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Quit Marijuana The Complete Guide

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Assessing Cannabis Craving in a Research Setting

The measurement of cue-elicited cannabis craving in studies testing human research volunteers is described in Subheadings 3.1.1.-3.1.7. This includes (1) recruiting cannabis users who are not seeking treatment for their cannabis use, (2) obtaining written informed consent from research participants, (3) training participants in completion of the MCQ, (4) cue presentation to elicit a craving response, (5) measuring the craving response with the MCQ and physiological The use of cannabis-experienced participants who are not seeking treatment for their cannabis use is critical. There are no proven methods for long-lasting craving reduction thus, it would be unethical to elicit craving in individuals who were trying to reduce or quit using cannabis. A thorough screening procedure, including a history of cannabis use (see Note 1), will generally ensure that appropriate participants are enrolled in the study. Various types of cues have been used to elicit craving in drug users (7). We have...

Measurement of Cannabis Effects

Periodic monitoring of heart rate and blood pressure during cannabis administration is recommended because of the expected effects of tachycardia and orthostatic hypotension. Monitoring should begin before cannabis administration, to provide a baseline, and continue until values have returned to baseline levels. Measurements should be obtained more frequently during periods of expected maximum cannabis effect (which will vary by route of administration), then less frequently as the cannabis effect subsides. Heart rate can be efficiently monitored using an electrocardographic (ECG) chest lead. This also provides information about heart rhythm (although cannabis administration is not commonly associated with cardiac arrhythmia). Blood pressure can be measured with a standard clinical sphygmomanometer. Cannabis and other drugs of abuse produce psychoactive effects, i.e., drug-induced changes in mood and feelings mediated by the central nervous system. Such changes in mood and feelings...

Adverse Events From Cannabis Administration

Acute cardiovascular effects of cannabis administration include tachycardia, slightly increased blood pressure when supine, orthostatic hypotension, increased cardiac output, and decreased left ventricular ejection fraction (32,33). These effects increase myocardial oxygen demand at the same time that oxygen delivery to tissues may be decreased because of the increased car-boxyhemoglobin from smoking. As a result, smoking one marijuana cigarette significantly reduces maximal exercise performance and exercise tolerance of physically healthy subjects (34) and patients with angina (35). However, in healthy subjects the acute cardiovascular effects of cannabis are mild, self-limiting, and rarely cause clinically significant adverse events (32,36-38). Orthostatic hypotension may be associated with light-headedness and syncope (39). This may be minimized by ensuring that subjects are well hydrated (including encouraging fluid intake during cannabis administration), avoiding sudden changes...

Antiinflammatory Effects of Cannabinoids

The early experimental data involving marijuana cannabinoids and immunity suggested the drugs were immunosuppressive. For example, in 1974 it was reported that T cell responses to mitogens were suppressed in cultured peripheral blood mononu Marijuana clear cells (PBMCs) taken from chronic marijuana smokers (Nahas et al. 1974). Since then, cannabinoid-based drugs have been shown to suppress the function of T cells, B cells, macrophages, NK cells, and dendritic cells. The studies in this area have been numerous and in vivo and in vitro animal systems from humans to mice have been explored and extensively reviewed over the years (Cabral and Dove Pettit 1998 Klein et al. 1998, 2000a, 2003 Klein 2005 Klein and Cabral 2006). However, more recently, drug effects on the cytokine network have been focused on and in these reports the drugs have been shown to modulate cytokine production, suggesting their therapeutic potential for the management of chronic inflammatory diseases that are often...

Endocannabinoids as Neurotransmitters

In addition to producing endogenous opioids, the brain also produces compounds with effects similar to the active ingredient in marijuana A9-tetrahydrocannabinol (THC). These endogenous cannabinoids, or endocannabinoids, are neurotransmitters that bind to the same receptor proteins in the brain as does THC from marijuana. The endocannabinoids, like the endogenous opioids, are believed to act as analgesics. Unlike the polypeptide opioids, however, the endocannabinoids are lipids. As such, they are the only lipid neurotransmitters currently identified. The endo-cannabinoids are also distinguished by evidence that they may function as backward, or retrograde, neurotransmitters. That is, they are produced in the postsynaptic neuron when it is depolarized, and then they diffuse backward to the presynaptic neuron to inhibit the release of the neurotransmitter (for example, GABA) from the presynaptic axon terminal. The physiological significance of these actions is presently unclear.

Assessing Cannabis Craving in a Treatment Setting

The use of the MCQ in a treatment setting may be more flexible than in a research setting. A patient's level of craving may be assessed at initial intake or at baseline before entering treatment. Craving can then be measured periodically during and at the end of treatment to determine treatment outcome. Presumably, craving levels will decrease as a person reduces cannabis use or achieves abstinence. 1. At a minimum, a history of cannabis use should include the following age of first use, age when use became regular (e.g., weekly, monthly), lifetime estimate of number of times using cannabis, frequency of use in past 6 mo, frequency of use in past 30 d, amount (e.g., number of joints) typically used at one time, and type of cannabis preparation typically used. a lot of static on the line and you can hear other voices faintly in the background. Your friend just told you that he's making plans to visit you in a couple of weeks. You're happy and excited. The two of you always had great...

Nonclassical Cannabinoids

A second class of cannabinergic ligands possessing close similarity with CCs was developed at Pfizer in an effort to simplify the CC structure, while maintaining or improving biological activity (52-56). This group of compounds is generally designated as nonclassical cannabinoids and includes AC-bicyclic (e.g., 26 and 27, Fig. 2) and ACD-tricyclic (e.g., 28, Fig. 2) ligands lacking the pyran Bring of CCs. NCCs share some of the key pharmacophores of the CCs, namely, the phenolic hydroxyl, the side chain, and the northern aliphatic hydroxyl groups. Additionally, this class of cannabinergics has a hydroxypropyl chain on the cyclohexyl ring contiguous and trans to the aromatic phenolic group (e.g., (-)-CP-55,940, 27, Fig. 2). This important new pharmacophore was designated as the southern aliphatic hydroxyl group (3) and has been subjected to extensive investigation by the Makriyannis and Tius groups (46,47,57-60). Synthetic approaches for the SAH group are given in hybrid cannabinoids...

