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Purpose of reviewCannabis may have beneficial anti-inflammatory effects in people with HIV (PWH); however, given this population's high burden of persisting neurocognitive impairment (NCI), clinicians are concerned they may be particularly vulnerable to the deleterious effects of cannabis on cognition. Here, we present a systematic scoping review of clinical and preclinical studies evaluating the effects of cannabinoid exposure on cognition in HIV.Recent findingsResults revealed little evidence to support a harmful impact of cannabis use on cognition in HIV, with few eligible preclinical data existing. Furthermore, the beneficial/harmful effects of cannabis use observed on cognition were function-dependent and confounded by several factors (e.g., age, frequency of use). Results are discussed alongside potential mechanisms of cannabis effects on cognition in HIV (e.g., anti-inflammatory), and considerations are outlined for screening PWH that may benefit from cannabis interventions. We further highlight the value of accelerating research discoveries in this area by utilizing translatable cross-species tasks to facilitate comparisons across human and animal work.

Cannabichromene (CBC) is a nonpsychoactive phytocannabinoid well-known for its wide-ranging health advantages. However, there is limited knowledge regarding its human metabolism following CBC consumption. This research aimed to explore the metabolic pathways of CBC by various human liver cytochrome P450 (CYP) enzymes and support the outcomes using in vivo data from mice. The results unveiled two principal CBC metabolites generated by CYPs: 8-hydroxy-CBC and 6,7-epoxy-CBC, along with a minor quantity of 1″-hydroxy-CBC. Notably, among the examined CYPs, CYP2C9 demonstrated the highest efficiency in producing these metabolites. Moreover, through a molecular dynamics simulation spanning 1 μs, it was observed that CBC attains stability at the active site of CYP2J2 by forming hydrogen bonds with I487 and N379, facilitated by water molecules, which specifically promotes the hydroxy metabolites formation. Additionally, the presence of cytochrome P450 reductase (CPR) amplified CBCs binding affinity to CYPs, particularly with CYP2C8 and CYP3A4. Furthermore, the metabolites derived from CBC reduced cytokine levels, such as IL6 and NO, by approximately 50% in microglia cells. This investigation offers valuable insights into the biotransformation of CBC, underscoring the physiological importance and the potential significance of these metabolites.

No preclinical experimental approach enables the study of voluntary oral consumption of high-concentration Δ9-tetrahydrocannabinol (THC) and its intoxicating effects, mainly owing to the aversive response of rodents to THC that limits intake. Here, we developed a palatable THC formulation and an optimized access paradigm in mice to drive voluntary consumption. THC was formulated in chocolate gelatin (THC-E-gel). Adult male and female mice were allowed ad libitum access for 1 and 2 hr. Cannabimimetic responses (hypolocomotion, analgesia, and hypothermia) were measured following access. Levels of THC and its metabolites were measured in blood and brain tissue. Acute acoustic startle responses were measured to investigate THC-induced psychotomimetic behavior. When allowed access for 2 hr to THC-E-gel on the second day of a 3-day exposure paradigm, adult mice consumed up to ≈30 mg/kg over 2 hr, which resulted in robust cannabimimetic behavioral responses (hypolocomotion, analgesia, and hypothermia). Consumption of the same gelatin decreased on the following third day of exposure. Pharmacokinetic analysis shows that THC-E-gel consumption led to parallel accumulation of THC and its psychoactive metabolite, 11-OH-THC, in the brain, a profile that contrasts with the known rapid decline in brain 11-OH-THC levels following THC intraperitoneal (i.p.) injections. THC-E-gel consumption increased the acoustic startle response in males but not in females, demonstrating a sex-dependent effect of consumption. Thus, while voluntary consumption of THC-E-gel triggered equivalent cannabimimetic responses in male and female mice, it potentiated acoustic startle responses preferentially in males. We built a dose-prediction model that included cannabimimetic behavioral responses elicited by i.p. versus THC-E-gel to test the accuracy and generalizability of this experimental approach and found that it closely predicted the measured acoustic startle results in males and females. In summary, THC-E-gel offers a robust preclinical experimental approach to study cannabimimetic responses triggered by voluntary consumption in mice, including sex-dependent psychotomimetic responses.

