A multitude of roles for the endogenous cannabinoid system has been proposed by recent research efforts. A large number of endogenous cannabinoid neurotransmitters or endocannabinoids have been identified, and the CB-1 and CB-2 cannabinoid receptors have been characterized. The presence of other receptors, transporters, and enzymes responsible for the synthesis or metabolism of endocannabinoids are becoming known at an extraordinary pace. The complex functions of this novel system have created multiple new targets for pharmacotherapies. Research has focused on separating the behavioral psychoactive effects of cannabinoid agonists from therapeutic effects. These efforts have been largely unsuccessful. Another strategy centers on changing the pharmacokinetics of drug delivery to maximize therapeutic effect and minimize cognitive and subjective drug effects. Development of oral, rectal, and transdermal medications of synthetic Δ9-tetrahydrocannabinol (THC)1) are examples of this type of approach. Additionally, the potential therapeutic benefits of administering unique combinations of cannabinoids and other chemicals present in the plant Cannabis sativa is being investigated by the oromucosal route. There also is strong interest in medications based on antagonizing endocannabinoid action. 







We have shown that the cardiovascular and subjective effects of cannabis are blocked by rimonabant, the first CB-1 cannabinoid-receptor antagonist, documenting that CB-1 receptors mediate these effects of smoked cannabis in humans. It is clear that the endogenous cannabinoid system plays a critical role in physiological and behavioral processes, and extensive research effort is being devoted to the biology, chemistry, pharmacology, and toxicology of cannabinoids.

Cannabis is one of the oldest and most commonly abused drugs in the world, and its use is associated with pathological and behavioral toxicity. Thus, it is important to understand cannabinoid pharmacokinetics and the disposition of cannabinoids into biological fluids and tissues. Understanding the pharmacokinetics of a drug is essential to understanding the onset, magnitude, and duration of its pharmacodynamic effects, maximizing therapeutic and minimizing negative side effects.

Cannabinoid pharmacokinetics encompasses absorption after diverse routes of administration and from different drug formulations, analyte distribution throughout the body, metabolism by the liver and extra-hepatic tissues, and elimination in the feces, urine, sweat, oral fluid, and hair. Pharmacokinetic processes are dynamic, may change over time, and may be affected by the frequency and magnitude of drug exposure. The many contributions to our understanding of cannabinoid pharmacokinetics from the 1970s and 1980s are reviewed, and the findings of recent research expanding upon this knowledge are detailed. Cannabinoid pharmacokinetics research is challenging due to low analyte concentrations, rapid and extensive metabolism, and physico-chemical characteristics hindering the separation of drugs of interest from biological matrices and from each other. Drug recovery is reduced due to adsorption of compounds of interest to multiple surfaces. Much of the early cannabinoid data are based on radiolabeled cannabinoids yielding highly sensitive, but less specific, measurement of individual cannabinoid analytes. New extraction techniques and mass-spectrometric (MS) developments now permit highly sensitive and specific measurement of cannabinoids in a wide variety of biological matrices, improving our ability to characterize cannabinoid pharmacokinetics.

Cannabis sativa contains over 421 different chemical compounds, including over 60 cannabinoids [1-3]. Cannabinoid plant chemistry is far more complex than that of pure THC, and different effects may be expected due to the presence of additional cannabinoids and other chemicals. Eighteen different classes of chemicals, including nitrogenous compounds, amino acids, hydrocarbons, carbohydrates, terpenes, and simple and fatty acids, contribute to the known pharmacological and toxicological properties of cannabis. THC is usually present in Cannabis plant material as a mixture of monocarboxylic acids, which readily and efficiently decarboxylate upon heating. THC decomposes when exposed to air, heat, or light; exposure to acid can oxidize the compound to cannabinol (CBN), a much less-potent cannabinoid. In addition, cannabis plants dried in the sun release variable amounts of THC through decarboxylation. During smoking, more than 2,000 compounds may be produced by pyrolysis. The pharmacokinetics of THC, the primary psychoactive component of cannabis, its metabolites ‘11-hydroxytetrahydrocannabinol’ (11-OH-THC) and ‘11-nor-9-carboxy-tetrahydrocannabinol’ (THC-COOH)]2), and another cannabinoid present in high concentration, cannabidiol (CBD), a non-psychoactive agent with an interesting array of potential therapeutic indications, are included. Mechoulam et al. elucidated the structure of THC in 1964, enabling studies of the drug's pharmacokinetics [4]. THC, containing no N-atom, but with two stereogenic centers in a trans configuration, has been described by two different atom-numbering systems, either the dibenzopyran (or Δ9) or the monoterpene (or Δ1) system. In this review, the dibenzopyran (Δ9) system is employed.