Neuropsychological Assessment of Marijuana Users

Neuropsychological procedures are used in an effort to provide an unbiased estimate of the individual's cognitive capacity. In neurology and psychiatry, these tests have been used to help clinicians to better diagnose patients and to provide them with better treatments. We chose to use a fixed battery in our effort to assess neurobehavioral changes that might be associated with the chronic use of marijuana. That battery included tests of language skills, visual and spatial memory, attention, concentration, executive function, visuo-constructive skills, manual dexterity, simple reaction time, and complex reaction time in subjects in our studies. The various tests used are listed below.

Cannabis

Indian hemp, Cannabis sativa (Cannabaceae) is an annual herb indigenous to Central and Western Asia, cultivated widely in India and many tropical and temperate regions for its fibre (hemp) and seed (for seed oil). The plant is also grown for its narcotic and mild intoxicant properties, and in most countries of the world its possession and consumption is illegal. Over many years, cannabis plants have been selected for either fibre production or drug use, the former resulting in tall plants with little pharmacological activity, whilst the latter tend to be short, bushy plants. Individual plants are almost always male or female, though the sex is not distinguishable until maturity and flowering. Seeds will produce plants of both sexes in roughly equal proportions. The active principles are secreted as a resin by glandular hairs, which are more numerous in the upper parts of female plants, and resin is produced from the time flowers first appear until the seeds reach maturity. However,...

Hybrid Cannabinoids

Hybrid cannabinoids, as the name indicates, were generated by combining the pharmacophoric features of classical and nonclassical cannabinoids (Fig. 3). The Fig. 3. Evolution of hybrid cannabinoids. Fig. 3. Evolution of hybrid cannabinoids. objective behind their design was to study more precisely the stereochemical requirements of the SAH pharmacophore, which was discovered during the development of NCCs. These hybrid cannabinoids had the added advantage of serving as conformationally more defined three-dimensional probes for the CB 1 and CB2 active sites than their nonclassical counterparts. First-generation hybrid cannabinoids (34, Fig. 4) were designed to find a correlation between the stereochemistry of the SAH group (6a or 60), the chain length, and the affinity of the compounds for CBi and CB2 receptors (46,58), whereas the second-generation hybrid cannabinoids (35-37, Fig. 4) were designed to obtain additional information on the stereochemical preferences of the SAH group with...

Cannabinoids

Mechoulam R and Ben-Shabat S (1999) From gan-zi-gun-nu to anandamide and 2-arachidonoylglycerol the ongoing story of cannabis. Nat Prod Rep 16, 131 -143. O'Driscoll C (2000) High hopes for cannabis. Chem Brit 36 (5), 27. Seth R and Sinha S (1991) Chemistry and pharmacology of cannabis. Prog Drug Res 36, 71-115. Stevenson R (1998) Cannabis proscribed or prescribed Chem Brit 34 (7), 34-36. Straus SE (2000) Immunoactive cannabinoids therapeutic prospects for marijuana constituents. Proc Natl Acad Sci USA 97, 9363-9364. Williamson EM and Evans FJ (2000) Cannabinoids in clinical practice. Drugs 60, 1303-1314.

History of Interventions in the Brain Using Psychotropic Substances

Fantasies of intervening in the psyche and the use of psychotropic agents have a venerable history in mankind. Even in prehistoric times, substances like opium, cannabis, coca, peyote and alcohol were used, especially in the context of religious and magic rituals and other cultural practices. In ancient Greece, for example in the Hippocratic writings and the writings of Dioscourides and Galen, the use of opium was recommended for the treatment of pain and sleep disorders, particularly in women. Helleborus was the treatment of choice in psychiatric diseases. The Greek authors distinguished the black helleborus, a purgative, from the white helleborus, a substance which induced vomiting. Ancient Greek medical writings show that doctors believed psychiatric illnesses to have somatic foundations. They therefore tried to heal through the extraction of illness-inducing substances using emetics or purgatives. As can be seen, the concept of the so-called biological psychiatry, meaning physical...

Modification of Gene Expression in Xenopus laeves Oocytes

Cannabinoids, endocannabinoids, alcohol, and other abused substances of interest are either co-applied or preapplied for a measured period of time such as 30-60 s with a period of about 5 min between applications to allow for drug washout and receptor recovery from desensitization. A schematic illustration of the expression system and electrophysiological recording is presented in Fig. 6. Fig. 6. Schematic illustration of receptors and ion channels in expressed Xenopus laeves oocytes for the study of the modification of receptors or ion channels by application of cannabinoids, endocannabinoids, or alcohol following current activation by 200 M kainic acid in the two-microelectrode voltage-clamp setup. Fig. 6. Schematic illustration of receptors and ion channels in expressed Xenopus laeves oocytes for the study of the modification of receptors or ion channels by application of cannabinoids, endocannabinoids, or alcohol following current activation by 200 M kainic acid in the...

Nancy E Buckley Diep Burbridge Manop Buranapramest Tanya Ferguson and Renee Y Paau

Marijuana components, such as A-9-tetrahydrocannabinol, and endogenous cannabinoids, such as anandamide and 2-arachydonoylglycerol, alter diverse immune functions. Two cannabinoid receptors have been discovered to date, the central cannabinoid receptor (CB1R) and the peripheral cannabinoid receptor (CB2R). The CB1R is expressed predominantly in the central nervous system. The CB2R is expressed mainly in cells of the immune system, suggesting that the CB2R is involved in immunoregulatory events. Cannabinoids have been shown to modulate diverse immune functions including cytokine production, lymphocyte proliferation, and humoral and cell-mediated immune responses. In addition, cannabinoids have been shown to induce different signal transduction pathways. However, the role of cannabi-noids and their receptors in the immune system remains unclear. The objective of the experimental methods described herein is to investigate the role of CB2R activation in specific splenocyte and macrophage...