Introduction Methods Results Discussion Conclusion Chronic pain (CP) affects 35.0%–51.3% of the UK population, with 67%–88% reporting sleep disturbances. Cannabis‐based medicinal products (CBMPs) have shown therapeutic potential in managing CP. Evidence suggests poor sleep worsens pain perception; therefore, this study aimed to assess patient‐reported outcome measures (PROMs) following CBMP treatment in CP patients with and without co‐morbid sleep impairment.A prospective cohort study of CP patients from the UK Medical Cannabis Registry was conducted. Participants were separated by baseline single‐item sleep quality scale (SQS) score into sleep impaired (SQS ≤3) and unimpaired (SQS ≥4) cohorts. The primary outcome assessed changes in PROMs from baseline to 1‐, 3‐, 6‐, and 12‐months. Participants completed the following: SQS, General Anxiety Disorder‐7, EQ‐5D‐5L, Brief Pain Inventory (BPI), and Short‐Form McGill Pain Questionnaire‐2. Significance was defined as p < 0.050.1139 participants met the inclusion criteria (sleep impaired: n = 517, 45.4%; sleep unimpaired: n = 622, 54.61%). The sleep impaired cohort showed improvements in all PROMs at each follow‐up (p < 0.010). The sleep unimpaired cohort showed similar results (p < 0.050), except in SQS and ED‐5Q‐5L: self‐care and anxiety/depression scores (p > 0.050). However, the sleep impaired cohort observed greater improvements in BPI pain severity (p < 0.050) and SQS (p < 0.001) than the sleep unimpaired cohort at all follow‐ups. 2817 adverse events were self‐reported between both cohorts (p = 0.197).These findings align with literature that shows associated improvements in pain outcomes following CBMP administration. Sleep impaired individuals were more likely to experience greater pain severity improvements. However, this was not confirmed on multivariate logistic regression analysis and instead may be confounded by baseline pain severity.Whilst these results show promise for the effects of CBMPs on CP, they must be examined within the limitations of the study design. These findings provide further evidence to support the design of subsequent randomized controlled trials to verify causality between CBMPs and pain outcomes. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance The cannabinoid cannabidiol has established antiseizure effects in drug‐resistant epilepsies such as Dravet syndrome and Lennox–Gastaut syndrome. Amorfrutin 2, honokiol, and magnolol are structurally similar to cannabinoids (cannabis‐like drugs) but derive from non‐cannabis plants. We aimed to study the antiseizure potential of these compounds in various mouse seizure models. In addition, we aimed to characterize their molecular pharmacology at cannabinoid CB1 and CB2 receptors and at T‐type calcium channels, which are known targets of the cannabinoids.Brain and plasma pharmacokinetic profiles were determined. Antiseizure activity was assessed against hyperthermia‐induced seizures in a Scn1a+/− mouse model of Dravet syndrome. We then elaborated on the most promising compounds in the maximal electroshock (MES) test in mice and the Gabrb3+/D120N mouse model of Lennox–Gastaut syndrome. Fluorescence‐based assays were used to examine modulatory activity at cannabinoid CB1 and CB2 receptors and T‐type calcium channel subtypes CaV3.1, CaV3.2, and CaV3.3 overexpressed in mammalian cells. Automated patch‐clamp electrophysiology was then used to confirm inhibitory activity on CaV3.1, CaV3.2, and CaV3.3 channels.Magnolol and honokiol had high brain‐to‐plasma ratios (3.55 and 7.56, respectively), unlike amorfrutin 2 (0.06). Amorfrutin 2 and magnolol but not honokiol significantly increased the body temperature threshold at which Scn1a+/− mice had a generalized tonic–clonic seizure. Both amorfrutin 2 and magnolol significantly decreased the proportion of mice exhibiting hindlimb extension in the MES test. Furthermore, magnolol reduced the number and duration of atypical absence seizures in Gabrb3+/D120N mice. The three compounds inhibited all T‐type calcium channel subtypes but were without specific activity at cannabinoid receptors.We show for the first time that amorfrutin 2 and magnolol display novel antiseizure activity in mouse drug‐resistant epilepsy models. Our results justify future drug discovery campaigns around these structural scaffolds that aim to develop novel antiseizure drugs for intractable epilepsies. [ABSTRACT FROM AUTHOR]

