Toxicological Evaluation and Pain Assessment of Four Minor Cannabinoids Following 14-Day Oral Administration in Rats

Kulpa, Justyna; Henderson, Rayetta G.; Schwotzer, Daniela; Dye, Wendy; Trexler, Kristen R.; McDonald, Jacob; Lefever, Timothy W.; Bonn-Miller, Marcel O.

doi:10.1089/can.2023.0049

Cited by 4 publications

(6 citation statements)

References 29 publications

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“…Previous studies have conflicting results regarding the cannabimimetic effects of CBN. This is likely due to differences in the route of administration; injection of CBN induced catalepsy, analgesia and hypolocomotion, key cannabimimetic behaviors, while oral administration did not (Takahashi and Karniol, 1975;Formukong et al, 1988;El-Alfy et al, 2010;Kulpa et al, 2023). We do not yet know how CBN affects chronic pain behaviors.…”

Section: Introductionmentioning

confidence: 96%

“…When injected, THCV has been shown to elicit cannabimimetic behaviors in male mice, though to a lower degree than THC (Zagzoog et al, 2020). As previously mentioned with the other minor cannabinoids, the route of administration is essential as cannabimimetic behaviors were not observed when THCV was given orally (Kulpa et al, 2023). Δ8-THC is an isomer of Δ9-THC.…”

Section: Introductionmentioning

confidence: 97%

“…However, Δ8-THC has less affinity to CB1 than THC, while both compounds (Tagen and Klumpers, 2022). Δ8-THC has also been shown to induce the cannabinoid tetrad in rodents when injected systemically but not when given orally; these studies are limited since the effects of Δ8-THC on female rodents were not assessed (Dewey et al, 1970;El-Alfy et al, 2010;Tagen and Klumpers, 2022;Kulpa et al, 2023). Despite the breadth of research on Δ8-THC, there has yet to be an investigation into its effects on chronic pain and cannabimimetic behaviors in female mice.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Select Minor Cannabinoids fromCannabis sativaare Cannabimimetic and Antinociceptive in a Mouse Model of Chronic Neuropathic Pain

Schwarz,

Kobeci,

Mancuso

et al. 2024

J Pharmacol Exp Ther

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Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Select Minor Cannabinoids fromCannabis sativaare Cannabimimetic and Antinociceptive in a Mouse Model of Chronic Neuropathic Pain

Schwarz,

Kobeci,

Mancuso

et al. 2024

J Pharmacol Exp Ther

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“…The management of pain remains a major health concern globally, and due in part to the opioid epidemic, there is a growing interest in the development of novel compounds that can be used to treat and manage pain [1][2][3][4]. Research has been conducted on the use of cannabis or individual cannabinoids to treat pain, including ∆ 9 -tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), and cannabinol (CBN) [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. In addition to these cannabinoids, cannabichromene (CBC) is a non-psychoactive minor cannabinoid (cannabinoid compounds found in the cannabis plant at low concentrations) that has been reported to have anti-microbial and anti-inflammatory activities [20][21][22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Antinociceptive Effects of Cannabichromene (CBC) in Mice: Insights from von Frey, Tail-Flick, Formalin, and Acetone Tests

Raup-Konsavage,

Sepulveda,

Wang

et al. 2023

Biomedicines

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Cannabis sativa contains minor cannabinoids that have potential therapeutic value in pain management. However, detailed experimental evidence for the antinociceptive effects of many of these minor cannabinoids remains lacking. Here, we employed artificial intelligence (AI) to perform compound–protein interaction estimates with cannabichromene (CBC) and receptors involved in nociceptive signaling. Based on our findings, we investigated the antinociceptive properties of CBC in naïve or neuropathic C57BL/6 male and female mice using von Frey (mechanical allodynia), tail-flick (noxious radiant heat), formalin (acute and persistent inflammatory pain), and acetone (cold thermal) tests. For von Frey assessments, CBC dose (0–20 mg/kg, i.p.) and time (0–6 h) responses were measured in male and female neuropathic mice. For tail-flick, formalin, and acetone assays, CBC (20 mg/kg, i.p.) was administered to naïve male and female mice 1 h prior to testing. The results show that CBC (10 and 20 mg/kg, i.p.) significantly reduced mechanical allodynia in neuropathic male and female mice 1–2 h after treatment. Additionally, CBC treatment caused significant reductions in nociceptive behaviors in the tail-flick assay and in both phase 1 and phase 2 of the formalin test. Finally, we found a significant interaction in neuropathic male mice in the acetone test. In conclusion, our results suggest that CBC targets receptors involved in nociceptive signaling and imparts antinociceptive properties that may benefit males and females afflicted with diverse forms of acute or chronic/persistent pain.