Cannabinoid Receptors

Although the observations described here have suggested a role for cannabi-noids in immunomodulation, the mechanisms by which cannabinoids induce these immunomodulatory effects remain elusive. To date, two receptors with high affinity for cannabinoid ligands are known (14-16).The central cannabinoid receptor (CB1R) was first cloned in 1990 by Matsuda et al. (14). This receptor is predominantly found in the central nervous system (CNS) (17-19) and to a much lesser degree in cells of the immune system (20-23). Because of its high expression in the CNS, the CB1R is thought to mediate most, if not all,of the effects of the cannabinoids in the CNS. The peripheral cannabinoid receptor (CB2R), cloned by Munro et al. in 1993 (15), is predominantly expressed in cells of the immune system (15,22,23). Therefore, the immunomodulatory effects of cannabinoids are thought to be mediated by the CB2R. Human blood cell subpopulations have different degrees of CB2R expression with the following rank...

Orexigenic and Anorexigenic Studies

The stimulatory effects of cannabis extracts on human appetite have been anecdotally known for over hundreds of years. A9-THC and other exogenous 1. A9-THC and other synthetic cannabinoids reliably induce hyperphagia and increase food intake in laboratory animals (61-64). These hyperphagic actions are mediated via cannabinoid CB1 receptors since they are selectively blocked by the cannabi-noid CB1 receptor antagonist SR141716A but not with the CB2 antagonist SR 144258 (71).

Adle Thomas and Roger G Pertwee

The mouse isolated vas deferens is a nerve-smooth muscle preparation that serves as a highly sensitive and quantitative functional in vitro bioassay for cannabinoid CB1 receptor agonists. Additionally, it is commonly used as a bioassay for competitive surmountable CB1 receptor antagonists, and also provides a means for distinguishing neutral CB1 antagonists from CB1 inverse agonists. The bioassay of CB1 receptor agonists relies on the ability of these ligands to produce concentration-related decreases in the amplitude of electrically evoked contractions of the vas deferens. This they do by acting on naturally expressed prejunctional neuronal CB1 receptors to inhibit release of the contractile neurotransmitters, noradrenaline and ATP, that is provoked by the electrical stimulation. The bioassay of competitive surmountable CB1 receptor antagonists involves determining the ability of these compounds to produce parallel dextral shifts in CB1 receptor agonist log concentration-response...

Alcohol and Other Substance Abuse Disorders

Alcohol accounted for 34 of this estimated rate, a figure substantially higher than that for the general population (14 ). Another recent investigation concluded that individuals with schizophrenia report rates of 16 for lifetime nonalcohol substance abuse (Duke et al. 2001). The most commonly abused substances include marijuana, stimulants, hallucinogens, opiates, and anticholinergics, and abuse was concentrated in males younger than 36 years. The suggested source of this increased vulnerability to addictive behaviors among schizophrenic patients is disturbance in the neural circuitry mediating drug desire and reinforcement. Chambers et al. (2001) argued that abnormalities in the hippocampal formation and frontal cortex (leading to disturbed dopamine and glutamate signaling in the nucleus accumbens) facilitate the positive reinforcing effects of drug reward and reduce inhibitory controls over drug-seeking behavior. See Chapter 9, Substance Use Disorders in...

David A Gorelick and Stephen J Heishman

Better scientific understanding of cannabis effects and the development of treatments for cannabis dependence require clinical studies involving cannabis administration. Cannabis can be administered by smoking a plant-derived cigarette or by oral or intravenous administration of A9-tetrahydrocannabinol (THC), the primary psychoactive chemical in cannabis. The smoked route is most commonly used outside the laboratory, but is subject to wide variation in absorbed dose. Oral synthetic THC is a legally marketed medication (dronabinol), also subject to wide pharmacokinetic variation, but offering a greater safety margin because of slower onset of action and lower potency. Intravenous THC offers precise investigator control of dose and timing. Acute adverse effects of cannabis administration include tachycardia, orthostatic hypotension, pulmonary irritation (if smoked), motor incoordination, cognitive impairment, anxiety, paranoia, and psychosis. Screening of research subjects should...

Ester Fride Alex Perchuk F Scott Hall George R Uhl and Emmanuel S Onaivi

In the absence of any specific behavioral assay for cannabinoids or endocannabinoids, a cannabinoid-induced profile in a series of four in vivo assays in mice is most commonly used to assess a specific cannabinoid activity at the behavioral level. Thus, when a given compound produces motor depression in an open field, catalepsy on an elevated ring, analgesia on a hot plate, as well as hypothermia, cannabinoid CB1 receptor activation is assumed, although exceptions are possible. The full cannabinoid profile, however, includes for example ataxia in dogs and discrimination learning in rats. In view of (1) the addictive reward potential of cannabis and the cannabinoids and (2) the multiple roles of the endocannabinoid physiological control system (EPCS) in behavioral functions, including memory, emotionality, and feeding, a number of behavioral techniques have been used to assess the effects of cannabinoids in these functions. In this chapter we will describe the tetrad of...

Endocannabinoid System 21 Cannabinoid Based Drugs

The main psychoactive substance in Cannabis extracts was isolated and synthesized in 1964 and shown to be A9-tetrahydrocannabinol (THC) (Gaoni and Mechoulam 1964). THC and cannabinoids are tricyclic ring structures containing a phenol ring with attached 5-carbon alkyl chain, a central pyran ring, and a monounsaturated cyclohexyl ring the structure and the function of THC and related compounds have been recently and extensively reviewed (Pertwee 2005 Pacher et al. 2006). Besides THC, other natural Cannabis products have been extracted and characterized such as A8-THC (also psychoactive), cannabinol, and cannabidiol (both nonpsychoactive) in addition, synthetic cannabinoid derivatives have been produced and studied such as CP55,940, HU-210, HU-211, ajulemic acid, and abnormal cannabidiol (Figure 1). The defined physiological and pharmacological effects of marijuana cannabinoids Cannabis sativa Cannabinoids

Completed Clinical Trials 41 Multiple Sclerosis MS

Marijuana Marijuana features of MS, and in these models, cannabinoid-based drugs were shown to attenuate the disease. For example, natural cannabinoids were shown to suppress disease progression in rat models of EAE possibly by suppressing the HPA axis (Lyman et al. 1989 Wirguin et al. 1994) furthermore, in Theiler murine encephalomyelitis virus models of demyelinating disease, synthetic cannabinoids attenuated disease as well as suppressed infiltrating T cells and the brain production of proinflammatory cytokines (Arevalo-Martin et al. 2003 Croxford and Miller 2003). Besides the attenuation of neurodegeneration (Pryce et al. 2003) and immune reactivity, cannabinoid treatment has also been shown to suppress encephalitis-associated spasticity (Baker et al. 2000). This effect appears to involve CB1 receptors more than CB2 (Pryce and Baker 2007). reported in 2003 from a UK study with 630 stable MS patients with spasticity (Zajicek et al. 2003). The patients received either A9-THC...

