Cannabinoid pharmacokinetics encompasses absorption after diverse routes of Cannabinoids in Sweat. To date, there are no published data on the. Drug use was also documented by a positive cannabinoid urinalysis, a hair For specimens with detectable cannabinoids, concentrations ranged from to .. However, drugs deposited in hair from sweat and/or sebum would have had. Usefulness of Sweat Testing for the Detection of Cannabis Smoke . for two basic drugs, cocaine and 3,4-methylenedioxymethamphetamine (MDMA) (4)(23).
Sweat in 3.4. Cannabinoids
One subject experienced a significant, acute paranoid reaction and was treated with 2 mg lorazepam. THC produced schizophrenia-like positive and negative symptoms and euphoria, and altered aspects of cognitive function. Plasma cortisol concentrations were not affected.
THC produced a broad range of transient symptoms, behaviors, and cognitive deficits in healthy individuals that resembled endogenous psychoses. The investigators suggested that brain-cannabinoid-receptor function could be an important factor in the pathophysiology of psychotic disorders. Cannabidiol CBD is a natural, non-psychoactive [ 49 ][ 50 ] constituent of Cannabis sativa , but possesses pharmacological activity, which is explored for therapeutic applications.
CBD has been reported to be neuroprotective [ 51 ], analgesic [ 37 ][ 38 ][ 52 ], sedating [ 37 ][ 38 ][ 53 ][ 54 ], anti-emetic [ 54 ], anti-spasmodic [ 55 ], and anti-inflammatory [ 56 ]. In addition, it has been reported that CBD blocks anxiety produced by THC [ 57 ], and may be useful in the treatment of autoimmune diseases [ 53 ].
These potential therapeutic applications alone warrant investigation of CBD pharmacokinetics. Further, the controversy over whether CBD alters the pharmacokinetics of THC in a clinically significant manner needs to be resolved [ 58 ][ 59 ]. Recently, Nadulski et al. The authors suggest that identification and quantification of CBD could be an additional proof of cannabis exposure and could improve interpretation of THC effects considering the potential ability of CBD to modify THC effects.
When comparing sublingual administration of THC 25 mg alone vs. The only statistically significant difference was in the time of maximum THC concentration. All three analytes were detectable ca.
High intra- and inter-subject variability was noted. THC Plasma concentrations decrease rapidly after the end of smoking due to rapid distribution into tissues and metabolism in the liver. THC is highly lipophilic and initially taken up by tissues that are highly perfused, such as the lung, heart, brain, and liver. Tracer doses of radioactive THC documented the large volume of distribution of THC and its slow elimination from body stores.
In animals, after intravenous administration of labeled THC, higher levels of radioactivity were present in lung than in other tissues [ 64 ].
Studies of the distribution of THC into brain are especially important for understanding the relationships between THC dose and behavioral effects. Plasma concentrations were of similar magnitude to those measured in men exposed to marihuana smoke. Kreuz and Axelrod were the first to describe the persistent and preferential retention of radiolabeled THC in neutral fat after multiple doses, in contrast to limited retention in brain [ 66 ]. The ratio of fat to brain THC concentration was approximately With prolonged drug exposure, THC concentrates in human fat, being retained for extended periods of time [ 69 ].
In addition, these investigators found that tolerance to the behavioral effects of THC in pigeons was not due to decreased uptake of cannabinoids into the brain. Tolerance also was evaluated in humans.
Pharmacokinetic changes after chronic oral THC administration could not account for observed behavioral and physiologic tolerance, suggesting rather that tolerance was due to pharmacodynamic adaptation. Adams and Martin studied the THC dose required to induce pharmacological effects in humans [ 73 ].
In a recent, highly interesting study, Mura et al. There was no correlation between blood and brain concentrations; brain levels were always higher than blood levels, and in three cases measurable drug concentrations remained in the brain, when no longer detectable in the blood. Blood concentrations were lower than in the two-paired brains. The authors postulate that long-lasting effects of cannabis during abstinence in heavy users may be due to residual THC and OH-THC concentrations in the brain.
Storage of THC after chronic exposure could also contribute to observed toxicities in other tissues. After single intramuscular administration of radioactive THC in rats, only 0.
The authors suggest that the blood—brain and blood—testicular barriers limit storage of THC in brain and testis during acute exposure; however, during THC chronic exposure, pharmacokinetic mechanisms are insufficient to prevent accumulation of THC in tissues, with subsequent deregulation of cellular processes, including apoptosis of spermatogenic cells.
In one of the latest investigations on THC distribution in tissues, the large-white-pig model was selected due to similarities with humans in drug biotransformation, including enzymes and isoenzymes of drug biotransformation, size, feeding patterns, digestive physiology, dietary habits, kidney structure and function, pulmonary vascular bed structure, coronary-artery distribution, propensity to obesity, respiratory rates, and tidal volume [ 75 ].
THC Plasma pharmacokinetics was found to be similar to those in humans. At 30 min, high THC concentrations were noted in lung, kidney, liver, and heart, with comparable elimination kinetics in kidney, heart, spleen, muscle, and lung as observed in blood. The fastest THC elimination was noted in liver, where concentrations fell below measurable levels by 6 h. Mean brain concentration was approximately twice the blood concentration at 30 min, with highest levels in the cerebellum, and occipital and frontal cortex, and lowest concentrations in the medulla oblongata.
THC Concentrations decreased in brain tissue slower than in blood. The slowest THC elimination was observed for fat tissue, where THC was still present at substantial concentrations 24 h later.