Cannabinoid hyperemesis syndrome presents as a complex of symptoms and signs encompassing nausea, vomiting, abdominal pain, and hot water bathing behavior, most typically in a heavy cannabis user. Its presentation is frequently associated with hypothalamic-pituitary-adrenal axis activation with stress and weight loss. Recent investigation has identified five statistically significant mutations in patients distinct from those of frequent cannabis users who lack the symptoms, affecting the TRPV1 receptor, two dopamine genes, the cytochrome P450 2C9 enzyme that metabolizes tetrahydrocannabinol, and the adenosine triphosphate-binding cassette transporter. The syndrome is associated with escalating intake of high potency cannabis, or alternatively, other agonists of the cannabinoid-1 receptor including synthetic cannabinoids. Some patients develop environmental triggers in scents or foods that suggest classical conditioned responses. Various alternative "causes" are addressed and refuted in the text, including exposure to pesticides, neem oil or azadirachtin. Nosological confusion of cannabinoid hyperemesis syndrome has arisen with cyclic vomiting syndrome, whose presentation and pathophysiology are clearly distinct. The possible utilization of non-intoxicating antiemetic cannabis components in cannabis for treatment of cannabinoid hyperemesis syndrome is addressed, along with future research suggestions in relation to its genetic foundation and possible metabolomic signatures. [ABSTRACT FROM AUTHOR]

Introduction: Cannabis, commonly known for both therapeutic and intoxicating effects, is gaining accessibility on legal markets and traction as a potential alternative therapy for pain mediation, particularly in those suffering from chronic low back pain. However, the effectiveness in this population of legal market forms of cannabis, particularly commonly used edibles, is unknown. Methods: Therefore, this study utilized a naturalistic prospective design where participants with chronic low back pain with intentions to initiate cannabis use for treatment were recruited and self-selected edible cannabis products containing varying amounts of delta- 9 tetrahydrocannabinol (THC) and cannabidiol (CBD). Products were categorized as CBD-dominant, THC-dominant, or combined THC and CBD (THC + CBD). Results: 249 participants [140 female (56.62%), mean (SD) age of 46.30 (16.02), 90% White] were tracked over 2 weeks of ad libitum use and assessed during a naturalistic acute cannabis administration session on changes in pain, mood, and subjective drug effects. During acute administration, a significant correlation between THC dose and short-term pain relief was found, suggesting that higher THC doses were associated with greater pain reduction (p <.05). In addition, THC was associated with higher levels of subjective cannabis drug effects (p <.001), regardless of whether CBD was also in the edible product. Acute CBD dose was primarily associated with short-term tension relief (p <.05); however, there were no associations between CBD dose and acute pain. Over the 2-week ad libitum administration period results suggested pain reductions across participants using all forms of cannabis. However, trends suggested that more frequent use of CBD-dominant edible cannabis may be associated with greater reductions in perceived pain over the 2-week observation period (p =.07). Discussion: These findings support the short-term analgesic effects of THC and anxiolytic effects of CBD and further suggest that orally-administered THC and CBD should continue to be evaluated for the potential to provide both acute and extended relief from chronic low back pain. Clinical Trial Registration: https://clinicaltrials.gov/study/NCT03522324?locStr=Boulder,%20CO&country=United%20States&state=Colorado&city=Boulder&cond=chronic%20low%20back%20pain&intr=Cannabis&rank=1, identifier NCT03522324. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications Recent research linking choline‐containing lipids to degeneration of basal forebrain cholinergic neurons in neuropathological states illustrates the challenge of balancing lipid integrity with optimal acetylcholine levels, essential for memory preservation. The endocannabinoid system influences learning and memory processes regulated by cholinergic neurotransmission. Therefore, we hypothesised that activation of the endocannabinoid system may confer neuroprotection against cholinergic degeneration.We examined the neuroprotective potential of sub‐chronic treatments with the cannabinoid agonist WIN55,212‐2, using ex vivo organotypic tissue cultures including nucleus basalis magnocellularis and cortex and in vivo rat models of specific cholinergic damage induced by 192IgG‐saporin. Levels of lipids, choline and acetylcholine were measured with histochemical and immunofluorescence assays, along with [35S]GTPγS autoradiography of cannabinoid and muscarinic GPCRs and MALDI‐mass spectrometry imaging analysis. Learning and memory were assessed by the Barnes maze and the novel object recognition test in rats and in the 3xTg‐AD mouse model.Degeneration, induced by 192IgG‐saporin, of baso‐cortical cholinergic pathways resulted in memory deficits and decreased cortical levels of lysophosphatidylcholines (LPC). WIN55,212‐2 restored cortical cholinergic transmission and LPC levels via activation of cannabinoid receptors. This activation altered cortical lipid homeostasis mainly by reducing sphingomyelins in lesioned animals. These modifications were crucial for memory recovery.We hypothesise that WIN55,212‐2 facilitates an alternative choline source by breaking down sphingomyelins, leading to elevated cortical acetylcholine levels and LPCs. These results imply that altering choline‐containing lipids via activation of cannabinoid receptors presents a promising therapeutic approach for dementia linked to cholinergic dysfunction. [ABSTRACT FROM AUTHOR]

