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Endogenous Cannabinoid Receptors and Medical Cannabis
Published in Sahar Swidan, Matthew Bennett, Advanced Therapeutics in Pain Medicine, 2020
Complementing what is known about the molecular structure of THC and CBD, elucidating these cannabinoids’ biosynthesis and breakdown revealed a single parent chemical—geranyl-pyrophosphate—that derives not only other cannabinoids, but also the plant’s terpenes, chemical molecules that animals perceive as smells. Plant cannabinoids exist naturally in a non-psychoactive acid form, and each has its own unique bioactivity. Only upon exposure to air and heating does the loss of CO2 by decarboxylation change the living plant’s precursor acid form known as THCA into THC, cannabis’ only psychoactive molecule. The consumption and digestion of THC allowing subsequent liver metabolism results in 11 hydroxy THC, a more potent psychoactive cannabinoid known to also have a considerably longer effective half-life than does its precursor molecule, THC (Figure 4.7).Several natural and physiologic conditions influence the primary phytocannabinoids’ biosynthetic pathways (Smokereports.com).
Characteristics and Theories Related to Acute and Chronic Tolerance Development
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
One can only speculate about the mechanisms of sensitization or reverse tolerance to cannabis and its products. Speculation includes the following: 1) induction of enzymes converting THC to a pharmacologically more potent metabolite, 2) cumulation of THC or an active metabolite, 3) learned response, 4) increased sensitivity of tissues to THC. The first two points are supported by the observations that: 1) THC is converted to 11-hydroxy-THC in the body93 and this metabolite is equally or more active than THC;40 2) the pharmacological effects of THC were greater when it was administered intra-peritoneally than when it was injected subcu-taneously237 (i.e., the venous outflow from the peritoneum is primarily through the liver by way of the portal circulation); 3) the rate of disappearance of THC (presumably by biotransformation in the liver) is more rapid in human chronic marijuana smokers compared to human subjects who have not previously used cannabis products;198 and 4) the metabolites of THC persist for one week or longer in human volunteers.198
The Solution to the Medicinal Cannabis Problem
Published in Michael E. Schatman, Ethical Issues in Chronic Pain Management, 2016
After initial investigations of analgesic effects by Noyes et al. in the 1970s (44–46), THC, as Marinol®, was approved for treatment of chemotherapy-associated nausea in 1985, and AIDS wasting in 1992. Results from pain studies have been mixed. Marinol was employed in two studies of central and peripheral neuropathic pain with oral doses up to 25 mg without clear benefit on pain or allodynia, and with prominent side effects (47,48). In a similar study of two- to five-year duration showed early benefits on pain that were not maintained (49). In a Swedish study (50) of Marinol doses to up to 10 mg/d in 24 multiple sclerosis patients with central neuropathic pain, median numerical pain scale in final week was reduced in the Marinol group (p = 0.02), and median pain relief was improved over placebo (p = 0.035). Moreover, pure oral THC in isolation may induce intoxicating and sedative complaints (51), as well as dysphoria, perhaps attributable to metabolism of THC to 11-hydroxy-THC. An RCT of Marinol in 40 post-operative patients failed to demonstrate analgesic efficacy (51a). When queried in surveys comparing Marinol to whole cannabis products, most medical patients who have utilized both prefer herbal cannabis (20).
Using measured cannabidiol and tetrahydrocannabinol metabolites in urine to differentiate marijuana use from consumption of commercial cannabidiol products
Published in Clinical Toxicology, 2021
Melissa M. Goggin, Gregory C. Janis
THC and CBD are isomers which to some extent share parallel metabolic pathways as presented in Figure 1. THC is primarily metabolized first to 11-hydroxy-THC, then further to 11-nor-carboxy-Δ9-THC. THC and its metabolites are further metabolized by conjugation with glucuronic acid for urinary excretion. The metabolite 11-COOH-THC-glucuronide is the most abundant metabolite of THC found in the urine of marijuana users, and is typically the only biomarker monitored in urine drug tests detecting marijuana use [9]. CBD, despite being structurally analogous to THC, has a more variable metabolic pathway. CBD is also hydroxylated, carboxylated, and glucuronidated without phase I transformation [10]. Unlike THC, where mainly the 11-COOH-THC metabolite is observed in urine, CBD-glucuronide, as well as 7-COOH-CBD-glucuronide, have been reported as major urinary metabolites of CBD [10]. In addition to CBD and 7-COOH-CBD, 7-hydroxy-cannabidiol has also been observed in the plasma of subjects following controlled CBD studies [11].
Disposition of oral delta-9 tetrahydrocannabinol (THC) in children receiving cannabis extracts for epilepsy
Published in Clinical Toxicology, 2020
George Sam Wang, David W A Bourne, Jost Klawitter, Cristina Sempio, Kevin Chapman, Kelly Knupp, Michael F. Wempe, Laura Borgelt, Uwe Christians, Kennon Heard, Lalit Bajaj
Each blood sample (∼4 mL) was collected in a K2EDTA blood collection tube and immediately placed on an ice bath for a maximum of 2 hours. Samples were centrifuged for 3 minutes, at 20 °C, at 1400 g and stored at −70 °C. Cannabinoid plasma concentrations were determined using a previously published method [7]. In brief, the assay was based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) coupled with atmospheric pressure chemical ionization. Online extraction technology was used to automatically up-concentrate cannabinoids for increased sensitivity and robustness. The API 5000 mass spectrometer (ABSciex, Concord, ON, Canada) was operated in positive multiple reaction monitoring mode (MRM). THC (9-delta tetrahydrocannabinol), 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THC-COOH), 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide (THC-C-gluc) and CBD were quantified. The assay had a lower limit of quantification of 0.39 ng/mL for THC, THC-COOH and CBD and 0.78 ng/mL for 11-OH-THC in plasma. The inter- and intra-day accuracy and imprecision were within 85–115% and less than 15% except at lower limit of quantification which was within 80–120% for accuracy and better than 20% for imprecision.
Aversiveness and Meaningfulness of Uncomfortable Experiences with Edible Cannabis
Published in Journal of Psychoactive Drugs, 2019
Stacey Farmer, Melissa N. Slavin, Mallory J. E. Loflin, Rachel Luba, Mitch Earleywine
Different methods of cannabis administration contribute to different effects, including the latency of onset and duration. For example, when inhaled, the primary intoxicating molecule in cannabis, Δ 9-THC, is absorbed through the lungs and reaches the brain quickly. Absorption of THC in the stomach or mucous membranes of the mouth is a slower process than in the lungs. Ingested cannabis enters the stomach, gets metabolized by the liver, and then reaches the brain via the bloodstream. Peak effects of ingested cannabis tend to occur one to two hours post ingestion compared to five to ten minutes post inhalation for smoking (Huestis 2007). Differences in bioavailability and rate of absorption in the stomach contribute to highly variable psychoactive effects of ingested cannabis (Favrat et al. 2005). The conversion of THC to 11-hydroxy-THC (which crosses the blood-brain barrier more readily) contributes to edibles’ more pronounced effects as well. (Vandrey et al. 2015).