The authors suggest that the prolonged retention of THC in brain and fat in heavy cannabis users is responsible for the prolonged detection of THC-COOH in urine and cannabis-related flashbacks. The author of this review hypothesizes that this residual THC may also contribute to cognitive deficits noted early during abstinence in chronic cannabis users. THC accumulation in the lung occurs because of high exposure from cannabis smoke, extensive perfusion of the lung, and high uptake of basic compounds in lung tissue.
Lung tissue is readily available during postmortem analysis, and would be a good matrix for investigation of cannabis exposure. Other possible explanations include lower plasma-protein binding of OH-THC or enhanced crossing of the blood—brain barrier by the hydroxylated metabolite. The distribution volume V d of THC is large, ca.
More recently, with the benefit of advanced analytical techniques, the steady state V d value of THC was estimated to be 3. THC-COOH was found to be far less lipophilic than the parent drug, whose partition coefficient P value at neutral pH has been measured at 6, or higher , and more lipophilic than the glucuronide [ 78 ]. The fraction of THC glucuronide present in blood after different routes of administration has not been adequately resolved, but, recently, the partition coefficient of this compound indicated an unexpectedly high lipophilicity, ca.
THC rapidly crosses the placenta, although concentrations were lower in canine and ovine fetal blood and tissues than in maternal plasma and tissues [ 79 ]. Blackard and Tennes reported that THC in cord blood was three to six times less than in maternal blood [ 82 ].
Transfer of THC to the fetus was greater in early pregnancy. THC also concentrates into breast milk from maternal plasma due to its high lipophilicity [ 83 ][ 84 ]. THC Concentration in breast milk was 8. They also documented that THC can be metabolized in the brain. Conjugation with glucuronic acid is a common Phase-II reaction.
Side-chain hydroxylation was common in all three species. THC Concentrations accumulated in the liver, lung, heart, and spleen. Hydroxylation of THC at C 9 by the hepatic CYP enzyme system leads to production of the equipotent metabolite OH-THC [ 89 ][ 90 ], originally thought by early investigators to be the true psychoactive analyte [ 64 ]. More than THC metabolites, including di- and trihydroxy compounds, ketones, aldehydes, and carboxylic acids, have been identified [ 21 ][ 70 ][ 91 ].
Less than fivefold variability in 2C9 rates of activity was observed, while much higher variability was noted for the 3A enzyme. THC-COOH and its glucuronide conjugate are the major end products of biotransformation in most species, including man [ 91 ][ 95 ].
The phenolic OH group may be a target as well. Addition of the glucuronide group improves water solubility, facilitating excretion, but renal clearance of these polar metabolites is low due to extensive protein binding [ 72 ]. No significant differences in metabolism between men and women have been reported [ 27 ]. After the initial distribution phase, the rate-limiting step in the metabolism of THC is its redistribution from lipid depots into blood [ 98 ].
However, later studies did not corroborate this finding [ 8 ][ 91 ]. More than 30 metabolites of CBD were identified in urine, with hydroxylation of the 7-Me group and subsequent oxidation to the corresponding carboxylic acid as the main metabolic route, in analogy to THC [ ]. Other tissues, including brain, intestine, and lung, may contribute to the metabolism of THC, although alternate hydroxylation pathways may be more prominent [ 86 ][ - ].
An extrahepatic metabolic site should be suspected whenever total body clearance exceeds blood flow to the liver, or when severe liver dysfunction does not affect metabolic clearance [ ]. Within the brain, higher concentrations of CYP enzymes are found in the brain stem and cerebellum [ ]. Metabolism of THC by fresh biopsies of human intestinal mucosa yielded polar hydroxylated metabolites that directly correlated with time and amount of intestinal tissue [ ].
In a study of the metabolism of THC in the brains of mice, rats, guinea pigs, and rabbits, Watanabe et al. Hydroxylation of C 4 of the pentyl side chain produced the most common THC metabolite in the brains of these animals, similar to THC metabolites produced in the lung. These metabolites are pharmacologically active, but their relative activity is unknown. CBD Metabolism is similar to that of THC, with primary oxidation of C 9 to the alcohol and carboxylic acid [ 8 ][ ], as well as side-chain oxidation [ 88 ][ ].
Co-administration of CBD did not significantly affect the total clearance, volume of distribution, and terminal elimination half-lives of THC metabolites.
Numerous acidic metabolites are found in the urine, many of which are conjugated with glucuronic acid to increase their water solubility. Another common problem with studying the pharmacokinetics of cannabinoids in humans is the need for highly sensitive procedures to measure low cannabinoid concentrations in the terminal phase of excretion, and the requirement for monitoring plasma concentrations over an extended period to adequately determine cannabinoid half-lives.
The slow release of THC from lipid-storage compartments and significant enterohepatic circulation contribute to a long terminal half-life of THC in plasma, reported to be greater than 4. Isotopically labeled THC and sensitive analytical procedures were used to obtain this drug half-life. No significant pharmacokinetic differences between chronic and occasional users have been substantiated [ ]. An average of This represents an average of only 0.
Prior to harvesting, cannabis plant material contains little active THC. When smoked, THC carboxylic acids spontaneously decarboxylate to produce THC, with nearly complete conversion upon heating. Pyrolysis of THC during smoking destroys additional drug. Drug availability is further reduced by loss of drug in the side-stream smoke and drug remaining in the unsmoked cigarette butt. These factors contribute to high variability in drug delivery by the smoked route.
