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Endogenous Cannabinoid Receptors and Medical Cannabis
Published in Sahar Swidan, Matthew Bennett, Advanced Therapeutics in Pain Medicine, 2020
Edible cannabis products come in many varieties, from infused chocolate and candies, to cookies and sodas. Cannabis tinctures suspended in alcohol or glycerin, similar to those of the last century, are widely available and can be added to food products or taken directly. Edible ingestion results in not only the longest time to onset, but also the longest duration of effect. The prolonged time to onset means naïve users may mistakenly believe that they have already experienced a full effect long before they actually do, and so they may then ingest even more cannabis. This is the most common way to an acutely uncomfortable experience that may induce intense paranoia that not infrequently brings an intoxicated dysphoric patient to the emergency room. The consequences are compounded by the more intense psychoactivity of 11-hydroxy-THC, the ∆-9THC metabolite produced by liver metabolism during digestion. The duration of effect from edibles lends itself to their use for overnight treatments, when extended relief and sleep assistance are primary goals. Many pain patients who are cannabis-savvy also report using low-dose edibles to maintain a baseline of analgesia, with inhalation for breakthrough pain.
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.
Cannabis and Epilepsy
Published in Journal of Dual Diagnosis, 2020
In 1949, Davis et al. described one of the earliest clinical trials using THC in the treatment of five children with epilepsy, in which two isomeric THC homologs were tested (Davis & Ramsey, 1949). The modern scientific investigations into the use of cannabinoids in treating epilepsy began to gain greater interest in the 1970s. In 1975, in a case report, Consroe and Buchsbaum described successfully controlling seizures in a 24-year-old when smoking marijuana was added to using phenobarbital and phenytoin (Consroe, Wood, & Buchsbaum, 1975). Several experiments in the 1970s and 1980s described the antiepileptic properties of various cannabinoids. In 1976, a study described anticonvulsive potencies of various cannabinoids in the maximal electroshock test and bar-walk test. In order of potency, these cannabinoids were listed as 11-hydroxy-THC (14 mg/kg) > delta-8-THC (83 mg/kg) > delta-9-THC (101 mg/kg) > CBD (118/mg/kg) > CBN (230 mg/kg; Karler & Turkanis, 1976). The protective index (comparison of therapeutic effect to underlying toxicity) was thought to be highest with CBD, and it was comparable to phenobarbital. In 1977, Consroe et al. described the proconvulsant effects of low-dose THC on a population of New Zealand white rabbits. These seizures were later controlled with carbamazepine, diazepam, and phenytoin and, surprisingly, with CBD (Consroe, Martin, & Eisenstein, 1977). Because of the lack of toxicity and anticonvulsant properties seen in these early studies, this led to further investigation into the use of CBD as an antiepileptic in the following decades.