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Human Cannabinoid Pharmacokinetics

Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) of the phenylacetic acid class. When given orally the absorption of diclofenac is rapid and complete. Diclofenac binds extensively to plasma albumin. The area under the plasma concentration-time curve (AUC) of diclofenac is proportional to the dose for oral doses between 25 to 150mg. Substantial concentrations of drug are attained in synovial fluid, which is the proposed site of action for NSAIDs. Concentration-effect relationships have been established for total bound, unbound and synovial fluid diclofenac concentrations. Diclofenac is eliminated following biotransformation to glucoroconjugated and sulphate metabolites which are excreted in urine, very little drug is eliminated unchanged. The excretion of conjugates may be related to renal function. Conjugate accumulation occurs in end-stage renal disease; however, no accumulation is apparent upon comparison of young and elderly individuals. Dosage adjustments for the elderly, children or for patients with various disease states (such as hepatic disease or rheumatoid arthritis) may not be required. Significant drug interactions have been demonstrated for aspirin (acetylsalicylic acid), lithium, digoxin, methotrexate, cyclosporin, cholestyramine and colestipol.

Clinical pharmacokinetics of diclofenac : Therapeutic insights and pitfalls

The effects of the South American psychotropic beverage ayahuasca on subjective and cardiovascular variables and urine monoamine metabolite excretion were evaluated, together with the drug's pharmacokinetic profile, in a double-blind placebo-controlled clinical trial. This pharmacologically complex tea, commonly obtained from Banisteriopsis caapi and Psychotria viridis, combines N,N-dimethyltryptamine (DMT), an orally labile psychedelic agent showing 5-hydroxytryptamine2A agonist activity, with monoamine oxidase (MAO)-inhibiting beta-carboline alkaloids (harmine, harmaline, and tetrahydroharmine). Eighteen volunteers with prior experience in the use of psychedelics received single oral doses of encapsulated freeze-dried ayahuasca (0.6 and 0.85 mg of DMT/kg of body weight) and placebo. Ayahuasca produced significant subjective effects, peaking between 1.5 and 2 h, involving perceptual modifications and increases in ratings of positive mood and activation. Diastolic blood pressure showed a significant increase at the high dose (9 mm Hg at 75 min), whereas systolic blood pressure and heart rate were moderately and nonsignificantly increased. Cmax values for DMT after the low and high ayahuasca doses were 12.14 ng/ml and 17.44 ng/ml, respectively. Tmax (median) was observed at 1.5 h after both doses. The Tmax for DMT coincided with the peak of subjective effects. Drug administration increased urinary normetanephrine excretion, but, contrary to the typical MAO-inhibitor effect profile, deaminated monoamine metabolite levels were not decreased. This and the negligible harmine plasma levels found suggest a predominantly peripheral (gastrointestinal and liver) site of action for harmine. MAO inhibition at this level would suffice to prevent first-pass metabolism of DMT and allow its access to systemic circulation and the central nervous system.

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Human Pharmacology of Ayahuasca: Subjective and Cardiovascular Effects, Monoamine Metabolite Excretion, and Pharmacokinetics

The combination of alcohol and cocaine is popular among drug users, perhaps because of more intense feelings of 'high' beyond that perceived with either drug alone, less intense feelings of alcohol-induced inebriation and tempering of discomfort when coming down from a cocaine 'high'. A review is presented of the medical literature on psychological and somatic effects and consequences of combined use of alcohol and cocaine in man. The search was carried out with Medline, the Science Citation Index/Web of Science and Toxline. Exclusion and inclusion criteria for this search are identified. There is generally no evidence that the combination of the two drugs does more than enhance additively the already strong tendency of each drug to induce a variety of physical and psychological disorders. A few exceptions must be noted. Cocaine consistently antagonizes the learning deficits, psychomotor performance deficits and driving deficits induced by alcohol. The combination of alcohol and cocaine tends to have greater-than-additive effects on heart rate, concomitant with up to 30% increased blood cocaine levels. Both prospective and retrospective data further reveal that co-use leads to the formation of cocaethylene, which may potentiate the cardiotoxic effects of cocaine or alcohol alone. More importantly, retrospective data suggest that the combination can potentiate the tendency towards violent thoughts and threats, which may lead to an increase of violent behaviours.