It is estimated that the systemic availability of smoked THC is ca. THC Bioavailability is reduced due to the combined effect of these factors; the actual available dose is much lower than the amount of THC and THC precursor present in the cigarette.
Another factor affecting the low amount of recovered dose is measurement of a single metabolite. Following controlled oral administration of THC in dronabinol or hemp oil, urinary cannabinoid excretion was characterized in 4, urine specimens [ ][ ].
THC Doses of 0. The two high doses 7. The availability of cannabinoid-containing foodstuffs, cannabinoid-based therapeutics, and continued abuse of oral cannabis require scientific data for the accurate interpretation of cannabinoid tests.
These data demonstrate that it is possible, but unlikely, for a urine specimen to test positive at the federally mandated cannabinoid cutoffs, following manufacturer's dosing recommendations for the ingestion of hemp oils of low THC concentration. An average of only 2. Specimen preparation for cannabinoid testing frequently includes a hydrolysis step to free cannabinoids from their glucuronide conjugates.
Alkaline hydrolysis appears to efficiently hydrolyze the ester glucuronide linkage. Mean THC concentrations in urine specimens from seven subjects, collected after each had smoked a single marijuana cigarette 3. Using a modified analytical method with E. We found that OH-THC may be excreted in the urine of chronic cannabis users for a much longer period of time, beyond the period of pharmacodynamic effects and performance impairment. Compared to other drugs of abuse, analysis of cannabinoids presents some difficult challenges.
Complex specimen matrices, i. Care must be taken to avoid low recoveries of cannabinoids due to their high affinity to glass and plastic containers, and to alternate matrix-collection devices [ - ]. Whole-blood cannabinoid concentrations are approximately one-half the concentrations found in plasma specimens, due to the low partition coefficient of drug into erythrocytes [ 96 ][ ][ ]. THC Detection times in plasma of 3. In the latter study, the terminal half-life of THC in plasma was determined to be ca.
This inactive metabolite was detected in the plasma of all subjects by 8 min after the start of smoking. The half-life of the rapid-distribution phase of THC was estimated to be 55 min over this short sampling interval.
The relative percentages of free and conjugated cannabinoids in plasma after different routes of drug administration are unclear. Even the efficacy of alkaline- and enzymatic-hydrolysis procedures to release analytes from their conjugates is not fully understood [ 24 ][ 77 ][ 93 ][ ][ ][ ][ - ].
In general, the concentrations of conjugate are believed to be lower in plasma, following intravenous or smoked administration, but may be of much greater magnitude after oral intake. There is no indication that the glucuronide conjugates are active, although supporting data are lacking.
Peak concentrations and time-to-peak concentrations varied sometimes considerably between subjects. Most THC plasma data have been collected following acute exposure; less is known of plasma THC concentrations in frequent users.
No difference in terminal half-life in frequent or infrequent users was observed. There continues to be controversy in the interpretation of cannabinoid results from blood analysis, some general concepts having wide support. It is well-established that plasma THC concentrations begin to decline prior to the time of peak effects, although it has been shown that THC effects appear rapidly after initiation of smoking [ 15 ].
Individual drug concentrations and ratios of cannabinoid metabolite to parent drug concentration have been suggested as potentially useful indicators of recent drug use [ 24 ][ ].
This is in agreement with results reported by Mason and McBay [ 96 ], and those by Huestis et al. Measurement of cannabinoid analytes with short time courses of detection e. This correlates well with the suggested concentration of plasma THC, due to the fact that THC in hemolyzed blood is approximately one-half the concentration of plasma THC [ ]. Accurate prediction of the time of cannabis exposure would provide valuable information in establishing the role of cannabis as a contributing factor to events under investigation.
Two mathematical models for the prediction of time of cannabis use from the analysis of a single plasma specimen for cannabinoids were developed [ ]. More recently, the validation of these predictive models was extended to include estimation of time of use after multiple doses of THC and at low THC concentrations 0.
Some 38 cannabis users each smoked a cigarette containing 2. The predicted times of cannabis smoking, based on each model, were then compared to the actual smoking times.
The most accurate approach applied a combination of models I and II. All time estimates were correct for 77 plasma specimens, with THC concentrations of 0. The models provide an objective, validated method for assessing the contribution of cannabis to accidents or clinical symptoms. These models also appeared to be valuable when applied to the small amount of data from published studies of oral ingestion available at the time. Additional studies were performed to determine if the predictive models could estimate last usage after multiple oral doses, a route of administration more popular with the advent of cannabis therapies.
Each of twelve subjects in one group received a single oral dose of dronabinol 10 mg of synthetic THC. In another protocol, six subjects received four different oral daily doses, divided into thirds, and administered with meals for five consecutive days.
There was a d washout period between each dosing regimen. The daily doses were 0. The actual times between ingestion of THC and blood collection spanned 0. These results provide further evidence of the usefulness of the predictive models in estimating the time of last oral THC ingestion following single or multiple doses. Detection of cannabinoids in urine is indicative of prior cannabis exposure, but the long excretion half-life of THC-COOH in the body, especially in chronic cannabis users, makes it difficult to predict the timing of past drug use.
This individual had used cannabis heavily for more than ten years. However, a naive user's urine may be found negative by immunoassay after only a few hours following smoking of a single cannabis cigarette [ ].
Assay cutoff concentrations and the sensitivity and specificity of the immunoassay affect drug-detection times. A positive urine test for cannabinoids indicates only that drug exposure has occurred. The result does not provide information on the route of administration, the amount of drug exposure, when drug exposure occurred, or the degree of impairment.
