Journal Article•
Tetrahydrocannabinol metabolism in man
01 Jan 1973-Drug Metabolism and Disposition (American Society for Pharmacology and Experimental Therapeutics)-Vol. 1, Iss: 1, pp 461-468
TL;DR: These studies provide direct evidence that after the administration of marihuana or hashish, the Δ9-THC is rapidly converted in man to 11-OH-Δ9- THC, which is responsible for the majority of the pharmacologic effects.
Abstract: In man the pharmacologic effects elicited afterΔ 9-THC administration appear to correlate with the plasma levels of metabolites of Δ9-THC. 11-OH-Δ9-THC produces pharmacologic effects in man similar to those seen after Δ9-THC administration. This suggests that Δ9-THC is converted in vivo to 11-OH-Δ9-THC and that the latter is the active compound responsible for the effects of marihuana and hashish. The observation that the subjective effects of 11-OH-Δ9-THC administered iv are almost immediate in onset, whereas the effects of the same dose of Δ9-THC administered in a like fashion showed a delayed onset, lends additional support for this hypothesis. The quantitative and qualitative similarity of the excretory and metabolic patterns for Δ9-THC and 11-OH-Δ9-THC in man further support this hypothesis (table 5).
In one subject who served as his own control (a typical cross-over experiment), the pharmacologic effects produced by 11-OH-Δ9-THC were comparable to those seen after Δ9-THC administration. In a second subject, 11-OH-Δ9-THC appeared to be twice as potent as Δ9-THC. It thus appears that in man these compounds vary from being almost equipotent to twice as active, differing only in their onset and duration of action. In a third subject, Δ9-THC produced only minimal effects. It appears as if the responses to a fixed 1-mg dose were correlated to the patients’ weights. These results are consistent with the effects in mice (16), where 11-OH-Δ9-THC has been reported to be about two times more potent than Δ9-THC. In summary, these studies provide direct evidence that after the administration of marihuana or hashish, the Δ9-THC is rapidly converted in man (presumably by microsomal hydroxylating enzymes) to 11-OH-Δ9-THC, which is responsible for the majority of the pharmacologic effects.
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TL;DR: Recent advances in understanding of the endocannabinoid system are highlighted and CNS disorders that may benefit from the therapeutic effects of cannabinoid treatment are indicated.
Abstract: The major psychoactive constituent of Cannabis sativa, delta(9)-tetrahydrocannabinol (delta(9)-THC), and endogenous cannabinoid ligands, such as anandamide, signal through G-protein-coupled cannabinoid receptors localised to regions of the brain associated with important neurological processes Signalling is mostly inhibitory and suggests a role for cannabinoids as therapeutic agents in CNS disease where inhibition of neurotransmitter release would be beneficial Anecdotal evidence suggests that patients with disorders such as multiple sclerosis smoke cannabis to relieve disease-related symptoms Cannabinoids can alleviate tremor and spasticity in animal models of multiple sclerosis, and clinical trials of the use of these compounds for these symptoms are in progress The cannabinoid nabilone is currently licensed for use as an antiemetic agent in chemotherapy-induced emesis Evidence suggests that cannabinoids may prove useful in Parkinson's disease by inhibiting the excitotoxic neurotransmitter glutamate and counteracting oxidative damage to dopaminergic neurons The inhibitory effect of cannabinoids on reactive oxygen species, glutamate and tumour necrosis factor suggests that they may be potent neuroprotective agents Dexanabinol (HU-211), a synthetic cannabinoid, is currently being assessed in clinical trials for traumatic brain injury and stroke Animal models of mechanical, thermal and noxious pain suggest that cannabinoids may be effective analgesics Indeed, in clinical trials of postoperative and cancer pain and pain associated with spinal cord injury, cannabinoids have proven more effective than placebo but may be less effective than existing therapies Dronabinol, a commercially available form of delta(9)-THC, has been used successfully for increasing appetite in patients with HIV wasting disease, and cannabinoid receptor antagonists may reduce obesity Acute adverse effects following cannabis usage include sedation and anxiety These effects are usually transient and may be less severe than those that occur with existing therapeutic agents The use of nonpsychoactive cannabinoids such as cannabidiol and dexanabinol may allow the dissociation of unwanted psychoactive effects from potential therapeutic benefits The existence of other cannabinoid receptors may provide novel therapeutic targets that are independent of CB(1) receptors (at which most currently available cannabinoids act) and the development of compounds that are not associated with CB(1) receptor-mediated adverse effects Further understanding of the most appropriate route of delivery and the pharmacokinetics of agents that act via the endocannabinoid system may also reduce adverse effects and increase the efficacy of cannabinoid treatment This review highlights recent advances in understanding of the endocannabinoid system and indicates CNS disorders that may benefit from the therapeutic effects of cannabinoid treatment Where applicable, reference is made to ongoing clinical trials of cannabinoids to alleviate symptoms of these disorders
239 citations
TL;DR: Interactions between agents commonly prescribed for patients with HIV and recreational drugs can occur and may be associated with serious clinical consequences, and Clinicians should encourage open dialog with their patients on this topic.