Altered States Of Consciousness External Influences

Many psychologists classify marijuana as a hallucinogenic drug. Smoking marijuana or eating it after it has been cooked may produce a psychoactive drug effect. Often the marijuana high is a state of elation in which the user claims an enrichment of sensory experiences. Research into the effects of marijuana has shown that the effects produced may be a function not only of the amount and characteristics of the marijuana used but also of the expectations of the user. Motivation, past experience, and many other variables may create potential effects greater or lesser than those expected from the properties of the marijuana itself. Some studies have suggested a reverse tolerance effect in which less drug is needed to produce the same high. This seems attributable to expectations and familiarity with the techniques for using the drug.

The Acetate Pathway Fatty Acids And Polyketides

Polyketides, metabolites built primarily from combinations of acetate units, are described. The biosynthesis of saturated and unsaturated fatty acids is covered, together with prostaglandins, thromboxanes, and leukotrienes. Cyclization of polyketides to give aromatic structures is then rationalized in terms of aldol and Claisen reactions. More complex structures formed via pathways involving alkylation reactions, phenolic oxidative coupling, oxidative cleavage of aromatic rings, and employing starter groups other than acetate are developed. The use of extender groups other than malonate gives rise to macrolides and polyethers, whilst further cyclization of polyketide structures may be achieved through Diels-Alder reactions. The application of genetic engineering to modify products from the acetate pathway is discussed. Monograph topics giving more detailed information on medicinal agents include fixed oils and fats, evening primrose oil, echinacea, prostaglandins and isoprostanes,...

The Mouse Tetrad Test

Analgesic (pain-reducing) effects of cannabinoids are measured by the tailflick (e.g., ref. 12) or hot plate method (e.g., refs. 11 and 15 see also ref. 16). In the tailflick test, radiant heat is focused on the tail, and the latency is measured until the animal flicks its tail away, which is taken as a measure of nociceptive sensitivity (17). In the hot plate test, the mouse is placed on a hot plate with temperature usually fixed at 54-55 C. The latency to responses such as jumping or licking a hindpaw is taken as the nociceptive response (18). The tailflick test is considered a reflex response at the spinal level, while the hot plate tests pain perception at higher (supraspinal) levels (17). In general, both tests are sensitive to cannabinoids (see Note 1, Fig. 1). 3.1.1. Biphasic Effects of Cannabinoids in Tetrad Tests

Agonist Stimulated [35SGTPyS Binding to Cell Membrane Homogenates

Cannabinoid Receptor Ec50

When performing these assays in a new tissue for the first time, it is helpful to first perform an assay to optimize assay conditions by determining nonspecific, basal, and agonist-stimulated (using a maximally effective concentration of agonist) with different amounts of membrane protein (see Fig. 2). Typically, using brain homogenates, 3-20 g of membrane protein per test tube yields good results. With cultured cells, the amount of protein required depends on the receptor expression level and, perhaps more importantly, the G protein expression level, which is often not as high as in brain, where the amount of Go-type G protein is estimated to make up nearly 1 of total brain protein. Experience has shown that even in a cell line in which cannabinoid inhibition of adenylyl cyclase has been observed, there may be no significant activity of cannabinoids for 35S GTPyS binding. In tissues in which cannabinoid-stimu-lated 35S GTPyS is observed (including brain tissue), the percent...

Patterns of Substance Abuse Among Persons With Schizophrenia

Phrenia, and then prospectively interviewed and followed another sample of 115 first-episode patients representing 86 of consecutive admissions for admissions in the local area (Buhler et al. 2002). The investigators found that 62 of those with drug abuse and 51 with alcohol abuse began their habit before any signs of the illness were manifest, including prodromal nonpsychotic symptoms. Significantly, there was no correlation found between onset of abuse and onset of psychotic symptoms, although it was noted that the onset of abuse and the psychotic disorder occurred in the same month in 18.2 who abused alcohol and 34.6 who used drugs, implying that there may be a subset of schizophrenia patients whose development of psychotic symptoms were speeded or precipitated by substance use, particularly cannabis use. These data from the combined pools of first-episode patients are similar to those reported for the original group of 232 first-episode patients analyzed separately (Hambrecht and...

Assays Using Electrically Unstimulated Tissue

Adrenoceptor

As stated in Subheading 3.2., even when bioassays are to be performed without electrical stimulation, all tissues are first subjected to an equilibration procedure that involves electrical stimulation (Subheading 3.2.3.). Bioassays without electrical stimulation are used, for example, to measure the ability of cannabinoids to modulate responses to ai-adrenoceptor and P2X receptor agonists that act directly on the smooth muscle to induce contractions. Care must be taken in such experiments to avoid the tissues becoming desensitized to these agents, particularly when high concentrations are used. Two protocols have been used in this laboratory to investigate interactions between cannabi-noids and an a1-adrenoceptor agonist (phenylephrine, methoxamine or noradrenaline) or a P2X receptor agonist (P, y-methyleneadenosine 5'-triphosphate) as described in Subheadings 3.4.1. and 3.4.2. Both protocols initially involve the addition of a submaximal dose, A, of the selected agonist to the organ...

Environmental Factors

Fetal Alcohol Syndrome Vulva

One of the increasing problems in today's society is the effect of social drugs, such as LSD (lysergic acid diethylamide), PCP (phencyclidine, or angel dust), marijuana, alcohol, and cocaine. In the case of LSD, limb abnormalities and malformations of the central nervous system have been reported. A comprehensive review of more than 100 publications, however, led to the conclusion that pure LSD used in moderate doses is not teratogenic and does not cause genetic damage. A similar lack of conclusive evidence for teratogenicity has been described for marijuana and PCP Cocaine has been reported to cause a number of birth defects, possibly due to its action as a vasoconstrictor that causes hypoxia.