THC-COOH concentration in the first specimen after smoking is indicative of how rapidly the metabolite can appear in urine. Thus, THC-COOH concentrations in the first urine specimen are dependent upon the relative potency of the cigarette, the elapsed time following drug administration, smoking efficiency, and individual differences in drug metabolism and excretion.
The mean times of peak urine concentration were 7. Although peak concentrations appeared to be dose-related, there was a twelvefold variation between individuals. Drug detection time, or the duration of time after drug administration in which the urine of an individual tests positive for cannabinoids, is an important factor in the interpretation of urine drug results.
Detection time is dependent on pharmacological factors e. Mean detection times in urine following smoking vary considerably between subjects, even in controlled smoking studies, where cannabis dosing is standardized and smoking is computer-paced.
During the terminal elimination phase, consecutive urine specimens may fluctuate between positive and negative, as THC-COOH concentrations approach the cutoff concentration. It may be important in drug-treatment settings or in clinical trials to differentiate between new drug use and residual excretion of previously used cannabinoids.
After smoking a cigarette containing 1. This had the effect of producing much longer detection times for the last positive specimen. Normalization of cannabinoid concentration to urine creatinine concentration aids in the differentiation of new from prior cannabis use, and reduces the variability of drug measurement due to urine dilution.
Due to the long half-life of drug in the body, especially in chronic cannabis users, toxicologists and practitioners are frequently asked to determine if a positive urine test represents a new episode of drug use or represents continued excretion of residual drug. Random urine specimens contain varying amounts of creatinine, depending on the degree of concentration of the urine.
Hawks first suggested creatinine normalization of urine test results to account for variations in urine volume in the bladder [ ]. Whereas urine volume is highly variable due to changes in liquid, salt, and protein intake, exercise, and age, creatinine excretion is much more stable. If the increase is greater than or equal to the threshold selected, then new use is predicted. This approach has received wide attention for potential use in treatment and employee-assistance programs, but there was limited evaluation of the usefulness of this ratio under controlled dosing conditions.
Huestis and Cone conducted a controlled clinical study of the excretion profile of creatinine and cannabinoid metabolites in a group of six cannabis users, who smoked two different doses of cannabis, separated by weekly intervals [ ]. As seen in Fig. Being able to differentiate new cannabis use from residual THC-COOH excretion in urine would be highly useful for drug treatment, criminal justice, and employee assistance drug testing programs.
The ratio times of the creatinine normalized later specimen divided by the creatinine normalized earlier specimen were evaluated for determining the best ratio to predict new cannabis use. The most accurate ratio To further substantiate the validity of the derived ROC curve, urine-cannabinoid-metabolite and creatinine data from another controlled clinical trial that specifically addressed water dilution as a means of specimen adulteration were evaluated [ ].
Sensitivity, specificity, accuracy, and false positives and negatives were These data indicate that selection of a threshold to evaluate sequential creatinine-normalized urine drug concentrations can improve the ability to distinguish residual excretion from new drug usage. Cannabinoids were detectable for 93 d after cessation of smoking, with a decreasing ratio of cannabinoids to creatinine over time. An excretion half-life of 32 d was determined. When cannabinoid concentrations had not been normalized to creatinine concentrations, a number of false positive indications of new drug use would have occurred.
Within this range, cannabinoid excretion is more variable, most likely based on the slow and variable release of stored THC from fat tissue. The factors governing release of THC stores are not known. Additional research is being performed to attempt to determine appropriate ratio cutoffs for reliably predicting new drug use in heavy, chronic users. Oral fluid also is a suitable specimen for monitoring cannabinoid exposure, and is being evaluated for driving under the influence of drugs, drug treatment, workplace drug testing, and for clinical trials [ - ].
The oral mucosa is exposed to high concentrations of THC during smoking, and serves as the source of THC found in oral fluid. Only minor amounts of drug and metabolites diffuse from the plasma into oral fluid [ ]. Following intravenous administration of radiolabeled THC, no radioactivity could be demonstrated in oral fluid [ ].
Oral fluid collected with the Salivette collection device was positive for THC in 14 of these 22 participants. Several hours after smoking, the oral mucosa serves as a depot for release of THC into the oral fluid. In addition, as detection limits continue to decrease with the development of new analytical instrumentation, it may be possible to measure low concentrations of THC-COOH in oral fluid.
Detection times of cannabinoids in oral fluid are shorter than in urine, and more indicative of recent cannabis use [ ][ ]. Oral-fluid THC concentrations temporally correlate with plasma cannabinoid concentrations and behavioral and physiological effects, but wide intra- and inter-individual variation precludes the use of oral-fluid concentrations as indicators of drug impairment [ ][ ].
THC may be detected at low concentrations by radioimmunoassay for up to 24 h after use. After these times, occasional positive oral-fluid results were interspersed with negative tests for up to 34 h. They suggested that the ease and non-invasiveness of sample collection made oral fluid a useful alternative matrix for detection of recent cannabis use. Oral-fluid samples also are being evaluated in the European Union's Roadside Testing Assessment ROSITA project to reduce the number of individuals driving under the influence of drugs and to improve road safety.
The ease and non-invasiveness of oral-fluid collection, reduced hazards in specimen handling and testing, and shorter detection window are attractive attributes to the use of this specimen for identifying the presence of potentially performance-impairing drugs. They determined that, with a limit of quantification of 0. As mentioned above, oral-fluid specimens tested positive for up to 34 h. Positive oral-fluid cannabinoid tests were not obtained more than 2 h after last use, suggesting that much lower cutoff concentrations were needed to improve sensitivity.