Effects of concurrent use of alcohol and cocaine

Background
Withdrawal is a necessary step prior to drug-free treatment or as the endpoint of long-term substitution treatment

Objectives
To assess the effectiveness of interventions involving the use of alpha2-adrenergic agonists compared with placebo, reducing doses of methadone, symptomatic medications, or an alpha2-adrenergic agonist regimen different to the experimental intervention, for the management of the acute phase of opioid withdrawal Outcomes included the withdrawal syndrome experienced, duration of treatment, occurrence of adverse effects, and completion of treatment

Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1946 to November week 2, 2015), EMBASE (January 1985 to November week 2, 2015), PsycINFO (1806 to November week 2, 2015), Web of Science, and reference lists of articles

Selection criteria
Randomised controlled trials comparing alpha2-adrenergic agonists (clonidine, lofexidine, guanfacine, tizanidine) with reducing doses of methadone, symptomatic medications or placebo, or comparing different alpha2-adrenergic agonists to modify the signs and symptoms of withdrawal in participants who were opioid dependent

Data collection and analysis
We used standard methodological procedures expected by The Cochrane Collaboration

Main results
We included 26 randomised controlled trials involving 1728 participants Six studies compared an alpha2-adrenergic agonist with placebo, 12 with reducing doses of methadone, four with symptomatic medications, and five compared different alpha2-adrenergic agonists We assessed 10 studies as having a high risk of bias in at least one of the methodological domains that were considered

We found moderate-quality evidence that alpha2-adrenergic agonists were more effective than placebo in ameliorating withdrawal in terms of the likelihood of severe withdrawal (risk ratio (RR) 032, 95% confidence interval (CI) 018 to 057; 3 studies; 148 participants) We found moderate-quality evidence that completion of treatment was significantly more likely with alpha2-adrenergic agonists compared with placebo (RR 195, 95% CI 134 to 284; 3 studies; 148 participants)

Peak withdrawal severity may be greater with alpha2-adrenergic agonists than with reducing doses of methadone, as measured by the likelihood of severe withdrawal (RR 118, 95% CI 081 to 173; 5 studies; 340 participants; low quality), and peak withdrawal score (standardised mean difference (SMD) 022, 95% CI -002 to 046; 2 studies; 263 participants; moderate quality), but these differences were not significant and there is no significant difference in severity when considered over the entire duration of the withdrawal episode (SMD 013, 95% CI -024 to 049; 3 studies; 119 participants; moderate quality) The signs and symptoms of withdrawal occurred and resolved earlier with alpha2-adrenergic agonists The duration of treatment was significantly longer with reducing doses of methadone (SMD -107, 95% CI -131 to -083; 3 studies; 310 participants; low quality) Hypotensive or other adverse effects were significantly more likely with alpha2-adrenergic agonists (RR 192, 95% CI 119 to 310; 6 studies; 464 participants; low quality), but there was no significant difference in rates of completion of withdrawal treatment (RR 085, 95% CI 069 to 105; 9 studies; 659 participants; low quality)

There were insufficient data for quantitative comparison of different alpha2-adrenergic agonists Available data suggest that lofexidine does not reduce blood pressure to the same extent as clonidine, but is otherwise similar to clonidine

Authors' conclusions
Clonidine and lofexidine are more effective than placebo for the management of withdrawal from heroin or methadone We detected no significant difference in efficacy between treatment regimens based on clonidine or lofexidine and those based on reducing doses of methadone over a period of around 10 days, but methadone was associated with fewer adverse effects than clonidine, and lofexidine has a better safety profile than clonidine

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Alpha2‐adrenergic agonists for the management of opioid withdrawal