Methods for the Synthesis of Cannabinergic Ligands

Cannabinoids Biosynthesis

During the last decade, numerous cannabinergic ligands with high affinity and selectivity profiles for cannabinoid receptors (CB1 and CB2) emerged from rigorously pursued structure-activity relationship studies. This chapter focuses on the synthetic aspects of key cannabi-noid receptor probes representing the different classes of cannabinergic ligands that encompasses classical cannabinoids (CCs) including some covalent binding derivatives, nonclassical cannabinoids (NCCs), hybrid cannabinoids, aminoalkylindoles (AAIs), diarylpyrazoles, and the endocannabinoids. The long history of worldwide self-medication by a mixture of cannabinoids present in Cannabis sativa generated the first wave of interest among synthetic and medicinal chemists in conjunction with the co-developments of modern separation, spectroscopic, and synthetic methods during the last half century. The identification of the family of C21 tricyclic cannabinoids led to the chi-rospecific partial syntheses of these...

Stephen J Heishman and Edward G Singleton

Cannabis is the most widely used illicit drug in the United States, with 14.6 million current users. Cannabis-dependent individuals presenting for treatment typically report cannabis craving however, the phenomenon has received little research attention. In the absence of a valid, multidimensional questionnaire to assess cannabis craving, we developed the Marijuana Craving Questionnaire (MCQ). The MCQ consists of four constructs or factors that characterize cannabis craving compulsivity, emotionality, expectancy, and purposefulness. A separate score is calculated for each factor. The MCQ can be used to measure cue-elicited craving in a research setting or natural craving in cannabis-dependent individuals presenting for treatment. Either the 47-item or 12-item version can be used, and standardized instructions for completion of the MCQ should be given. The MCQ can be administered using a paper and pencil form or a computerized version. In a research setting, the MCQ should be...

In Vitro Peristalsis Studies in Isolated Intestine

The experimenter's laboratory equipment, a number of peristaltic parameters are recorded. For example, (1) the intraluminal pressure at the aboral end of the segments as well as peristaltic pressure threshold, the residual baseline pressure, the amplitude of peristaltic waves, and the maximal acceleration of peristaltic waves can be measured with a pressure transducer whose signal is fed via an analog digital converter into a computer and is then analyzed by appropriate software (42), (2) the volume expelled at the end of each contraction can be measured with a use of a cylinder (41), and (3) mechanical events during peristalsis and changes in intestinal wall morphology can be recorded by a camera synchronized with polygraphic traces, which can be analyzed by specialized software (43). Several recent reviews (2-4) have summarized the effects of cannabinoids on peristalsis 1. Structurally diverse cannabinoid CB1 CB2 agonists inhibit peristalsis induced in segments of isolated intestine...

In Vitro Studies on Isolated Gastrointestinal Muscle Preparations

Contractions of the intestine are affected by the activities of two layers of smooth muscle cells an outer layer with the long axis of the cells arranged longitudinally and an inner layer with the long axis of the cells arranged circularly. The study of inhibitory effects of cannabinoids on the contraction of isolated gastrointestinal tissue began over three decades ago in the laboratory of Paton (31). These experiments involved the utilization of guinea pig ileum in which contractions were produced indirectly via electrical stimulation of prejunctional neurons rather than by direct stimulation of intestinal smooth muscle. This preparation is generally referred to as the myenteric plexus-longitudinal muscle preparation (MPLM), which has been mainly utilized in the laboratories of Pertwee for more than 35 yr for the in vitro study of cannabinoids on intestinal contractility (3). This muscle preparation is obtained by stretching a 7- to 10- cm length of guinea pig ileum on a 6- to 8-...

Jean Lud Cadet Karen Bolla and Ronald I Herning

This chapter summarizes the neurological approaches used to assess the potential long-term effects of drugs on the nervous system of drug abusers. These include the use of neuropsycho-logical assessments, transcranial Doppler (TCD) sonography, and electroencephalographic (EEG) recordings. Neuropsychological procedures are used in an effort to provide an unbiased estimate of the individual's cognitive capacity, and included tests of language skills, attention, memory, and motor skills. TCD allows for the measurements of blood flow in the anterior cerebral and middle cerebral arteries, which supply blood to the cortex. An EEG recording was included in our assessment on marijuana abusers using a sound-attenuated, electronically shielded chamber. These neurological approaches have allowed the detection of various neurological and neurovascular deficits that are associated with the abuse of marijuana.

Specific Activities as Potential Triggers of Acute Myocardial Infarction

Trigger Worksheets For Mental Health

Marijuana use (106) report from the same group found a 4.8-fold increase in risk of infarction in the 60 min after smoking marijuana (95 confidence interval 2.4-9.5) (106). The Myocardial Infarction Onset Study, which was conducted in the Boston area, also identified small but statistically significant risk increases (1.48-1.69) for myocardial infarction on days of higher concentrations of particulate airborne pollutants in that city (107).

Some Interpretational Difficulties

Although there is good evidence that cannabinoids can act via neuronal cannabinoid CB1 receptors to inhibit electrically evoked contractions of the mouse isolated vas deferens (Subheading 1.), there is also evidence that this tissue contains additional pharmacological targets with which some cannabinoids can interact to produce this inhibitory response. Thus, the endocannabi-noid anandamide appears to inhibit electrically evoked contractions of the vas deferens by acting not only on CBi receptors but also on neuronal vanilloid (TRPV1) receptors (Subheading 1.). There is also evidence that anandamide and several other established CB1 CB2 receptor agonists can act though a CB2-like cannabinoid receptor to inhibit electrically evoked contractions of this tissue preparation (17). In addition, other as yet uncharacterized neuronal and non neuronal targets for cannabinoids may be present in the mouse vas deferens (11,12). A further complication is that some cannabinoids, including the...