Detection of cannabinoids in oral fluid is a rapidly developing field; however, there are many scientific issues to resolve. One of the most important is the degree of absorption of the drug to oral-fluid collection devices.
Recently, there has been renewed interest in oral-fluid drug testing for programs associated with drug treatment, workplace, and driving under the influence of drugs. Small and inconsistent specimen volume collection, poor extraction of cannabinoids from the collection device, low analyte concentrations for cannabinoids, and the potential for external contamination from environmental smoke are limitations to this monitoring method.
Recently, independent evaluations of the extraction of cannabinoids from the collection device [ - ] and measurement of oral-fluid THC-COOH in concentrations as low as picograms per milliliter appear to adequately address these potential problems.
Association with an increased risk of myocardial infarction has also been reported, with aggravation of coronary ischemia and even triggering of myocardial infarction [ ].
Also, myocardial infarction, sudden cardiac death, cardiomyopathy, stroke, transient ischemic attack, and arteritis have been described [ ]. Complications can occur in young users without preexisting cardiovascular problems [ ] and at a greater frequency [ ]. Recreational consumption by adolescents may lead to subsequent drug abuse. Cannabis has been proposed as a gateway drug [ , ]. This hypothesis is still debated and neurobiological mechanisms are still not fully understood.
Preclinical studies suggest nevertheless that cannabis may facilitate the sampling of other drugs of abuse such as alcohol, cocaine, and heroin. Academic difficulties have also been observed among occasional cannabis users during adolescence [ ].
Regular consumption is predictive of a person having a higher risk of problems with other drugs in adulthood, along with psychological and societal issues [ ]. It has been shown that consumption during adolescence may increase chronic psychosis and this phenomenon is reinforced when there is a genetic predisposition to the problem [ 19 ].
As opposed to cocaine or heroin, cannabis has often been considered a less harmful drug with low dependence properties and minimal negative effects, but its addictive potential has long been questioned [ ].
Recent research has made strong progress in the knowledge of the mechanisms of action of cannabis and no doubt has subsisted that cannabis is an addictive drug. Moreover, an increasing number of cannabis consumers are seeking efficient treatments indicating that a growing fraction of the population is being dependent on cannabis. Chronic consumption of a drug may lead to addiction and this brain disease can be characterized by specific behavioral consequences: This addictive behavior evolves despite its adverse consequences on everyday life.
This phenomenon has been well documented by several reviews which propose a model for this spiral of addiction [ 62 , — ]. It develops in a small proportion of casual users and relies on psychological, genetic and environmental factors participating to the individual vulnerability [ — ]. Several criterions are documented for this evaluation and allow classifying the severity of the individual addiction depending on the numbers of criterions identified.
Among the criterion listed for cannabis, the development of tolerance [ ] and withdrawal syndromes caused by the interruption of consumption [ ] are well recognized. Tolerance is characterized by a decrease of the effects following repeated drug consumption or by a need to increase the amount taken to reach similar effects [ ].
Nevertheless, development of tolerance can vary between individuals in terms of physiological responses or behavior [ ]. Withdrawal syndromes appear when the individual is under abstinence following chronic intake of the drug or when the individual seeks for the same drug or another one to alleviate these symptoms [ 15 , ].
Spontaneous withdrawal is observed in humans to cause increased agitation and excitability, insomnia, anxiety, aggressiveness, depression state, anorexia, and tremors [ 13 , ]. Specific animal models have been developed to study drug rewarding effects mediated by specific brain structures in preclinical research. In order to characterize cannabis effects observed in humans, rodent models using repeated administration of cannabinoid agonists have been elaborated to evaluate consequences of such a chronic exposure as well as the addictive power of these cannabinoids [ ].
This allowed a better understanding of motivational and reinforcing properties of these drugs [ 15 ]. It is an operant system based on a voluntary procedure to obtain the drug, coupled with the association of a signal [ ]. Indeed drug priming, low doses, food restriction, and animal restraint were useful to measure cannabinoid agonists properties in this task [ 96 , , ].
A task evaluating the conditioned place preference CPP has been developed to study reinforcing properties of drugs associated with an environmental cue like the context in which the drug is administered [ ]. Interestingly, conflicting evidence exist about either positive CPP or negative CPA properties of cannabinoids, depending on experimental conditions used [ 96 ]. This nonoperant paradigm with specific experimental conditions has been used to study cannabinoid effects in genetically modified mice for review see [ ].
They may be either spontaneous or precipitated by a selective CB1 antagonist, and somatic signs can be scored for providing an index of dependence [ , ]. For example, mice exhibited several signs including tremor, ataxia, piloerection, ptosis, and decreased motor activity [ , ].
This illustrates the fact that an increasing number of people are dependent on cannabis. In the United States of America, more people are dependent on cannabis than cocaine 4. In , about , people aged more than 12 years old received treatment because of their cannabis consumption [ 5 ].
In general, adults seeking treatment have been regular users for more than 10 years and have already tried to reduce or stop their behavior [ , ]. There are currently no approved medications for the treatment of cannabis dependence and cannabinoid antagonists could be a potential pharmacotherapy [ ].
The use of selective CB1 antagonists for the treatment of drug dependence has been investigated in preclinical studies as CB1 receptors are highly expressed in brain structures related to reward see Section 2. Cognitive behavioral therapy associated with contingency management is quite efficient for treating cannabis dependence [ 4 , ]. Proposed therapeutic approaches are based on existing ones known to be effective in the treatment of other drug use disorders like baclofen for alcoholic withdrawal.
