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Cannabidiol (CBD) is a non-psychoactive component of cannabis with potential applications in biomedicine, food, and cosmetics due to its analgesic, anti-inflammatory, and anticonvulsant properties. However, increasing reports of adverse CBD exposure events underscore the necessity of evaluating its toxicity. In this study, we investigated the developmental toxicity of CBD in zebrafish during the embryonic (0-4 dpf, days post fertilization) and early larval stages (5-7 dpf). The median lethal concentration of CBD in embryos/larvae is 793.28 μg/L. CBD exhibited concentration-dependent manner (ranging from 250 to 1500 μg/L) in inducing serious malformed somatotypes, like shorter body length, pericardial cysts, vitelline cysts, spinal curvature, and smaller eyes. However, no singular deformity predominates. The 5-month-old zebrafish treated with 100 and 200 μg/L of CBD during the embryonic and early larval stages produced fewer offspring with higher natural mortality and malformation rate. Gonadal growth and gamete development were inhibited. Transcriptomic and metabolomic analyses conducted with 400 μg/L CBD on embryos/larvae from 0 to 5 dpf suggested that CBD promoted the formation and transportation of extracellular matrix components on 1 dpf, promoting abnormal cell division and migration, probably resulting in random malformed somatotypes. It inhibited optical vesicle development and photoreceptors formation on 2 and 3 dpf, resulting in damaged sight and smaller eye size. CBD also induced an integrated stress response on 4 and 5 dpf, disrupting redox, protein, and cholesterol homeostasis, contributing to cellular damage, physiological dysfunction, embryonic death, and inhibited reproductive system and ability in adult zebrafish. At the tested concentrations, CBD exhibited developmental toxicity, lethal toxicity, and reproductive inhibition in zebrafish. These findings demonstrate that CBD threatens the model aquatic animal, highlighting the need for additional toxicological evaluations of CBD before its inclusion in dietary supplements, edible food, and other products., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Cannabidiol (CBD) is the main component of plant Cannabis (Cannabis sativa), which exhibits strong antioxidant and anti-inflammatory activities. With the legalization of CBD in the United States, it is an inevitable tendency for its global legalization in the future. Therefore, it has become an urgent task to conduct the toxicological evaluation of CBD before clinical application. In this study, the developmental toxicities of CBD on zebrafish embryos were systematically evaluated, and the mechanisms were revealed. The results showed that the phenotype of liver degeneration was observed in 96 hpf zebrafish embryos after 0.1-5 μmol/L CBD exposure, further RT-qPCR experiments indicated that the above result may attributed by the alterations of FABP10A, GCLC, and GSR. Besides, 1 and 5 μmol/L CBD contributed to the developmental toxicities of heart and eye in zebrafish embryos, characterizing by the decrease in heart rate, the phenotype of pericardial edema, and the reduce of eye area. Compared to other organs, the liver of zebrafish displayed the most sensitive characteristic to CBD exposure, as 0.1 μmol/L CBD already led to the phenotype of liver degeneration. In summary, this paper provided theoretical supports for CBD toxicology research, and laid the foundation for its future clinical application., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

In light of legislative changes and the widespread use of cannabis as a recreational and medicinal drug, delayed effects of cannabis upon brief exposure during embryonic development are of high interest as early pregnancies often go undetected. Here, zebrafish embryos were exposed to cannabidiol (CBD) and Δ 9 -tetrahydrocannabinol (THC) until the end of gastrulation (1-10 h post-fertilization) and analyzed later in development (4-5 days post-fertilization). In order to measure neural activity, we implemented Calcium-Modulated Photoactivatable Ratiometric Integrator (CaMPARI) and optimized the protocol for a 96-well format complemented by locomotor analysis. Our results revealed that neural activity was decreased by CBD more than THC. At higher doses, both cannabinoids could dramatically reduce neural activity and locomotor activity. Interestingly, the decrease was more pronounced when CBD and THC were combined. At the receptor level, CBD-mediated reduction of locomotor activity was partially prevented using cannabinoid type 1 and 2 receptor inhibitors. Overall, we report that CBD toxicity occurs via two cannabinoid receptors and is synergistically enhanced by THC exposure to negatively impact neural activity late in larval development. Future studies are warranted to reveal other cannabinoids and their receptors to understand the implications of cannabis consumption on fetal development.