Impact of Substance Use Disorders on Course of Illness and Outcomes

The second issue discussed by Cantor-Graae and colleagues is the degree to which history of substance abuse is associated with a more chronic clinical course of schizophrenia (p. 72). Although research on the impact of drug and alcohol use on course of illness has produced variable results, the overwhelming weight of evidence points toward substance abuse and dependence having adverse short-term and long-term affects. Overall, persons with schizophrenia who abuse drugs and or alcohol have more psychotic symptoms and psychotic relapses compared with persons with schizophrenia without substance use disorders (Negrete et al. 1986). One of the first short-term prospective studies in recent-onset schizophrenia patients (Linszen et al. 1994) found that significantly more and earlier psychotic relapses occurred in cannabis abusers. This finding was replicated in a long-term follow-up case-control study of 39 cannabis-abusing schizophrenia patients without other major drug use matched for...

Demographics of Substance Use in Patients With Schizophrenia

In addition to the lifetime prevalence data, the ECA study found that the odds of having a substance abuse diagnosis were 4.6 times greater for persons with schizophrenia compared with the rest of the population, with the odds of alcohol disorders more than 3 times greater and those of other drug disorders 6 times greater (Regier et al. 1990). Among all substances, nicotine is clearly the most frequently abused agent, with prevalence estimates ranging from 70 to 90 , over 3 times greater than the general population estimate of approximately 25 (Davidson et al. 2001). (See more extensive discussion in Chapter 5, Nicotine and Tobacco Use in Schizophrenia.) Excluding nicotine use, the ECA study results are consistent with other prevalence studies of schizophrenia demonstrating that alcohol tends to be the most frequently abused agent (20 -60 ), followed by cannabis (12 -42 ) and cocaine (15 -50 ) (Chambers et al. 2001). Use of amphetamines (2 -25 ), hallucinogens, opiates, and sedative...

Conclusions

It is now known that the cannabinoid system includes at least two receptors and several endogenous ligands widely distributed throughout the body (16). Despite these findings, the role of the cannabinoid system in immune function remains unclear. It is very tempting to speculate that the cannabinoid system has a role in immunity due to the diverse effects of cannabinoids on immune functions and the reversion of some of these effects using cannabinoid receptor antagonists. However, we have yet to show direct evidence implicating cannabinoid receptor activation in immune events and specifically on immune cells. The primary objective of the experimental methods described herein is to help us determine the role of CB2R activation in cannabinoid-induced immune responses specifically, the role of CB2R activation on cell proliferation and cytokine production from lymphocytes, macrophage phagocytic activity, and putative signal transduction pathways mediating the immune responses to...

General Aspects

From Methods in Molecular Medicine Marijuana and Cannabinoid Research Methods and Protocols Edited by E. S. Onaivi Humana Press Inc., Totowa, NJ Endocannabinoids are present in the peripheral and CNS (7). In the CNS, endocannabinoids exert most of their pharmacological actions by activating the CB1 receptor, which is expressed in neurons of specific brain regions (8,9). The CB1 cannabinoid receptor is also expressed in astroglial cells (10,11), strengthening the importance of the neuron-astroglial relationship. The administration of endocannabinoids to experimental animals produces several of the pharmacological and behavioral actions associated with cannabinoids (12-15). Endocannabinoids may play a role as modulators of neurotransmitters release and action (10). On the other hand, the CB1 receptor may be involved in synap- In the present work, morphological changes were analyzed in the neuronal and astroglial cytoskeleton as well as the alterations in the area covered by neuronal...

Pip3

THC activates the CBi receptor in the plasma membrane of neurons in the brain, triggering a signaling cascade that involves MAPKs. One consequence of CB1 activation is the stimulation of appetite, one of the well-established effects of marijuana use. The normal ligands for the CB1 receptor are endocannabi-noids such as anandamide, which serve to protect the brain from the toxicity of excessive neuronal activity as in an epileptic seizure, for example. Hashish has for centuries been used in the treatment of epilepsy.

Acute Effects

As indicated in Table 1, smoking a marijuana cigarette containing 10 mg of THC produced changes in subjects' responses in constrained association tests in which they were presented with a category name (e.g., CLOTHING) and provided examples of that category for 2 min or were presented with a category name followed by a letter (e.g., WEAPON G) and provided an instance of that category beginning with that letter (e.g., GUN) (3). In both tests marijuana produced changes in the direction of giving more uncommon associations. Changes in the direction of giving more uncommon associations were likewise produced by smoking a marijuana cigarette containing a higher dose of THC (19 mg) in a test in which subjects were presented with a word and cued to give either a free association or one of five types of constrained associations (5).

Chronic Effects

As indicated in Table 3, effects of chronic marijuana use were examined with the three tests of episodic memory used to examine effects of smoking a marijuana cigarette containing 19 mg of THC. In Buschke's Test, chronic marijuana users who used seven or more times weekly on average for the previous 2 yr or more (the heaviest usage group) showed deficits, in comparison to nonusers, for long-term retrieval and consistent long-term retrieval of high-imagery (but not low imagery) words (see Note 10) (6). These effects are illustrated in Fig. 2, as is a more equivocal difference among the user groups in effects of imagery on short-term retrieval. No effects of chronic marijuana use were observed in the paired-associate learning test or the text learning test. In a later study that also used Buschke's Test (7), subjects learned a list of words to a criterion of two consecutive perfect recalls during an initial session, followed by relearning of the same list, again to a criterion of two...

Intestinal Disorders

Anecdotal reports on the use of marijuana suggest usefulness in the treatment of intestinal disorders. This is in agreement with recent animal studies showing that CB1 receptors are present on neurons of the enteric nervous system as well as on sensory nerves and that CB2 receptors are located on immune cells. Furthermore, activation of CB1 receptors has been reported to modulate intestinal functions such as reducing emesis, gastric secretion, and intestinal motility (Massa et al. 2005 Di Marzo and Izzo 2006). Endocannabinoids are detected in the digestive tract and experimentally they have been shown to inhibit colonic propulsion in an animal model (Pinto et al. 2002). Activation of CB2 receptors have also been shown to regulate intestinal responses. For example, increased GI transit in rats due to the inflammatory action of LPS was attenuated by CB2 activation rather than CB1 (Mathison et al. 2004), and these receptors were significantly increased in colon biopsies from patients...