Some clinical studies suggest that existing medications for other indications may be promising target for cannabis use disorder. It is used to treat nicotinic withdrawal, and is an antidepressant. Buspirone is used as an anxiolytic and lithium as a thymoregulator. A more recent problem that has strongly increased the risks of drug use is the proliferation worldwide of new derivatives of synthetic cannabinoids.
Spices usually look like a mixture of dry herb plants where a multitude of compounds have been sprayed. These synthetic compounds are analogs of cannabinoids, but the exact content of the mixtures is not fully known and many chemical types of compounds are now being produced.
They induce similar euphoric and relaxing effects as classical cannabis derivatives but they present a much higher potency. There may be specific risks associated with these new drugs compared to those known for cannabis. Indeed, they produce increased or even additional adverse effects, such as tachycardia, hypertension, chest pain, cardiac palpitation, intense sweating, convulsions, drowsiness, and agitation [ , , ]. In adolescents, hallucinations, paranoia, and myocardial infarction have been reported [ ].
More toxicology studies are needed to better characterize the adverse effects of these substances [ ]. Altogether, synthetic cannabinoids represent a significant public health issue with an evolving legal market place that specifically target young populations and is difficult to control.
Mechanisms of action are yet more complex as the endocannabinoid system interacts with other neuromodulatory systems such as the hypocretin, dopaminergic, adenosinergic, and opioid systems. The latter is of particular interest as the endocannabinoid and the opioid systems share neuroanatomical, neurochemical, and pharmacological characteristics [ — ].
The opioid system consists of three GPCR named mu, delta, and kappa receptors which interact with endogenous ligands enkephalins, dynorphins, and endorphins as well as exogenous ligands, including morphine or heroin.
Evidence for specific interactions in the modulation of nociception has been provided both with in vitro and in vivo approaches [ , ]. In the context of responses associated with reward and relapse, specific mechanisms have been highlighted, in particular with the use of knockout approaches [ ].
Noticeably the mu opioid receptor has been proposed as a convergent molecular target mediating rewarding properties of opioid compounds but also of other drugs of abuse, including cannabinoids [ , ]. The participation of the enkephalinergic system, with a joint action of mu and delta receptors, in behavioral responses associated with cannabinoid dependence has been clearly demonstrated.
Moreover, chronic exposure to cannabinoid agonists induced a modification in both the density of mu opioid receptors and their activity in structures related to reward, which may contribute to the development of cannabinoid dependence [ ]. Interestingly, studies using cannabinoid iv SA experiments have shown that opioid antagonists can block cannabinoid intake in mice and rats [ ] and in squirrel monkeys [ ].
Moreover, iv SA of morphine is abolished in animals deficient for the CB1 receptor [ ], confirming a role for CB1 receptor in the modulation of opioid reward [ , ]. Additionally, the antagonist rimonabant can precipitate withdrawal signs in morphine dependent animals and reciprocally, the opioid antagonist naloxone can precipitate these effects in cannabinoid dependent rats [ ].
Also, heterodimerization processes between cannabinoid and opioid receptors have been reported in both in vitro and more recently in vivo, in neuronal populations [ , ]. This physical proximity is suggested mainly for CB1 receptors and delta or mu receptors and may impact on signaling properties of these receptors in specific brain structures, therefore possibly influencing analgesic or addictive responses involving these receptors.
More research remains to be done to decipher the physiological role of such heteromers [ , ]. Even though cannabinoids are considered a drug of abuse and can induce dependence, they are used to treat several pathologies, including drug dependence. On the other hand, the beneficial effects of cannabinoids in specific pathologies are worth trying to develop for medical use and therefore represent a main therapeutic challenge for health science.
Several therapeutic strategies are currently being developed with some limitations. Therapeutic interventions targeting the endocannabinoid system. Commercialized compounds or molecules under study for targeting the endocannabinoid system are acting on different processes. Two main strategies are being developed to target the endocannabinoid system.
Only the presynaptic neuron is represented here. Thin arrows represent the action of endogenous hatched or exogenous plain ligands on cannabinoid receptors. For detailed references, see the text. Cannabidiol CBD is a phytocannabinoid that has a low affinity for both receptors CB1 and CB2 with inverse agonistic properties [ 96 , ] and antagonistic effects, with CB2 receptors in particular [ ] see Section 1.
Other properties such as anxiolytic, antidepressor, and antipsychotic effects have been observed with CBD [ ]. Evidence from several research domains suggests that CBD can be used for antipsychotic treatment for reviews, see [ , ].
Animal studies investigated the pharmacological profile of this phytocannabinoid and revealed a similar pattern to atypical antipsychotic drugs clozapine or risperidone. Also, clinical studies on schizophrenic patients using CBD demonstrated a potential for this drug to be used as an alternative treatment for schizophrenia [ ]. More investigations are still needed to better demonstrate the potential of this phytocannabinoid as a medication. This table lists examples of strategies targeting directly or indirectly the endocannabinoid system being developed or in progress for treating several pathologies.
Most of trials were perform in preclinical studies. For most of candidate medications clinical trials must be perform or completed to confirm the efficiency in human and the safety of the various compounds. Interestingly, a rodent study using iv SA of heroin has revealed a potential for CBD as a medication for heroin dependence [ ].
Indeed, the authors show in their model that CBD does not alter the intake of heroin, but specifically impairs the seeking behavior reinstated by a conditioned stimulus cue. This CBD effect is associated with the normalization of neurobiological changes observed in this model, noticeably in the CB1 receptor expression in structures related to reward like Nucleus Accumbens. In humans, opiate dependence is mostly treated with substitutive therapy like methadone but this molecule does not affect heroin craving.
