Search Results (85)

The synthesis of cannabigerol—a cannabinoid with significant pharmaceutical potential—is described. The synthesis involves four stages. In the first step, (E)-non-3-en-2-one reacts with dimethyl malonate to yield a cyclic enone, which is subsequently oxidized with bromine to produce the olivetol ester. This ester then undergoes an alumina-catalyzed coupling reaction with geraniol, followed by ester hydrolysis to obtain cannabigerol. By modifying the chain length of the enone in the initial step and employing allylic alcohols other than geraniol, a range of cannabigerol derivatives can be synthesized, including the natural product cannabigerovarin. Full article

As high-CBD cannabis (Cannabis sativa L.) gains legal and commercial relevance in the United States, studies evaluating how external inputs impact critical traits remain limited. This study investigates the effects of methyl jasmonate (MeJA), ammonium bicarbonate (AB), and the genetic source (mother plant identity) on the growth and secondary metabolite traits of indoor cannabis. Plants were treated with 1 mM MeJA and/or AB under controlled conditions, and key traits, such as plant height, chlorophyll content, biomass, trichome density, and cannabinoid concentration, were measured. The MeJA treatment led to a significant 32% increase in trichome density. However, it did not significantly alter CBD or THC concentrations. The AB treatment enhanced vegetative growth, increasing chlorophyll content and plant height while reducing CBD concentrations, but the biomass gains could compensate for the lower cannabinoid in the total production. An interaction between MeJA and AB altered the CBD content, suggesting that MeJA may mitigate AB’s negative effect on cannabinoid synthesis. The genetic source significantly influenced most of the measured traits, highlighting the role of the genotype in trait expression and the importance of clonal consistency. These findings highlight the complex dynamics of external inputs and genetic factors in cannabis production, emphasizing the need for further research to optimize cultivation strategies. Future studies should refine input combinations and doses to improve both yield and cannabinoid profiles. Full article

New psychoactive substances (NPSs) are emerging narcotics or psychotropics that pose a public health risk. The most commonly reported NPSs are synthetic cannabinoids and synthetic cathinones. Synthetic cannabinoids mimic the effects of Δ9-tetrahydrocannabinol (Δ9-THC), often with greater potency, while synthetic cathinones act as stimulants, frequently serving as cheaper alternatives to amphetamines, 3,4-methylenedioxymethamphetamine (MDMA) and cocaine. While some synthetic cannabinoids exhibit chirality depending on their synthesis precursors, synthetic cathinones are intrinsically chiral. Biotargets can recognize and differentiate between enantiomers, leading to distinct biological responses (enantioselectivity). Understanding these differences is crucial; therefore, the development of enantioresolution methods to assess the biological and toxicological effects of enantiomer is necessary. This work systematically compiles enantioselectivity studies and enantioresolution methods of synthetic cannabinoids and synthetic cathinones, following PRISMA guidelines. The main aim of this review is to explore the impact of chirality on these NPSs, improving our understanding of their toxicological behavior and evaluating advances in analytical techniques for their enantioseparation. Key examples from both groups are presented. This review highlights the importance of continuing research in this field, as demonstrated by the differing properties of synthetic cannabinoid and synthetic cathinone enantiomers, which are closely linked to variations in biological and toxicological outcomes. Full article

Bone-associated pathologies are major contributors to chronic pathology statistics. Current gold standard treatments present limitations such as the ability to act as scaffolds whilst effectively delivering medications to promote cellular proliferation. Recent advancements in biomaterials have suggested whey protein isolate (WPI) hydrogel as a potential candidate to act as a scaffold with the capacity for drug delivery for bone regeneration. In this study, we investigate whey protein isolate hydrogels enhanced with the phytocannabinoid cannabidiol (CBD). The use of CBD in WPI hydrogels for bone regeneration is original. The results suggest that CBD was successfully incorporated into the hydrogels bound potentially through hydrophobic interactions formed between hydrophobic patches of the protein and the hydrophobic cannabinoid. The incorporation of CBD into the WPI hydrogels improved the mechanical strength of the hydrogels. The Young’s modulus was improved from 2700 kPa ± 117 kPa to 7100 kPa ± 97 kPa when compared to the WPI control, without plant-derived cannabinoids, to the WPI with the maximum CBD concentration. Furthermore, statistically significant differences for both Young’s modulus and compressive strength were observable between the WPI control and CBD hydrogel variables. The release of CBD from the WPI hydrogels was confirmed with the results suggesting a maximum release of 20 μM over the 5-day period. Furthermore, the hydrogels supported the proliferation and synthesis of collagen and calcium, as well as the alkaline phosphatase activity of MC3T3-E1 pre-osteoblasts, which demonstrates the potential of WPI/CBD hydrogels as a biomaterial for osseous tissue regeneration. Full article

