussion in Chapter 6). Plate 7. Hordeum vulgare (see full discussion in Chapter 7). Plate 8. Larrea tridentata (see full discussion in Chapter 8). Plate 9. Nicotiana tabacum (see full discussion in Chapter 9). Plate 10. Olea europaea (see full discussion in Chapter 10). Plate 11. Oryza sativa (see full discussion in Chapter 11). Plate 12. Plantago ovata (see full discussion in Chapter 12). Plate 13. Saccharum officinarum (see full discussion in Chapter 13). Plate 14. Serenoa repens (see full discussion in Chapter 14). Plate 15. Sesamum indicum (see full discussion in Chapter 15). Plate 16. Zingiber officinale (see full discussion in Chapter 16).

Miscellaneous agents

Stimulant drugs of abuse (e.g. amphetamines and cocaine) produce insomnia. Amphetamines increase wakefulness, suppress REM sleep, and delay sleep onset. Cocaine reduces REM sleep and increases sleep latency and REM latency. On cessation, this may cause REM rebound. Hallucinogens, such as lysergic acid diethylamide and mescaline, may produce a state resembling dreaming. Marijuana, through its active ingredient tetrahydrocannabinol, may cause sedation at lower doses and hallucination at higher doses. Tetrahydrocannabinol increases slow-wave sleep and reduces REM sleep. Drugs of abuse mostly alter the amount and timing of REM sleep and produce REM rebound on discontinuation.

Cognitive Functions

In vivo, anandamide impaired performance in a non-match-to-position task testing for working memory (140). This was reversed by SR141716A (75). If anandamide acts in similar ways as exocannabinoids in this mnemonic task, it would seem that the memory impairment occurs by interfering with the encoding of information that takes place in the hippocampus. As a result, short-term memory cannot be formed (141). There is also evidence, however, that anandamide impairs memory consolidation (142). Comparisons between mouse strains for an avoidance memory task indicated that dramatic strain-specific differences exist for the effects of anandamide on memory consolidation, causing inhibition or enhancement, depending on the strain (143). Recent studies may clarify this complex situation. High doses disrupt the development of LTP, as has been thought for a long time however, endocannabinoid release may enhance memory by triggering depolarization-induced depression of inhibition (DSI) (144). Thus,...

Feeding and Appetite

Cannabinoids enhance appetite (93,152). Indeed D9-THC is used clinically for this purpose, particularly in acquired immunodeficiency syndrome (AIDS) and cancer patients (93). Anandamide increased food intake in rats (77), while SR141716A has been reported to inhibit the intake of palatable food (153-155). Evidence for a function of the endogenous cannabinoid system in the feeding response has been obtained for the primitive invertebrate Hydra vulgaris (17). These data point to a very ancient history of the endocannabinoid system in the regulation of feeding.

Drug detection

NRL and US Drag Testing (now Lifepoint, Inc.), a commercial prototype was built and tested (Yu et al., 1996). From the late 1990's to the present time, the flow immunosensor developed under this program has demonstrated accurate, quantitative assays for the five National Institutes of Drug Abuse (NIDA-5) drugs cocaine, opiates (heroin morphine codeine), phencyclidine (PCP), amphetamines methamphetamines, and tetrahydro-cannabinol (THC, marijuana). In addition, the company has completed validation of their instrument and received FDA 510K approval of the NIDA assays. Commercially available disposable cassettes can accommodate a number of immunoassays and allow for the analysis of up to 10 analytes simultaneously. Potential markets and customers of this technology include on-site drug screening, law enforcement personnel, and medical testing laboratories. The company expects to market the IMPACT Test System instruments in late 2001 (Lifepoint, Inc., First Quarter Report, 2001).

Substance abuse

Substance abuse is a robust predictor of an increased probability of violence and criminality in the mentally disordered. The coexistence of substance abuse with mental disorders significantly increases the risks of violent behaviour. (.1. 75777 and 79 The association between intoxication and violent behaviour is as complex as it is clear.(80) It should also be noted that the unwanted effects of therapeutically administered agents can contribute to risk. The disinhibiting effects of benzodiazepines are well known (and possibly overemphasized) less well known is the potential for the intense restlessness and agitation of akathisia to erupt in violence. The presence of continuing substance abuse with intermittent or chronic intoxication remains one of the most potent predictors of future violence in the mentally disordered. No particular form of substance abuse has been demonstrated to be more or less predictive. Alcohol and marijuana are the most frequently abused intoxicants and will...