Therefore, CBD represents a potential alternative to treat heroin craving and relapse [ ]. CBD has been shown to have analgesic properties.
Paclitaxel is an anticancer drug that induces neuropathic pain. It had no conditioned rewarding effects and did not affect conditioned learning and memory. The precise mechanism of action is still not clear and may partly involve the serotonin system [ ]. CBD may be an efficient treatment to reduce the neuropathic pain induced by chemotherapy without any of the potential side effects of cannabinoids. Finally, other pathological situations, such as neurodegenerative diseases Parkinson and Alzheimer , cerebral ischemia, diabetes, nausea, rheumatoid arthritis, or other inflammatory problems could be treated with CBD [ , ].
Additionally, the potential for CBD as a medical intervention in psychotic disorder has been reviewed recently [ ]. CBD represents a therapeutic approach for several disorders, but more clinical studies are needed. Pharmacology has provided many synthetic cannabinoid ligands that specifically interact with cannabinoid receptors and therefore represent great tools for research and clinical applications. The limitation for the use of these compounds as therapeutic drugs so far is that most of them target CB1 receptors and therefore may lead to adverse psychotic effects [ ].
Indeed, CB1 receptor activation induces most of the central and psychotic effects of cannabis see Section 2. Noteworthy activation of CB2 is not associated with tolerance or withdrawal syndrome in animal models of neuropathic pain [ ]. Targeting these receptors for therapeutic purposes is therefore of strong interest [ 93 ]. As CB2 is highly expressed in immune cells, a potential role in treating several diseases including inflammation, cancer, osteoporosis, and liver diseases has been proposed for a recent review, see [ ].
Thus, CB2 agonists represent promising medication strategies in several therapeutic applications with modulation of inflammatory processes without triggering psychotic effect [ , ].
This effect may be of interest in the context of neurodegenerative and neuroinflammatory diseases such as Alzheimer disease AD , MS, or Huntington's disease [ — ]. Interestingly, a strong increase of CB2 mRNA expression is observed in the spinal cord of this mouse model [ ]. These observations highlight the therapeutic potential of CB2 agonists for the treatment of these chronic pathologies.
A study using genetically modified mice deficient for CB2 receptors has revealed a low bone mass phenotype, suggesting that endocannabinoids play an essential role in the maintenance of bone mass by signaling through CB2. Thus CB2 selective agonists could play a protector role in osteoporosis and represent a treatment strategy. In addition, selective agonists for CB2 receptors have been proposed for the treatment of inflammatory disorders in periphery, including atherosclerosis [ ], nephropathy [ ] or chronic liver disease [ ].
Finally, CB2 receptor expression has been detected in neurons and a modulator role of this receptor has been proposed in drug addiction see Section 2. A similar effect is observed in the ventral tegmental area with inhibition of dopaminergic activity both in vivo and in vitro [ 66 ].
Therefore, the development of CB2 agonists for the treatment of cocaine dependence may be a future strategy. In conclusion, preclinical studies are encouraging for CB2 agonist use in therapeutic approaches, but clinical results are rather poor and more studies are still needed.
These limited results may be due to low in vivo selectivity of the tested compounds which may also interact with CB1 receptors , individual gender, age or interspecies differences in CB2 receptors and associated signaling pathways [ 93 ]. Other therapeutic strategies have explored the use of specific antagonists to block cannabinoid effects [ ]. Rimonabant was the first CB1 antagonist introduced into clinical practice [ ]. The anorexigenic properties of rimonabant were also encouraging to evaluate the potential of this compound to avoid weight gain when stopping nicotine consumption.
Besides promising effects of this compound, it was withdrawn from the market in as strong psychiatric adverse effects have been observed during clinical trials increased anxiety, deep depression, and suicide [ 38 , , ] and was therefore not authorized by the Food and Drug Administration in the United States of America.
Knowing the adverse effects of rimonabant in human, development of any new selective cannabinoid antagonists with different pharmacodynamics properties more neutral antagonist that would possess the same activity both in animals and humans is greatly needed.
Alternative perspectives for specific medical conditions are oriented toward cannabinoid antagonists that will only act on the periphery without CNS related adverse effects. Likewise, peripheral antagonism may be beneficial for other pathologies with noticeable peripheral pathophysiologic mechanisms including gastrointestinal, liver, pancreatic, or coronary artery diseases [ ] and references therein.
Indeed, bidirectional interactions between cannabinoid and opioid systems on reward processes revealed by both pharmacological and genetic approaches see Section 3.
Another therapeutic use for cannabinoid antagonists would be for treatment of nicotine abuse. Besides, clinical studies have shown that rimonabant was efficient for tobacco smoking cessation, but the therapeutic effects were not better than other substitutive medications and results for abstinence were not fully convincing [ ].
Moreover, CB1 antagonists have been evaluated for their use in alcohol dependence recently reviewed in [ ]. In preclinical studies, evidence accumulates for the good efficiency of cannabinoid antagonists to significantly reduce alcohol consumption and attenuate alcohol withdrawal symptoms. For example, a preclinical study demonstrated that rimonabant may be effective in reduction of alcohol consumption, most probably by indirect modulation of dopaminergic transmission [ ].
On the other hand, results obtained in animals do not necessary translate to human studies. Globally, results on cannabinoid efficiency for alcohol dependence are highly inconsistent and more clinical studies are needed to confirm an effect in human for this major health concern worldwide.