Abstract: OBJECTIVE:To summarize existing data regarding potential interactions between recreational drugs and drugs commonly used in the management of HIV-positive patients.DATA SOURCES:Information was obtained via a MEDLINE search (1966–August 2002) using the MeSH headings human immunodeficiency virus, drug interactions, cytochrome P450, medication names commonly prescribed for the management of HIV and related opportunistic infections, and names of commonly used recreational drugs. Abstracts of national and international conferences, review articles, textbooks, and references of all articles were also reviewed.STUDY SELECTION AND DATA EXTRACTION:Literature on pharmacokinetic interactions was considered for inclusion. Pertinent information was selected and summarized for discussion. In the absence of specific data, prediction of potential clinically significant interactions was based on pharmacokinetic and pharmacodynamic properties.RESULTS:All protease inhibitors (PIs) and nonnucleoside reverse transcriptase inh...
140 citations
TL;DR: Omnisol gives a quick onset of pharmacodynamic effects in healthy volunteers, which implies a rapid initiation of therapeutic effects in patients and showed promising PK and PD characteristics.
Abstract: WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Cannabis based medicines are registered as a treatment for various indications, such as pain and spasms in multiple sclerosis (MS) patients, and anorexia and nausea in patients with HIV or receiving cancer treatment.
• the pharmacokinetics of the various administration routes of cannabis and cannabis based medicines are variable and dosing is hard to regulate.
WHAT THIS STUDY ADDS
• Namisol is a new tablet containing pure THC (>98%) that has a beneficial pharmacokinetic profile after oral administration.
• Namisol gives a quick onset of pharmacodynamic effects in healthy volunteers, which implies a rapid initiation of therapeutic effects in patients.
AIMS Among the main disadvantages of currently available Δ9-tetrahydrocannabinol (THC) formulations are dosing difficulties due to poor pharmacokinetic characteristics. Namisol® is a novel THC formulation, designed to improve THC absorption. The study objectives were to investigate the optimal administration route, pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of Namisol®.
METHODS This first in human study consisted of two parts. Panel I included healthy males and females (n = 6/6) in a double-blind, double-dummy, randomized, crossover study with sublingual (crushed tablet) and oral administration of Namisol® (5 mg THC). Based on these results, male and female (n = 4/5) participants from panel I received oral THC 6.5 and 8.0 mg or matching placebo in a randomized, crossover, rising dose study during panel II. PD measurements were body sway; visual analogue scales (VAS) mood, psychedelic and heart rate. THC and 11-OH-THC population PK analysis was performed.
RESULTS Sublingual administration showed a flat concentration profile compared with oral administration. Oral THC apparent t1/2 was 72–80 min, tmax was 39–56 min and Cmax 2.92–4.69 ng ml−1. THC affected body sway (60.8%, 95% CI 29.5, 99.8), external perception (0.078 log mm, 95% CI 0.019, 0.137), alertness (−2.7 mm, 95% CI −4.5, −0.9) feeling high (0.256 log mm, 95% CI 0.093, 0.418) and heart rate (5.6 beats min–1, 95% CI 2.7, 6.5). Namisol® was well tolerated.
CONCLUSIONS Oral Namisol® showed promising PK and PD characteristics. Variability and tmax of THC plasma concentrations were smaller for Namisol® than reported for studies using oral dronabinol and nabilone. This study was performed in a limited number of healthy volunteers. Therefore, future research on Namisol® should study clinical effects in patient populations.
74 citations
TL;DR: Results suggested that licit sources of methamphetamine are expected to be only of significance in populations where its illicit use is minor, and that further research is required to assess the importance of fecal elimination of 11-nor-9-carboxy-tetrahydrocannabinol.
70 citations
TL;DR: An elimination half‐life of Δ1‐tetrahydrocannabinol in blood plasma of about 4 days is more in line with apparent half‐ life excretion of Δ 1‐teticannabinol metabolites in the urine of chronic marijuana smokers.
Abstract: The aim of this study was to characterize the elimination half-life of delta 1-tetrahydrocannabinol in blood plasma in chronic marijuana users. The subjects smoked four cigarettes during a two day period, each cigarette containing 15 mg deuterium-labelled delta 1-tetrahydrocannabinol. The plasma concentrations of deuterium-labelled tetrahydrocannabinol were measured for 13 days using gas chromatography-mass spectrometry equipped with selected ion monitoring. The elimination half-life for delta 1-tetrahydrocannabinol in blood plasma was calculated to be 4.1 +/- 1.1 days (range 2.9-5.0 days) from the two week plasma level curves. Albeit the present results are based upon a small sample, an elimination half-life of delta 1-tetrahydrocannabinol in blood plasma of about 4 days is more in line with apparent half-life excretion of delta 1-tetrahydrocannabinol metabolites in the urine of chronic marijuana smokers.
70 citations