Despite promise of its supplementation as both monotherapy and add-on treatment in autism spectrum disorder (ASD), the biobehavioral effects of Palmitoylethanolamide (PEA) in autistic adults have never been explored so far. We discussed the cases of two autistic adults with different degrees of severity (level 1 and level 2) presenting with symptoms of psychic distress, who were treated with ultramicronized-PEA (um-PEA) 600 mg/day monotherapy for a sustained period of 4 months. The level 1 autistic patient showed improved depressive symptoms and social engagement at a 12-week follow-up, in parallel to a tendency toward reduced inflammatory response and enhanced endocannabinoid (eCB) signaling, partially relapsing after um-PEA discontinuation at four months. Opposedly, the level 2 autistic patient exhibited a generally stable psychosocial functioning for the initial 12 weeks, consistent with basically unchanged immune and eCBs levels, abruptly deteriorating and leading to antipsychotic initiation afterwards. No significant side effects were reported in both cases during the observation period. The two cases suggest that um-PEA could be an effective option for the treatment of psychic distress in level 1 autistic adults, warranting further investigation of its age- and level-specificity and of the biological underpinnings of its therapeutic effect in ASD. [ABSTRACT FROM AUTHOR]

The increasing legalization of Cannabis sativa plant products has sparked growing interest in their therapeutic applications. Prohibition laws established in 1937 hindered formal research on cannabis, a plant with cultural and medicinal roots dating back to 2700 BC in Chinese history. Despite regulatory hurdles, published research on cannabis has emerged; yet elite athletes remain an underrepresented population in these studies. Athletes, known for exploring diverse substances to optimize performance, are drawn to the potential benefits of cannabinoid therapy, with anecdotal reports suggesting positive effects on issues ranging from anxiety to brain injuries. This review aims to evaluate empirical published cannabis research with a specific focus on its potential applications in athletics. The changing legal landscape, especially the removal of cannabis from drug testing programs in leagues such as the National Basketball Association (NBA), and endorsements by Major League Baseball (MLB) for cannabinoid products and the National Football League (NFL) for cannabis research, reflects a shift in the acceptability of such substances in sports. However, stigma, confusion, and a lack of education persist, hindering a cohesive understanding among sports organizations, including business professionals, policymakers, coaches, and medical/training staff, in addition to athletes themselves. Adding to the confusion is the lack of consistency with cannabinoid regulations from sport to sport, within or out of competition, and with cannabis bioactive compounds. The need for this review is underscored by the evolving attitudes toward cannabinoids in professional sports and the potential therapeutic benefits or harms they may offer. By synthesizing current cannabis research, this review aims to provide a comprehensive understanding of the applications and implications of cannabinoid use in the realm of athletics. [ABSTRACT FROM AUTHOR]