An indirect strategy that is currently developed to target the endocannabinoid system is to limit the endocannabinoid degradation in order to increase their natural concentration in situ and amplify their effects. For example, the URB is a selective inhibitor of this enzyme [ , ]. In both rats and mice it elicits antidepressive and antianxiolytic like effects, likely via CB1 receptor mediated modulation of serotonin and norepinephrine neurotransmission [ — ].
These observations highlight FAAH as an interesting pharmacological target to directly modulate endocannabinoid levels in the brain and therefore offer a potential treatment for depression and anxiety phenotype.
Moreover, these inhibitors reduce somatic morphine withdrawal signs but not aversive aspects CPA paradigm [ ]. Interestingly, the FAAH inhibitors do not show any adverse effects such as hypothermia, hypomotility, or catalepsia [ 81 , ]. In addition, they do not show reinforcing properties and therefore are a promising therapeutic strategy to treat opiate dependence with the minimal risk of abuse that is classically observed with cannabinoid agonists [ , ].
The endocannabinoid uptake inhibitor AM can have antidepressant effects in the forced swim test in rat decreased immobility , suggesting a potential therapeutic effect as for the FAAH inhibitors [ ]. All these indirect strategies are of particular interest as they amplify cannabinoid receptor activation specifically where the endocannabinoids are produced, therefore increase signaling in defined brain structures [ ].
The growing consumption of cannabis and its derivatives in the population and particularly in the adolescent population represents a real public health challenge. A growing interest has been developed in cannabis and related compounds in research. Furthermore, considerable debates involving its legalization are still being conducted and this may have political consequences. Risk should not be neglected and it seems crucial to widely disseminate more scientific knowledge about this family of compounds before legalization becomes a normalization.
Recent research using genomic technology has investigated plasticity mechanisms taking place in brain structures involved in reward circuitry and highlighted epigenetic control of gene transcription see Section 3. An expected increase of scientific data in this field will help clarify the molecular mechanisms of drug abuse vulnerability.
Cannabinoid derivatives have positive effects on several other pathologies besides drug dependence. In conjunction, a combination of strategies may be foreseen, as this is the case in other pharmacological fields, with specific care to the dose and duration of treatments. Inventive therapeutic approaches for treating pain or dependence may also consider targeting heterodimers of cannabinoid and opioid receptors using antibodies or bivalent ligands or indirectly acting on both systems using dual enkephalinase and cannabinoid catabolic enzyme inhibitors [ , ].
Intensive research is now oriented toward such perspectives. To conclude, and as for the opiate compounds that are used as medication, in particular, to treat pain e.
Therefore, future investigations are necessary in order to propose optimal therapeutic approaches for managing complex diseases and promising strategies for reducing dependence. The ultimate goal is to propose innovative strategies to current treatments with increased safety usage. We would like to thank Dominique Massotte for constant support and fruitful discussions and Emma Stephens for English proof reading of the manuscript. Embed this code snippet in the HTML of your website to show this chapter.
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Open access peer-reviewed chapter Cannabinoids: June 15th DOI: Abstract This chapter aims at exploring the use and misuse of cannabinoids as it has become a major societal issue.
Keywords animal models cannabis dependence endocannabinoid pharmacology therapies. Cannabis as medication 1. Historical uses of cannabis Cannabis is a botanical genus belonging to annual plants from the Cannabaceae family. Psychological and systemic effects of cannabis People primarily use cannabis for its positive effect on mood. Current uses of medicinal cannabis Medicinal or therapeutic cannabis refers to preparations using Cannabis sativa for a pure medicinal purpose.
Pathologies and associated symptoms targeted by cannabinoids. The endogenous cannabinoid system In recent decades, the discovery and characterization of the endogenous cannabinoid system represents a great milestone for research in the field, with considerable efforts being given to create a better understanding of the mode of action of cannabinoids. Cannabinoid receptors Cannabinoid receptors are receptors that were discovered in the early s with CB1 and CB2 cloned from rat brain in and rat spleen in , respectively [ 51 — 53 ].
Endocannabinoid synthesis and degradation Two main endogenous ligands were discovered in the early s: Signaling pathways Several signaling pathways are activated by cannabinoid receptors and have been extensively reviewed [ 54 , 55 , 88 ]. Physiological roles of the endocannabinoids Endocannabinoids, by regulating the release of many neurotransmitters, act on various biological processes in the nervous, digestive, reproductive, pulmonary, and immune systems.
Cannabis misuse and dependence 3. Cannabis and adolescents The popularity of cannabis has grown substantially in recent years among young people. Dependence on cannabis As opposed to cocaine or heroin, cannabis has often been considered a less harmful drug with low dependence properties and minimal negative effects, but its addictive potential has long been questioned [ ].
Synthetic cannabinoids A more recent problem that has strongly increased the risks of drug use is the proliferation worldwide of new derivatives of synthetic cannabinoids.
Usefulness of Sweat Testing for the Detection of Cannabis Smoke
Nov 15, Cannabinoid hyperemesis syndrome (CHS) is a paradoxical condition in Other symptoms may include sweating, flushing, thirst, weight loss, and .. of regular marijuana use before CHS developed was ± years . fluid · Sweat · Hair · Plasma · Urine · Alternate matrix · Marijuana. 1 . OH-THC ng/ml (range –), and THCCOOH 26 ng/ml (range 14–46) were found 1 . Cannabinoids in Sweat. To date, there are no published data on the excretion of cannabinoids in sweat following controlled THC administration, although.