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“…Cannabinol (CBN), a partial agonist at cannabinoid receptor Type 1 (CB1) that is formed through the oxidation of delta-9-tetrahydrocannabinol (THC), has both alone and in combination with cannabidiol (CBD) garnered increased attention as a potential pharmacological intervention for sleep difficulties (Corroon, 2021). Extant preclinical evaluations of CBN have focused primarily on interactions with THC (Karniol et al, 1975), examinations of behavior including basic sleep effects (Yamamoto et al, 1987), and overall toxicology at a range of doses (Kulpa et al, 2023). Human studies of CBN are similarly limited.…”

mentioning

confidence: 99%

A double-blind, randomized, placebo-controlled study of the safety and effects of CBN with and without CBD on sleep quality.

Bonn-Miller,

Feldner,

Bynion

et al. 2024

Experimental and Clinical Psychopharmacology

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The present study sought to determine the effects of cannabinol (CBN) alone and in combination with cannabidiol (CBD) on sleep quality. This was a double-blind, randomized, placebo-controlled study conducted between May and November 2022. Participants were randomized to receive either (a) placebo, (b) 20 mg CBN, (c) 20 mg CBN + 10 mg CBD, (d) 20 mg CBN + 20 mg CBD, or (e) 20 mg CBN + 100 mg CBD for seven consecutive nights. Participants were 18-55 years of age who self-rated sleep quality as "very poor" or "poor." The primary endpoint was sleep quality, while secondary endpoints included sleep onset latency, number of awakenings, wake after sleep onset (WASO), overall sleep disturbance, and daytime fatigue. In a modified intent-to-treat analyses (N = 293), compared to placebo, 20 mg CBN demonstrated a nonsignificant but potentially meaningful effect on sleep quality (OR [95% CI] = 2.26 [0.93, 5.52], p = .082) and significantly reduced number of awakenings (95% CI [−0.96, −0.05], p = .025) and overall sleep disturbance (95% CI [−2.59, −0.14], p = .023). There was no difference from placebo among any group for sleep onset latency, WASO, or daytime fatigue (all p > .05). Individuals receiving 20 mg CBN demonstrated reduced nighttime awakenings and overall sleep disturbance relative to placebo, with no impact on daytime fatigue. The addition of CBD did not positively augment CBN treatment effects. No differences were observed for latency to sleep onset or WASO. Findings suggest 20 mg of CBN taken nightly may be helpful for improving overall sleep disturbance, including the number of times one wakes up throughout the night, without impacting daytime fatigue. Public Health SignificanceThe present study serves as the first placebo-controlled study of CBN for sleep. This study demonstrated that 20 mg CBN was effective in improving several aspects of sleep, including nighttime awakenings and overall sleep disturbance, without impacting daytime fatigue. Adding CBD to CBN did not appear to positively augment the effects of CBN alone.

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Toxicological Evaluation and Pain Assessment of Four Minor Cannabinoids Following 14-Day Oral Administration in Rats

Cited by 4 publications

References 29 publications

Select Minor Cannabinoids fromCannabis sativaare Cannabimimetic and Antinociceptive in a Mouse Model of Chronic Neuropathic Pain

Select Minor Cannabinoids fromCannabis sativaare Cannabimimetic and Antinociceptive in a Mouse Model of Chronic Neuropathic Pain

Antinociceptive Effects of Cannabichromene (CBC) in Mice: Insights from von Frey, Tail-Flick, Formalin, and Acetone Tests

A double-blind, randomized, placebo-controlled study of the safety and effects of CBN with and without CBD on sleep quality.

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