Objective: This study aims to describe patterns, sources, and reasons for cannabis use among cancer patients during active treatment (+CDTX) compared to no‐use during active treatment (−CDTX). Methods: Data are from 385 surveys collected via REDCap during phase I of an ongoing study among adult cancer patients seen at an NCI‐designated comprehensive cancer center within the last 5 years of treatment. A harmonized survey was created with 11 other NCI centers to assess cannabis use patterns, sources, and reasons for use. Sociodemographics and cancer details were also collected via self‐report. Descriptive statistics were calculated and stratified by +/−CDTX. Chi‐squared tests were conducted to compare proportions between groups. Results: Among the sample [49.5 years (SD 15.9); 53.0% male; and 41.6% Hispanic/Latino], 41.0% + CDTX and 59.0% −CDTX. A majority (71.8%) of +CDTX initiated use before diagnosis versus 44.1% in −CDTX (p < 0.0001); patients diagnosed with stage 4 cancer had a statistically significant higher prevalence of +CDTX (60.0%; p = 0.003); 53.3% in radiation reported +CDTX compared to 42.8% in chemotherapy, and 36.4% in immunotherapy. Dispensaries and local dealers were the top sources of cannabis in both groups. Among +CDTX, 44.3% consumed cannabis at least once a day DTX, dominant cannabinoids used were CBD (35.2%), Delta‐8‐THC (18.3%), and CBD + THC ratio (14.1%); 12.7% were unsure what they consumed. Joints were the most common inhalation method (61.5%), and store‐bought candy was the most common edible (39.2%). Depression/mood, pain, and enjoyment were the top three reasons for +CDTX compared to enjoyment, depression/mood, and nausea/upset stomach in −CDTX (p = 0.02). Conclusions: Patterns, sources, and reasons for cannabis use varied between +CDTX and ‐CDTX. Future studies should examine the impacts of cannabis and specific cannabinoids on cancer treatment, drug interactions, survival outcomes, and quality of life. [ABSTRACT FROM AUTHOR]

The reactivity of Cannabigerol (CBG, 1) in organic solvents under photochemical and acid catalyzed conditions has been investigated in detail. The obtained results pointed out the presence of different reaction paths in the photochemical and the acid‐catalyzed conditions, with a remarkable selectivity toward the formation of a 2,2‐disubstituted‐chromane derivative in the first case. [ABSTRACT FROM AUTHOR]

Yoghurts are the most popular fermented dairy products. Consumer attention is directed towards products containing inputs that enrich the product with bioactive substances. The growing interest in the Cannabis sativa L. plant has resulted in the development of a market for hemp products. The main aim of this research work was to determine the effect of the lactic fermentation process on the stability of cannabinoids in fermented milk beverages containing hemp inputs (hemp oil, dried hemp, ethanolic hemp extract) at 0.5, 1 and 2% (w/v). The effect of the type of hemp input on the technological process (i.e., pH value, viability of LAB during 28 days of storage) was also checked and the sensory quality of the prepared samples was evaluated. It was shown that the choice of type/form and amount of hemp addition influenced the final cannabinoid content of the product after fermentation and post-fermentation, but no effect on the survival of yoghurt bacteria or pH changes during storage was confirmed. Fermented milk drinks containing hemp oil had the highest cannabinoid content. The QDA results of the sensory evaluation of the yoghurts show that the most acceptable product in terms of overall quality is the yoghurt containing 0.5% hemp extract and 2% hemp oil. [ABSTRACT FROM AUTHOR]