Violent offences

There are a number of ways in which violent offending may occur in substance misusers and in comorbid individuals. Simple intoxication on alcohol or other depressants such as benzodiazepines or barbiturates, leads initially to apparently excited behaviour. Stimulants such as cocaine or amphetamines, may produce arousal and irritability. Most forms of intoxication are also associated with impaired judgement, perception, and impulse control. Severe intoxication on alcohol, cannabis, sedatives, or stimulants can lead to a toxic psychosis and highly disturbed behaviour. Even at levels of consumption insufficient to intoxicate, disinhibition and autonomic arousal may facilitate recklessness and aggression. Pathological intoxication, in which aggression is supposed to occur within minutes of consuming moderate amounts of alcohol, is an entity of doubtful validity.(4) Most cases probably result from alcohol-induced hypoglycaemia, head injury, or other organic disorder.

Drug abuse

Whether illicit substances actually cause schizophrenia is very contentious. Perhaps the methodologically most sound investigation is the study of Andreason et al.,(56) which followed up 45 570 Swedish conscripts and found that a history of cannabis consumption, at 18 years, was positively correlated with a later admission to hospital with schizophrenia. The cohort design and a dose-response effect (heavy users had the highest risk of later schizophrenia) suggest a causal link. However, it might be that those individuals who did manifest schizophrenia in later life were destined to do so in any event, and their premorbid state made them more likely than their peers to use high doses of cannabis.

Chris Good

In the UK and many other countries, there is still no restriction on what medical practitioners may have manufactured or prescribed for a particular patient, whether the intended medicine is licensed or not, providing that it is legal and in the patient's best interests. In this context a recent case is of interest. A doctor was reported to the disciplinary body of the country's General Medical Council by the statutory health authority for prescribing single vaccine in place of the triple vaccine MMR, advocated by the health authority. This is clearly a political attempt to restrict a doctor's right to prescribe and may presage further steps in that direction. Another example is provided by the growing claims by patients that cannabis relieves their symptoms (mainly in multiple sclerosis). The possession and use of cannabis are illegal in the UK and therefore doctors are forbidden to prescribe it, despite patient claims for its benefit. The clear ethical solution is for the state to...

CB1 receptors

Gpcr Family

Fig. 4.5 Retrograde signaling by endocanna-binoids. Postsynaptic depolarization opens voltage-dependent Ca2+ channels. An increase in postsynaptic Ca2+ elicits an activation of phospholipase D, which leads to endocannabinoid synthesis from lipid precursors. Activation of postsynaptic mGluRs can also generate endo-cannabinoids. A pathway which seems to involve phospholipase C and the generation of diacylglycerol is further cleaved by Fig. 4.5 Retrograde signaling by endocanna-binoids. Postsynaptic depolarization opens voltage-dependent Ca2+ channels. An increase in postsynaptic Ca2+ elicits an activation of phospholipase D, which leads to endocannabinoid synthesis from lipid precursors. Activation of postsynaptic mGluRs can also generate endo-cannabinoids. A pathway which seems to involve phospholipase C and the generation of diacylglycerol is further cleaved by

Adverse effects

It became apparent within the first few years of experimentation with LSD that this class of drugs was capable of inducing visual disturbances days to weeks following drug exposure. Subsequent research found that these disturbances, dubbed 'flashbacks' because of their evanescent visual appearance, appeared to be an intermittent form of postdrug visual disorder that in its extreme form was experienced continually. Thus, hallucinogen persisting perception disorder patients are capable of describing a range of visual disturbances that fluctuate in intensity, but are observable from moment to moment. Such imagery includes geometric hallucinations, false perceptions of movement, usually in the peripheral visual field, afterimagery, and the perception of trails of images as an object moves across the visual field. Patients can also visualize myriad clear or coloured pinpoint dots in a bright sky, an experience that they describe as seeing the air ('aeropsia'). These visual disturbances may...

Conjugates of AA

(-)-A9-Tetrahydrocannabinol, the main psychoactive component of Cannabis sativa has long been known to exert hypothermic effects in mammals (Holtzman et al., 1969). Two types of cannabinoid receptor, CB1 (Matsuda et al., 1990) and CB2 (Munro et al., 1993), have been identified. Whereas the CB1 receptor is present in the CNS and some peripheral tissues, the CB2 receptor is mainly expressed by immune cells (Pertwee and Ross, 2002). Several AA conjugates have been shown to serve as endogenous cannabinoid receptor ligands, the best characterized being anand-amide (arachidonoylethanolamide, AEA) and A role for endocannabinoids and the CB1 receptor in normal thermoregulation is suggested by the findings that (1) AEA and 2-AG are produced in detectable quantities within the CNS (Sugiura et al., 1995) and their concentrations vary in a diurnal fashion (Valenti et al., 2004) (2) the peripheral injection of AEA provokes hypothermia in animal models (Fride and Mechoulam, 1993) and (3) highly...

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