The adaptation of the body when exposed to a lower-than-usual temperature is a challenge that involves neuro-endocrine–immune mechanisms and affects the pharmacokinetics and/or pharmacodynamics of drugs taken before or after cold exposure. The experiments presented in this study clearly show differences in the analgesic effect of an exogenously introduced model substance (C-terminal fragment of calcium-binding protein, spermatid-specific 1) before and after cold exposure compared to its effect at an ambient temperature. The model substance used for the experiments is an octapeptide, TDIFELLK, which was synthesized via standard solid-phase peptide synthesis. Preliminary studies proved TDIFELLK’s analgesic activity. The ANOVA analysis performed showed statistically significant differences in the pain thresholds, measured by a paw pressure test, in 109 rats distributed among 14 groups and subjected to cold exposure according to different set-ups. Cold exposure immediately after TDIFELLK administration appears to enhance its analgesic effect, while cold exposure before administration reduces the effect. In some of the set-ups, antagonists of the most significant for analgesia receptors, i.e., opioid, cannabinoid, and serotonergic, were also introduced. The results showed that cold exposure had a modulating influence on the effect of the exogenously administered substances. The modulating effect was manifested differently depending on whether the intake occurred before or after cold exposure. The results also showed that the interaction with individual mediator systems was also subjected to differences depending on intake occurring before and after cold exposure. Full article

Synthetic cannabinoid use raises concerns about its neuroinflammatory effects, including molecular adaptations of the endocannabinoid system (ECS) in the brain. This study investigates the pharmacological effects of 14-day repeated intraperitoneal administration, as well as 14-day administration followed by a 7-day withdrawal period of two synthetic cannabinoids: WIN55,212-2 and HU-210. The study assessed gene expression and protein markers related to the ECS, gliosis, and inflammation in two brain regions critical for cognitive processes and memory—key components of addiction pathways—the prefrontal cortex (PFC) and the hippocampus of rats. Our findings showed that repeated WIN55,212-2 administration induced adaptations in the ECS and reduced IBA1, a glial protein marker, along with inflammatory responses likely mediated through CB2 activity. Notably, regional differences emerged in the hippocampus, where repeated administration of WIN55,212-2 and HU-210 increased IBA1 and inflammatory markers, effects unrelated to CB2 activity. Withdrawal from WIN55,212-2 in the PFC, as well as from both compounds in the hippocampus, decreased IBA1 levels. This was associated with altered protein expression of cannabinoid-synthesizing and degrading enzymes, favoring acylethanolamide synthesis. These findings highlight region-specific effects of synthetic cannabinoids on cannabinoid signaling, gliosis, and inflammation. Further research is needed to elucidate the long-term neurobiological consequences of synthetic cannabinoid use and withdrawal. Full article

Objectives/Background: The Cannabis genus contain a mixture of cannabinoids and other minor components which have been studied so far. In this narrative review, we highlight the main aspects of the polarized discussion between abuse and toxicity versus the benefits of the compounds found in the Cannabis sativa plant. Methods: We investigated databases such as PubMed, Google Scholar, Web of Science and World Anti-doping Agency (WADA) documents for scientific publications that can elucidate the heated discussion related to the negative aspects of addiction, organ damage and improved sports performance and the medical benefits, particularly in athletes, of some compounds that are promising as nutrients. Results: Scientific arguments bring forward the harmful effects of cannabinoids, ethical and legislative aspects of their usage as doping substances in sports. We present the synthesis and metabolism of the main cannabis compounds along with identification methods for routine anti-doping tests. Numerous other studies attest to the beneficial effects, which could bring a therapeutic advantage to athletes in case of injuries. These benefits recommend Cannabis sativa compounds as nutrients, as well as potential pharmacological agents. Conclusions and Future Perspectives: From the perspective of both athletes and illegal use investigators in sport, there are many interpretations, presented and discussed in this review. Despite many recent studies on cannabis species, there is very little research on the beneficial effects in active athletes, especially on large groups compared to placebo. These studies may complete the current vision of this topic and clarify the hypotheses launched as discussions in this review. Full article