Atherosclerosis

Atherosclerosis is a chronic inflammatory disease that involves disturbances in the biology of the cells lining the vessels as well as homing to and activation of the inflammatory cells that reside in the vascular plaque. The putative role of endocan-nabinoid system in vascular biology and disease stems from findings that endocan-nabinoids are produced by vascular endothelial cells and these and the natural cannabinoids have been shown to cause vasodilation, hypotension, and bradycardia (Wagner et al. 1998). This could be due to stimulation of presynaptic CB1 receptors on peripheral sympathetic nerve terminals or as mentioned above to stimulation of TRPV1 on endothelium and nerves. Many of the elements of the endocannabinoid system are upregulated during systemic vascular inflammatory disease such as en-dotoxic shock (Wang et al. 2001) and experimentally induced endotoxin induced hypotension (Varga et al. 1998), suggesting that vascular inflammatory tone might be partly regulated by...

Robert I Block

This chapter summarizes the methods and results of studies in which the author examined the acute or chronic effects of marijuana on human associative processes and memory. Eleven tests used to assess marijuana's effects on associative processes, semantic memory, and episodic memory are described. Key Words A9-tetrahydrocannabinol acute effects associative processes chronic effects constrained associations episodic memory free associations free recall human learning marijuana memory paired-associate learning reaction time recall retrieval semantic memory THC.

Termites Isoptera

Insect Being Step

Of the framework is completely covered with either more grass or leaves. Other people are said to use chamba (Cannabis sativa), another aromatic herb, as medicine. The smoke of the herb is gently blown (-fukiza) into the galleries (mcholo) of the termite mound. The medicines are said to have a good smell that encourages the alates to emerge. Water may or may not be placed in the tin or pot.

Vomiting Studies

Platin-induced vomiting in the cat (84,85). Since then, the antiemetic potential of both A9-THC and representatives of other classes of synthetic cannabinoids (CP 55, 940 WIN55,212-2, or HU 210) against cisplatin-induced emesis has been confirmed in several other emetic species, including the pigeon (86,87), the ferret (88), the house musk shrew (89), and the least shrew (90-92). In addition, A9-THC appears to possess broad-spectrum antiemetic activity since it also suppresses emesis produced by the opiate morphine (93,94), the endocannabinoid 2-AG (18), the serotonin precursor 5-hydroxytryptophan and direct-acting serotonin 5-HT3 receptor agonists (95), and various selective and nonselective dopamine D2 D3 receptor agonists such as apomorphine, quinpi-role, quinelorane, and 7-OH DPAT (96). The receptor mechanism by which cannabinoid CB1 CB2 receptor agonists prevent emesis produced by diverse emetic stimuli remained unknown until recently. The first dose-dependent indication that...

Nissar A Darmani

This chapter briefly describes the physiological neural mechanisms by which diverse neuro-transmitter receptor systems control several aspects of gastrointestinal functions such as motility, secretion, feeding, and emesis. The current techniques used to study the effects of cannabinoids on these gastrointestinal functions are then sequentially described, starting with isolated gastrointestinal muscle preparations and ultimately evolving to whole animal models. Both A9-tetrahydro-cannibinol ( A9-THC) and well-studied representatives of other classes of exogenous cannabinoid CB1 CB2 receptor agonists inhibit gastrointestinal motility, peristalsis, defecation, and secretions via cannabinoid CB1 receptors since the CB1 (SR141716A)- and not the CB2 (SR144528)-recep-tor antagonist reverses these effects in a dose-dependent manner. In addition, exogenous cannabi-noids inhibit vomiting produced by diverse emetic stimuli in a SR141716A-sensitive manner in different animal models of emesis....

TCD Sonography

Prolonged effects of marijuana on cerebral hemodynamics in marijuana users. Blood flow velocity is measured by using a temporal window (zygomatic arch) middle (MCA) and anterior (ACA) cerebral arteries by using pulsed transcranial Doppler sonography. The temporal window may also be used for the posterior cerebral artery. The transorbital window is used for the ophthalmic artery and the carotid siphon. The transforaminal window (suboccipital) is used to determine blood flow velocity in the vertebral and basilar arteries. We have chosen the ACA and MCA because they supply blood to the cortex. Recording of both the ACA and MCA is possible via the temporal window because of the anatomy of the brain and these blood vessels. The carotid artery in the neck splits into the external and internal carotid arteries. As the internal carotid artery enters the base of the brain near the optic chiasm, it bifurcates into the ACA and MCA. The MCA then travels toward the outside of the cortex via the...

Synthetic

Cannabinoid-based drugs are either derived from the Cannabis plant or produced in the body from arachidonic acid. Many but not all have affinity for cannabinoid receptors. See text for explanation. suggested the existence of an endogenous ligand with similar activity and the isolation of the first of these was reported in 1992 (Devane et al. 1992). This so-called endocannabinoid was demonstrated to be the arachidonic acid derivative, -arachidonoyl ethanolamide (AEA), and since its discovery, several other similar compounds have been isolated and extensively studied including 2-arachidonoyl-glycerol (2-AG) (Mechoulam et al. 1995), 2-arachidonylglycerylether (noladin ether) (Hanus et al. 2001), and O-arachidonoyl ethanolamine (virohdamine) (Porter et al. 2002). Most of the cannabinoid-based drugs and endogenous ligands have immuno-modulating activity and most, but not all, bind to one or both of the two known can-nabinoid receptors, (see below). However, some,...

Male Fertility

Oligospermic Mane And Enzymes Levels

A sperm concentration below about 20 million per milliliter is termed oligospermia (oligo few) and is associated with decreased fertility. A total sperm count below about 50 million per ejaculation is clinically significant in male infertility. Oligospermia may be caused by a variety of factors, including heat from a sauna or hot tub, various pharmaceutical drugs, lead and arsenic poisoning, and such illicit drugs as marijuana, cocaine, and anabolic steroids. It may be temporary or permanent. In addition to low sperm counts as a cause of in

CB2R Knockout Mouse

In our CB2R- - mouse model, the CB2R gene has been mutated to render the receptor incapable of binding cannabinoids and coupling to G proteins. Therefore, this animal model is unique in that it can provide us with different information from that obtained by using the CB2R antagonist. The CB2R- - mice have been backcrossed to c57BL 6 mice more than 12 times to ensure c57BL 6 genetic background strain. Therefore, the control (wild-type, CB2R+ +) mice are c57BL 6.