While Δ 9 -tetrahydrocannabinol (THC) has been widely studied in the realm of developmental and reproductive toxicology, few studies have investigated potential toxicities from a second widely used cannabis constituent, cannabidiol (CBD). CBD is popularized for its therapeutic potential for reducing seizure frequencies in epilepsy. This study investigated developmental origins of health and disease (DOHaD) via multigenerational gene expression patterns, behavior phenotypes, and reproductive fitness of a subsequent F1 following an F0 developmental exposure of zebrafish (Danio rerio) to THC (0.024, 0.12, 0.6 mg/L; 0.08, 0.4, 2 μM) or CBD (0.006, 0.03, 0.15 mg/L; 0.02, 0.1, 0.5 μM). Embryonic exposure at these concentrations did not cause notable morphological abnormalities in either F0 or F1 generations. However, during key developmental stages (14, 24, 48, 72, and 96 h post fertilization) THC and CBD caused differential expression of c-fos, brain-derived neurotrophic factor (bdnf), and deleted-in-azoospermia like (dazl), while in F1 larvae only CBD differentially expressed dazl. Larval photomotor behavior was reduced (F0) or increased (F1) by THC exposure, while CBD had no effect on F0 larvae, but decreased activity in the unexposed F1 larvae. These results support our hypothesis of cannabinoid-related developmental neurotoxicity. As adults, F0 fecundity was reduced, but it was not in F1 adults. Conversely, in the adult open field test there were no significant effects in F0 fish, but a significant reduction in the time in periphery was seen in F1 fish from the highest THC exposure group. The results highlight the need to consider long-term ramifications of early-life exposure to cannabinoids., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cannabidiol (CBD) is a non-psychotomimetic compound of the Cannabis sativa that has been used for the treatment of severe epilepsy as well as other diseases of nervous system. However, toxicity studies of CBD have great relevance to guarantee the patients safety. In this context, morphological analyses of zebrafish can contribute to evaluate the teratogenic potential, as well as evaluation of acetylcholinesterase activity and motor activity of zebrafish are valuable tools to verify the neurotoxicity potential. In the present work, we use this methodology to test the toxicity of CBD to zebrafish embryos. No malformation was observed in morphological analysis of embryos exposed to all tested concentrations of CBD. Although, twenty per cent of embryos exposed to maximal dose of CBD (300 μg/L) hatched after 96hpf, while embryos in control solution had already hatched in this period. Embryos exposed to CBD did not show differences in acetylcholinesterase activity, but embryos exposed to CBD 20-300 μg/L were 1.4 up to 1.7-fold more active when compared to the control. Despite that, at 48 hpf, motor activity returned to control values. Our results suggest that the effects observed after CBD exposure are intimately related to CB1 receptor that is present in zebrafish since early stages of development. The present work showed early light effects induced by CBD exposure in concentrations that did not alter biochemical activity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Cannabidiol (CBD) has gained much attention in the past several years for its therapeutic potential in the treatment of drug-resistant epilepsy, such as Dravet syndrome. Although CBD has shown anecdotal efficacy in reducing seizure frequency, little is known regarding the potential adverse side effects of CBD on physiology, development, organogenesis, or behavior. The goal of this project was to compare the relative morphological, behavioral, and gene expression phenotypes resulting after a developmental exposure to Δ9-tetrahydrocannabinol (THC) or CBD. Zebrafish were exposed from blastula through larval stage (96 h postfertilization [hpf]) to 0.3, 0.6, 1.25, 2.5, 5 mg/l (1, 2, 4, 8, 16 µM) THC or 0.07, 0.1, 0.3, 0.6, 1.25 mg/l CBD (0.25, 0.5, 1, 2, 4 µM). Despite the similarity in THC and CBD dysmorphologies, ie, edemas, curved axis, eye/snout/jaw/trunk/fin deformities, swim bladder distention, and behavioral abnormalities, the LC50 for CBD (0.53 mg/l) was nearly 7 times lower than THC (3.65 mg/l). At 96 hpf, c-fos, dazl, and vasa were differentially expressed following THC exposure, but only c-fos expression was significantly increased by CBD. Cannabidiol was more bioconcentrated compared with THC despite higher THC water concentrations. This work supports the potential for persistent developmental impacts of cannabinoid exposure, but more studies are needed to assess latent effects and their molecular mechanisms of toxicity.