Background: The cannabigerol derivative VCE-003.2, which has activity at the peroxisome proliferator-activated receptor-γ has afforded neuroprotection in experimental models of Parkinson's disease (PD) based on mitochondrial dysfunction (6-hydroxydopamine-lesioned mice) and neuroinflammation (LPS-lesioned mice). Now, we aim to explore VCE-003.2 neuroprotective properties in a PD model that also involves protein dysregulation, other key event in PD pathogenesis. Methods: To this end, an adeno-associated viral vector serotype 9 coding for a mutated form of the α-synuclein gene (AAV9-SynA53T) was unilaterally delivered in the substantia nigra pars compacta (SNpc) of mice. This model leads to motor impairment and progressive loss of tyrosine hydroxylase-labelled neurons in the SNpc. Results: Oral administration of VCE-003.2 at 20 mg/kg for 14 days improved the performance of mice injected with AAV9-SynA53T in various motor tests, correlating with the preservation of tyrosine hydroxylase-labelled neurons in the SNpc. VCE-003.2 also reduced reactive microgliosis and astrogliosis in the SNpc. Furthermore, we conducted a transcriptomic analysis in the striatum of mice injected with AAV9-SynA53T and treated with either VCE-003.2 or vehicle, as well as control animals. This analysis aimed to identify gene families specifically altered by the pathology and/or VCE-003.2 treatment. Our data revealed pathology-induced changes in genes related to mitochondrial function, lysosomal cell pathways, immune responses, and lipid metabolism. In contrast, VCE-003.2 treatment predominantly affected the immune response through interferon signaling. Conclusion: Our study broadens the neuroprotective potential of VCE-003.2, previously described against mitochondrial dysfunction, oxidative stress, glial reactivity and neuroinflammation in PD. We now demonstrate its efficacy against another key pathogenic event in PD as α-synuclein dysregulation. Furthermore, our investigation sheds light on the molecular mechanisms underlying VCE-003.2 revealing its role in regulating interferon signaling. These findings, together with a favorable ADMET profile, enhance the preclinical interest of VCE-003.2 towards its future clinical development in PD. [ABSTRACT FROM AUTHOR]

Cannabinoids, derived from the Cannabis sativa plant, have garnered increasing attention for their potential therapeutic applications in various diseases. The pharmacologically active compounds in Cannabis , such as delta-9-tetrahydrocannabinol and cannabidiol, exhibit diverse immunomodulatory properties. Although studies have explored the effects of cannabinoids on immune function, their specific interactions with the thymus, a primary immune organ critical for T-cell development and maturation, remain an intriguing area of investigation. As the thymus plays a fundamental role in shaping the immune repertoire, understanding the interplay between cannabinoids and thymic function may shed light on potential benefits or concerns associated with Cannabis -based therapies. This article aims to provide an overview of the current scientific knowledge regarding the impact of medicinal Cannabis on the thymus and its implications for disease treatment and immune health. [ABSTRACT FROM AUTHOR]

Cannabidiol (CBD) is a non-psychotropic cannabinoid with multiple pharmacological properties. Cannabidiol has attracted growing attention in the cosmetic industry, with an increasing number of CBD-containing skincare products on the market in recent years. The aim of this review is to evaluate the current evidence on the use of CBD for cosmetic purposes. Following an overview of CBD and the endocannabinoid system in the skin, we summarize pre-clinical and clinical studies that address the potential of CBD in cosmetic dermatology. Available in vitro and in vivo evidence suggests that CBD has anti-oxidant, anti-inflammatory, moisturizing, anti-acne, wound-healing, and anti-aging properties. However, only a few clinical studies have been conducted on the use of CBD in the skin. In addition, there is a critical need to develop an efficient drug-delivery system for topical/transdermal application of CBD. Further research, including clinical and pharmacokinetic studies, are needed to fully evaluate the role of CBD in cosmetic dermatology. [ABSTRACT FROM AUTHOR]

