Acute Toxicity and Pharmacokinetic Profile of an EU-GMP-Certified Cannabis sativa L. in Rodents

Abstract

The conundrum of Cannabis sativa’s applications for therapeutical purposes is set apart by the hundreds of known and commercially available strains, the social, cultural and historical context, and the legalization of its use for medical purposes in various jurisdictions around the globe. In an era where targeted therapies are continuously being developed and have become the norm, it is imperative to conduct standardized, controlled studies on strains currently cultivated under Good Manufacturing Practices (GMP) certification, a standard that guarantees the quality requirements for modern medical and therapeutic use. Thus, the aim of our study is to evaluate the acute toxicity of a 15.6% THC: <1% CBD, EU-GMP certified, Cannabis sativa L. in rodents, following the OECD acute oral toxicity guidelines, and to provide an overview of its pharmacokinetic profile. Groups of healthy female Sprague-Dawley rats were treated orally with a stepwise incremental dose, each step using three animals. The absence or presence of plant-induced mortality in rats dosed at one step determined the next step. For the EU GMP-certified Cannabis sativa L. investigated, we determined an oral LD50 value of over 5000 mg/kg in rats and a human equivalent oral dose of ≈806.45 mg/kg. Additionally, no significant clinical signs of toxicity or gross pathological findings were observed. According to our data, the toxicology, safety and pharmacokinetic profile of the tested EU-GMP-certified Cannabis sativa L. support further investigations through efficacy and chronic toxicity studies in preparation for potential future clinical applications and especially for the treatment of chronic pain.

Exploring Cannabinoids with Enhanced Binding Affinity for Targeting the Expanded Endocannabinoid System: A Promising Therapeutic Strategy for Alzheimer’s Disease Treatment

“…Specifically, for JWH-133, we opted for a dosing range aligned with findings from short-term studies in the literature [ 23 , 24 , 60 ]. As for Cannabixir ® Medium Flos, our dosing decision was based on both the LD50 data and the favorable pharmacokinetic profile identified in our previous research [ 22 ]. JWH-133 (0.2 mg/kg), Cannabixir ® Medium Flos (2.5 mg/kg), donepezil (0.65 mg/kg), and a 0.1% aqueous suspension of CMC-Na used as a vehicle were administered via gavage at a volume of 0.5 mL/100 g of body weight.…”

“…The selection of JWH-133 and Cannabixir ® Medium Flos—an EU GMP-certified batch of a dried inflorescence of Cannabis sativa L.—as the drug candidates for our study was guided by scientific evaluation and the need to fill knowledge gaps. The Cannabixir ® Medium Flos was chosen due to its promising pharmacokinetic profile, which was thoroughly investigated in toxicity studies conducted by our research team [ 22 ]. Also, it has been subject to rigorous quality control procedures in accordance with EU-GMP standards.…”

JWH-182: a safe and effective synthetic cannabinoid for chemotherapy-induced neuropathic pain in preclinical models

“…The primary monitoring protocol and parameters were adapted from the Primary Observation (Irwin) Test in Rodents 80 . After receiving a single dose of JWH-182, each individual was monitored continuously for the first 24 h, monitoring toxicity parameters such as sedation, convulsions, motor incoordination and tremors, using a video-tracking system, and once a day, recording general health parameters, for the next 13 days, as described previously by our group 81 (Fig. 6 ).…”

“…A full necropsy was carried out on all individuals involved in acute and repeated dose toxicity studies following lethal injection, involving a careful examination of the external surface of the body, all openings, internal cavities and their contents. After gross necropsy, twenty-two internal organs were collected and histopathological analyzed as previously described by our team 81 (Fig. 6 ).…”

Preclinical Studies of Canagliflozin, a Sodium-Glucose Co-Transporter 2 Inhibitor, and Donepezil Combined Therapy in Alzheimer’s Disease

“…Biochemistry analysis was used to investigate the implications of SGLT2i canagliflozin and donepezil, under separate or combined 21-day treatment, on the primary organs responsible for drug metabolism (e.g., kidney and liver). A series of biochemical parameters (creatinine, aspartate transaminase (AST), alanine transaminase (ALT), total cholesterol, glucose, albumin, urea and total protein) were used, as previously described by our team [74].…”