Cannabis (Cannabis sativa L.) flower glandular trichomes (GTs) are the main site of cannabinoid synthesis. Phytohormones, such as jasmonic acid (JA) and salicylic acid (SA), have been shown to increase cannabinoid content in cannabis flowers, but how this is regulated remains unknown. This study aimed to understand which biological processes in GT disc cells phytohormones control by using an in vitro assay. Live GT disc cells were isolated from a high-tetrahydrocannabinol cannabis cultivar and incubated on basal media plates supplemented with either kinetin (KIN), JA, SA, abscisic acid, ethephon, gibberellic acid, brassinolide, or sodium diethyldithiocarbamate. Quantitative proteomic analysis revealed that KIN, JA, and SA caused the greatest number of changes in the GT disc cell proteome. Surprisingly, none of the treatments concertedly increased cannabinoid content or the abundance of related biosynthetic proteins in the GT, suggesting that cannabinoid increases in previous in planta phytohormone studies are likely due to other processes, such as increased GT density. As well, KIN-, JA-, and SA-treated GTs had numerous differentially abundant proteins in common. Several were key proteins for leucoplast differentiation, cuticular wax and fatty acid metabolism, and primary metabolism regulation, denoting that cytokinin, JA, and SA signalling are likely important for coordinating cannabis GT differentiation and development. Full article

Over the last three decades, the decriminalization and legalization of therapeutic and recreational marijuana consumption have increased. Consequently, the availability of marijuana-based products associated with its therapeutic use has increased. These developments have stimulated research on cannabinoids involving a wide range of animal models and clinical trials. Also, it is reported that cannabinoids promote sleep in animal models and naïve human participants, and they seem to improve insomnia and sleep apnea in patients. However, evidence from rigorous clinical trials is needed. In addition, among several physiological processes, cannabinoid receptors modulate dopamine synthesis and release. In this regard, the side effects of marijuana and marijuana derivatives must not be ignored. The chronic consumption of marijuana could reduce dopamine responsivity, increase negative emotionality, and induce anhedonia. Research on the neurobiological changes associated with cannabinoid ligands in animal models, in regard to the consumption of both marijuana and marijuana-based compounds, must improve and the effectiveness of the therapeutic outcomes in clinical trials must be guaranteed. In this review, we include a detailed description of the mechanisms of action of cannabinoids on the brain and their impact on sleep disorders and addictive behaviors to emphasize the need to understand the potential risks and benefits of their therapeutic and recreational use. Evidence from basic research and clinical trials from papers published between 2000 and 2024 are included. The pharmacodynamics of these compounds is discussed in terms of sleep–wake regulation, drug addiction, and addictive behaviors. Full article

Background: Our recent studies have identified a link between sphingolipid metabolites and the induction of a specialized form of regulated cell death termed immunogenic cell death (ICD). We have recently demonstrated that the synthetic cannabinoid (±) 5-epi CP 55,940 (5-epi) stimulates the accumulation of ceramide (Cer), and that inhibition of sphingosine kinase 1 (SphK1) enhances Cer accumulation and ICD-induction in human colorectal cancer (CRC) cell lines. Methods: We employed flow-cytometric, western blot analyses, pharmacological inhibitors of the sphingolipid metabolic pathway and small molecule agonists and antagonists of the CB receptors to further analyze the mechanism by which 5-epi induces Cer accumulation. Results: Herein, and report that 5-epi induces de novo synthesis of Cer primarily through engagement of the cannabinoid receptor 2 (CB2) and depletion of intracellular calcium levels. Moreover, we report that 5-epi stimulates Cer synthesis through dysregulation of the endogenous inhibitor of the de novo Cer pathway, ORMDL3. We also observed a remarkable and specific accumulation of one Cer species, C20:4 Cer, generated predominantly by ceramide synthase 4, as a key factor required for 5-epi-induced ICD. Conclusions: Together, these data indicate that engagement of CB2, by 5-epi, alters regulation of the de novo ceramide synthesis pathway to generate Cer species that mediate ICD. Full article

Synthetic cannabinoids (SCs) are one of the largest groups of new psychoactive substances (NPSs). However, the relationship between their chemical structure and the affinity to human CB₁ receptors (hCB₁), which mediates their psychotropic activity, is not well understood. Herein, the synthesis of the 2-, 4-, 5-, 6- and 7-chloroindole analogues of the synthetic cannabimimetic MDMB-CHMICA, along with their analytical characterization via ultraviolet–visible (UV/VIS), infrared (IR), nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry, is described. Furthermore, all five derivatives of MDMB-CHMICA were analyzed for their hCB₁ binding affinities. Chlorination at position 4 and 5 of the indole core reduced the binding affinity compared to MDMB-CHMICA, while the test compounds chlorinated in positions 2, 6, and 7 largely retained their binding affinities relative to the non-chlorinated parent compound. Full article