Chronic neuropathic pain is a debilitating pain syndrome caused by damage to the nervous system that is poorly served by current medications. Given these problems, clinical studies have pursued extracts of the plant Cannabis sativa as alternative treatments for this condition. The vast majority of these studies have examined cannabinoids which contain the psychoactive constituent delta‐9‐tetrahydrocannabinol (THC). While there have been some positive findings, meta‐analyses of this clinical work indicates that this effectiveness is limited and hampered by side‐effects. This review focuses on how recent preclinical studies have predicted the clinical limitations of THC‐containing cannabis extracts, and importantly, point to how they might be improved. This work highlights the importance of targeting channels and receptors other than cannabinoid CB1 receptors which mediate many of the side‐effects of cannabis. [ABSTRACT FROM AUTHOR]

For public health protection, informed decision-making relies on having a robust foundation of evidence concerning risks and their prevention. Application of an evidence-based framework depends on the availability of pertinent, scientifically sound data generated by well-directed and valid research endeavors. In this essay, we address the current state of research in humans and the evidential base concerning high-concentration delta-9-tetrahydrocannabinol (delta-9-THC) products, which are readily available in the United States. Furthermore, we explore the intricate challenges faced in carrying out research on these products, which reflect the full range of study design issues: measurement of exposure and outcomes, confounding, selection bias, and the generalizability of findings. We offer recommendations to guide future research toward providing more informative evidence. By following these recommendations, researchers and funders on this emerging topic could move toward generating the valid and comprehensive evidence needed to effectively inform public health initiatives and guide policy decisions regarding high-concentration delta-9-THC products and their use. The urgency of generating such evidence cannot be overstated, given the widespread legalization and increasing availability and use of these products. (Am J Public Health. 2024;114(S8):S639–S644. https://doi.org/10.2105/AJPH.2024.307724) [ABSTRACT FROM AUTHOR]

Objective. To characterize adverse event (AE) cases received by the US Food and Drug Administration (FDA) reportedly involving cannabinoid hemp products (CHPs). Methods. We searched the FDA Adverse Event Reporting System and Center for Food Safety and Applied Nutrition Adverse Event Reporting System for cases reported directly to the FDA from 2019–2023 involving CHPs, which are defined as products containing 1 or more of the following: cannabidiol, delta-8 tetrahydrocannabinol, and emerging cannabinoids (i.e., other intoxicating cannabinoids often synthesized from hemp-derived cannabidiol). We abstracted and summarized information on reporting trends, consumer demographics, reporter information, product information, and AEs. Results. We identified 610 AE cases reportedly involving CHPs containing 1 or more of the following: delta-8 tetrahydrocannabinol (n=355), cannabidiol (n=253), and emerging cannabinoids (n=36). Multiple trends and safety issues were identified, including an annual increase in the number of cases involving intoxicating cannabinoids since 2021, potential quality issues, and the occurrence of fatalities and pediatric exposures. Conclusions. Our findings emphasize the importance of monitoring AE cases received by the FDA involving CHPs as part of a comprehensive surveillance strategy to identify trends and safety issues with these products. (Am J Public Health. 2024;114(S8):S664–S672. https://doi.org/10.2105/AJPH.2024.307712) [ABSTRACT FROM AUTHOR]

Many medications commonly used to treat neuropathic pain are associated with significant, dose-limiting adverse effects, including sedation, dizziness, and fatigue. These adverse effects are due to the activity of these medications within the central nervous system. The objective of this work was to investigate the interactions between peripherally restricted cannabinoid receptor and mu-opioid receptor (MOR) agonists on ongoing and evoked neuropathic pain behaviors in mouse models. RNAscope analysis of cannabinoid receptor type 1 (CB1R) and MOR mRNA demonstrated that the mRNA of both receptors is colocalized in both mouse and human dorsal root ganglion. Single-cell RNAseq of dorsal root ganglion from chronic constriction injury mice showed that the mRNA of both receptors (Cnr1 and Oprm1) is coexpressed across different neuron clusters. MycCB1R and FLAG-MOR were cotransfected into immortalized HEK-293T cells and were found to interact at a subcellular level. We also find that CB-13 (a peripherally restricted dual CB1R and cannabinoid receptor type 2 agonist) and DALDA (a peripherally restricted MOR agonist) both attenuate mechanical hypersensitivity in a murine model of neuropathic pain. Using isobolographic analysis, we demonstrate that when coadministered, these agents synergistically attenuate mechanical hypersensitivity. Importantly, combination dosing of these agents does not cause any detectable preferential behaviors or motor impairment. However, repeated dosing of these agents is associated with the development of tolerance to these drugs. Collectively, these findings suggest that leveraging synergistic pain inhibition between cannabinoid receptor and MOR agonists in peripheral sensory neurons may be worth examining in patients with neuropathic pain. [ABSTRACT FROM AUTHOR]