Aminoalkylindoles

Aminoalkylindole

Nonulcerogenic analogs of nonsteroidal anti-inflammatory drugs (NSAIDs) (64) and bear no structural relationship to the cannabinoids (e.g., 48,49, Fig. 5). These analogs also exhibited antinociceptive properties that eventually were attributed to their interactions with the cannabinoid receptors (65,66). The most widely studied compound of this series is WIN55,212-2 (49), a potent CBi and CB2 agonist with a slight preference for CB2. Cannabinergic activity resides principally with only one optical antipode and is more potent than A9-THC in several pharmacological and behavioral assays. WIN55,212-2 has played an important role in the identification and characterization of cannabinoid receptors and their associated functions and is now in standard use as a CB1 CB2 radioligand. Scheme 11. Stereoselective synthesis of conformationally restricted hybrid cannabinoids (47). Reagents and conditions (a) (i) LDA, THF, -78 C, 30 min, (ii) 41, -78 C, 30 min, (iii) AcOH, 68 (b) NaBH4, MeOH, room...

Anatoxins

Lactone Ring Aflatoxin And

Hexanoate is also likely to feature as a starter unit in the formation of the cannabinoids, a group of terpenophenolics found in Indian hemp (Cannabis sativa Cannabaceae). This plant, and preparations from it, known under a variety of names including hashish, marihuana, pot, bhang, charas, and dagga, have been used for centuries for the pleasurable sensations and mild euphoria experienced after its consumption, usually by smoking. The principal psychoactive component is tetrahy-drocannabinol (THC) (Figure 3.51), whilst structurally similar compounds such as cannabinol (CBN) and cannabidiol (CBD), present in similar or larger amounts, are effectively inactive. In recent years, the beneficial effects of cannabis*, and especially THC, in alleviating nausea and vomiting in cancer patients undergoing chemotherapy, and in the treatment of glaucoma and multiple sclerosis, has led to a study of cannabinoid analogues for potentially useful medicinal activity. All the cannabinoid structures...

Tissue SetUp

The next two sections describe the electrical stimulation procedures used in this laboratory (Subheadings 3.2.1. and 3.2.2.). Whether cannabinoids are to be assayed using electrically stimulated tissue (Subheading 3.3.) or not (Subheading 3.4.), vasa deferentia are first subjected to an equilibration procedure that always involves electrical stimulation, as described in Subheading 3.2.3. Dose Cycles and Typical Concentrations for Some Common Cannabinoids Dose Cycles and Typical Concentrations for Some Common Cannabinoids

Research Subjects

The ethical principle of distributive justice requires that the burdens and benefits of research be distributed fairly across the population with the condition under study. The external validity (generalizability) of a study is enhanced when the study sample is representative of the population with the condition under study. Thus, for both ethical and scientific reasons, recruiting of subjects for cannabis-administration studies should involve the broadest possible population. Such studies will almost certainly enroll only subjects with some prior cannabis use (for reasons described below). Cannabis use and abuse occur in all US population groups, but is greatest among young adults 18-25 yr of age. The 2002 National Survey on Drug Use and Health (NSDUH) found that 17.3 of this age group were current (past month) cannabis users (2). Recruiting efforts could efficiently include sites with large concentrations of young adults, such as college campuses. However, individuals younger than...

Alzheimers Disease

Animals to examine the anti-inflammatory potential of cannabinoid-based drugs in AD models. One of the first studies utilized and in vitro model of ap toxicity (Milton 2002). The NT2 human neuron cell line was treated with ap and toxicity determined by the MTT assay. AEA and noladin ether co-treatment with ap attenuated the toxic-ity effect of the peptide, and the attenuation was inhibited by treatment with a CB1 antagonist. Thus, the endocannabinoids prevented ap toxicity and the drug effect was mediated by CB1. Studies in rats showed similar protective effects by CB2 agonists (Ramirez et al. 2005), and in addition, the cannabinoids were shown to inhibit the activation of brain microglia cells stimulated by various agents including ap (Ehrhart et al. 2005 Ramirez et al. 2005). Finally, a recent study showed that THC is a competitive inhibitor in vitro of acetylcholinesterase (AChE) (Eubanks et al. 2006). This has relevance to AD because this enzyme promotes the aggregation of ap,...

Phagocytosis Assay

Phagocytosis is one of the first lines of defense against invading microorganisms. Macrophages play a central role in this process as a host defends against intruding foreign bodies. This phagocytosis assay was developed in order to further elucidate the level at which macrophage function is compromised, if at all, in the presence of cannabinoids. 1. Thioglycolate-elicited peritoneal macrophages from CB2R+ + or CB2R- - are plated and treated with cannabinoids as indicated in Subheading 3.1.3. After incubating with cannabinoids for 1 h, in order to reduce cannabinoid interference, media is removed and 1 mL of fresh complete media is added prior to the addition of the foreign particles. Ten to 25 L of opsonized microspheres or 100 1 bacteria to macrophage are added and allowed to incubate for 1 h at 37 C.

Future Directions

This chapter has described methods for the assessment of cannabinoid-induced behavioral changes. In view of the widespread presence of cannabinoid receptors and their ligands (see for example refs. 84a, 84b), it is hardly surprising that the cannabinoids are involved in virtually every mode of behavior. Moreover, it has recently become evident that the endocannabinoids play a pivotal role as the retrograde messengers in glutamatergic and GABA-ergic synapses in a number of brain structures (84b-84d). With new technologies, in this era of the genome, the creation and availability of transgenics and knockout and knockin mice will allow the determination of the mechanisms associated with specific behaviors induced by cannabinoids. As the identity of previously unknown components of the EPCS become available, these behavioral tests and new methods to tease out the contribution of cannabinoid genetics in mediating the behavioral effects of cannabinoids will be needed. Although several...

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