Cannabis sativa, a versatile plant containing over 150 cannabinoids, is increasingly valued for its medicinal properties. It is classified into hemp and marijuana based on its Δ9-tetrahydrocannabinol (Δ9-THC) content. The objective of this study was to optimize cannabinoid production in hemp within a vertical farming system by investigating the effects of methyl jasmonate (MeJA) on plant growth and specific cannabinoid contents. After propagating hemp plants, they were treated with various concentrations of MeJA (0, 100, 200, and 400 μM). Plant growth parameters, glandular trichome (GT) density, and the contents of specific cannabinoids—cannabidiolic acid (CBDA), cannabidiol (CBD), tetrahydrocannabinolic acid (THCA), and Δ9-THC—were analyzed. The results showed that MeJA treatment decreased plant height and leaf area while increasing GT density and the synthesis of CBDA and THCA at lower concentrations. Specifically, treatment with 100 μM MeJA provided optimal conditions for enhancing cannabinoid production while controlling plant height, which is advantageous for vertical farming. These findings suggest that precise application of MeJA in controlled environments can increase yields of valuable cannabinoids with efficient use of space, thereby enhancing the commercial and medicinal value of hemp. Full article

Cannabinoids represent a highly researched group of plant-derived ingredients. The substantial investment of funds from state and commercial sources has facilitated a significant increase in knowledge about these ingredients. Cannabinoids can be classified into three principal categories: plant-derived phytocannabinoids, synthetic cannabinoids and endogenous cannabinoids, along with the enzymes responsible for their synthesis and degradation. All of these compounds interact biologically with type 1 (CB1) and/or type 2 (CB2) cannabinoid receptors. A substantial body of evidence from in vitro and in vivo studies has demonstrated that cannabinoids and inhibitors of endocannabinoid degradation possess anti-inflammatory, antioxidant, antitumour and antifibrotic properties with beneficial effects. This review, which spans the period from 1940 to 2024, offers an overview of the potential therapeutic applications of natural and synthetic cannabinoids. The development of these substances is essential for the global market of do-it-yourself drugs to fully exploit the promising therapeutic properties of cannabinoids. Full article

Δ⁹-Tetrahydrocannabiphorol (Δ⁹-THCP, THCP) a psychoactive cannabinoid recently found in Cannabis sativa L., is widely used as a legal marijuana substitute. THCP is encountered in sprayed Cannabis, edibles, and vape liquids. The distributors of such products claim that the THCP in use originates from a natural source. The legal status of this substance varies from country to country. THCP and similar cannabinoids with a dibenzoyprane structure have been banned in Switzerland since October 2023. A vape liquid, which contains 90% THCP and 10% terpenes according to the distributor, was analyzed by gas chromatography coupled with mass spectrometry (GC-MS). Besides CBP, CBDP, Δ⁹-THCP and Δ⁸-THCP and some terpenes, other compounds were found which probably result from a synthetic procedure. This sample contained 5-heptylresorcinol, the heptyl homologue of olivetol, a common precursor for the synthesis of tetrahydrocannabinol (THC). Bisalkylated compounds (m/z 476) were found as a result of the reaction of one equivalent of 5-heptylresorcinol with two equivalents of (+)-p-mentha-1,8-dien-4-ol or another precursor. Similar bisalkylated compounds are known as undesired side products of the synthesis of THC. The sample contained unidentified isomers of Δ⁹-THCP, presumably abnormal cannabinoids (abn-Δ⁹-THCP; abn-Δ⁸-THCP) and iso-cannabinoids (iso-THCP). Chiral derivatization with Mosher acid chlorides revealed that the Δ⁹-THCP in the sample was enantiopure. Full article

Colorectal cancer (CRC) is a global problem. Oncology currently practices conventional methods of treating this carcinoma, including surgery, chemotherapy, and radiotherapy. Unfortunately, their efficacy is low; hence, the exploration of new therapies is critical. Recently, many efforts have focused on developing safe and effective anticancer compounds. Some of them include cannabinoids. In the present study, we obtained cannabinoids, such as cannabidiol (CBD), abnormal cannabigerol (abn-CBG), cannabichromene (CBC), and cannabicitran (CBT), by chemical synthesis and performed the biological evaluation of their activity on colon cancer cells. In this study, we analyzed the effects of selected cannabinoids on the lifespan and metabolic activity of normal colonic epithelial cells and cancer colon cells. This study demonstrated that cannabinoids can induce apoptosis in cancer cells by modulating mitochondrial dehydrogenase activity and cellular membrane integrity. The tested cannabinoids also influenced cell cycle progression. We also investigated the antioxidant activity of cannabinoids and established a relationship between the type of cannabinoid and nitric oxide (NO) production in normal and cancerous colon cells. To conclude, it seems that, due to their interesting properties, the cannabinoids studied may constitute an interesting target for further research aimed at their use in alternative or combined therapies for human colon cancer. Full article