The effects of 100 mg of intranasal cocaine (COC) in acute alcohol intoxication (1 g/kg) was assessed in nine experienced and non-dependent healthy volunteers in a double-blind, controlled, randomized, cross-over clinical trial. Alcohol alone impaired psychomotor performance, whereas COC alone produced subjective effects related to euphoria and well-being, improved the reaction time and increased heart rate and blood pressure. The combination of COC and alcohol induced a nonsignificant decrease in the subjective feelings of drunkeness, an increase in COC-induced euphoria, a significant improvement in alcohol-related changes in psychomotor performance and a marked increase in heart rate. Subjects experienced subjective and performance effects that could be self-interpreted as more pleasant compared to the effects of alcohol alone. When alcohol was given simultaneously, COC plasma levels were higher (possibly as a result of an inhibition of hepatic metabolism of COC produced by alcohol), norcocaine plasma levels almost doubled and cocaethylene was detected in plasma, so that its basic pharmacokinetic profile could be described. The simultaneous use of both drugs produced changes in heart rate and blood pressure that could increase the risk of cardiovascular toxicity associated with the use of COC.

Alcohol and cocaine interactions in humans.

The efficacy of a rapid detoxification schedule (8 to 10 days) with clonidine or methadone was evaluated in 30 patients addicted to heroin. The dose of study drug was preestablished according to the subject's weight and the amount of opioid consumption, and the total daily dose was reduced by approximately 15% during the study. All subjects completed the detoxification program and stayed in the hospital for at least 12 days. Clonidine and methadone therapies proved to be highly effective. There was a marked reduction in anxiety during opioid detoxification, although subjects' experiences differed according to the drug used. On the day of discharge, subjects who had received methadone still had attenuated withdrawal symptoms, whereas there were no such symptoms in the clonidine group. Muscular aching, flatulence, and daily drowsiness were more common among subjects in the methadone group, while subjects in the clonidine group had more sleep disturbances and weeping. Syncopal episodes and bradycardia occurred more frequently in the clonidine group.



Clinical Pharmacology and Therapeutics (1985) 38, 336–341; doi:10.1038/clpt.1985.182

Efficacy of clonidine and of methadone in the rapid detoxification of patients dependent on heroin.

Subject expectancy on cannabis effects was assessed in a balanced-placebo study in experienced consumers who smoked cigarettes containing hashish (200 mg hashish with 11.5% THC per 1 g tobacco cigarette) (n = 24) or placebo (n = 24). Although statistically significant differences were not found between subjects who received the drug with positive or negative expectancy, a tendency toward more marked subjective effects was shown in subjects who expected and received the drug. This trend was supported by the significant difference observed in the mean AUC0-25 of the heart rate between subjects who smoked hashish with positive or negative expectancies. In subjects who received hashish, the sum AUC0-205 of THC and COOH-THC of those who expected the drug was greater than in those who did not expect it (p less than 0.05). The ratio THC/COOH-THC AUC0-205 was lower in those with positive expectancy than in those with negative expectancy (p less than 0.02). An increased metabolism of THC was shown in subjects with positive expectancy. Positive expectancy induced powerful subjective effects in the absence of active THC. Expectancy appeared to influence smoking behavior, as seen in higher plasma levels of cannabinoids for the group who received the drug.

Effect of subject expectancy on the THC intoxication and disposition from smoked hashish cigarettes.

Personality of healthy volunteers participating in phase I clinical trials

A sensitive and reliable gas chromatography/mass spectrometric assay for diclofenac in plasma using selected ion monitoring is described. The procedure is based on the acidic extraction of diclofenac and ketoprofen (internal standard) with toluene. Both compounds are converted into their ethyl ester derivatives with ethanol containing 0.5% (v/v) sulphuric acid. No internal cyclization to indolone side product is produced in these conditions. The ions monitored are m/z 214 for diclofenac and m/z 209 for ketoprofen. The main recovery of diclofenac added to plasma has been estimated around 84.6% (120 ng ml−1, n = 4). The intra-assay and inter-assay variability were 1.9% and 10.3%, respectively. The sensitivity was lower than 2 ng ml−1. The applicability of the assays to study the bioavailability of two formulations in a multiple-dosage trial is described. The method has been used in more than 600 determinations without any interference.

B. Ugena

Papers

Alcohol and cocaine interactions in humans.

Efficacy of clonidine and of methadone in the rapid detoxification of patients dependent on heroin.

Effect of subject expectancy on the THC intoxication and disposition from smoked hashish cigarettes.

Personality of healthy volunteers participating in phase I clinical trials

Detection and quantification of non‐steroidal anti‐inflammatory agents by gas chromatography/mass spectrometry: Diclofenac