Background: Phytocannabinoids inhibit the aggregation and neurotoxicity of the neurotoxic Alzheimer's disease protein β amyloid (Aβ). We characterised the capacity of five proprietary medical cannabis extracts, heated and non‐heated, with varying ratios of cannabidiol and Δ9‐tetrahydrocannabinol and their parent carboxylated compounds to protect against lipid peroxidation and Aβ‐evoked neurotoxicity in PC12 cells. Methods: Neuroprotection against lipid peroxidation and Aβ1–42‐induced cytotoxicity was assessed using the thiazolyl blue tetrazolium bromide (MTT) assay. Transmission electron microscopy was used to visualise phytocannabinoid effects on Aβ1–42 aggregation and fluorescence microscopy. Results: Tetrahydrocannabinol (THC)/tetrahydrocannabinolic acid (THCA)‐predominant cannabis extracts demonstrated the most significant overall neuroprotection against Aβ1–42‐induced loss of PC12 cell viability. These protective effects were still significant after heating of extracts, while none of the extracts provided significant neuroprotection to lipid peroxidation via tbhp exposure. Modest inhibition of Aβ1–42 aggregation was demonstrated only with the non‐heated BC‐401 cannabis extract, but overall, there was no clear correlation between effects on fibrils and conferral of neuroprotection. Conclusions: These findings highlight the variable neuroprotective activity of cannabis extracts containing major phytocannabinoids THC/THCA and cannabidiol (CBD)/cannabidiolic acid (CBDA) on Aβ‐evoked neurotoxicity and inhibition of amyloid β aggregation. This may inform the future use of medicinal cannabis formulations in the treatment of Alzheimer's disease and dementia. [ABSTRACT FROM AUTHOR]

The primary objective of this study was to investigate the ability of seven ionic liquids (ILs), NaBF4 salt, and five deep eutectic solvents (DESs) to extract five cannabinoids from hemp tea. Among the solvents examined, 1-butyl-3-methyl-imidazolium chloride (BMIMCl) proved to be a promising solvent for the recovery of cannabinoids, and it was selected for the subsequent optimization of ultrasound-assisted extraction (UAE) using response surface methodology (RSM). The optimized theoretical conditions were as follows: 0.071 M BMIMCl, a solvent-to-solid ratio of 24.15 mL/g of dried hemp tea material, and an extraction time of 20.80 min. These conditions resulted in theoretical extraction yields of 98.34 μg/g for sample material for cannabichromene (CBC), 1104.69 μg/g for cannabidiol (CBD), 209.64 μg/g for Δ9-tetrahydrocannabinol (Δ9-THC), 40.43 μg/g for cannabinol (CBN), and 55.49 μg/g for cannabigerol (CBG). For comparison purposes, the optimized extraction parameters were applied to three more cannabis teas, originating from the Netherlands, Greece, and Italy. The analysis revealed varying levels of detected cannabinoids and exhibited levels of Δ9-THC, ranging from 34.93 ± 0.24 μg/g to 199.46 ± 1.02 μg/g. Consequently, these findings have significant regulatory implications, as none of the examined hemp tea samples met the permitted zero tolerance threshold for Δ9-THC. [ABSTRACT FROM AUTHOR]

There is emerging evidence that the endocannabinoid system (ECS) plays a significant role in the pathophysiology of many psychiatric disorders, including attention deficit hyperactivity disorder (ADHD). Increasing evidence suggests that a number of neurobiological correlates between endogenous cannabinoid function and cognitive dysfunction are seen in ADHD, making the ECS a possible target for therapeutic interventions. Cannabis use and cannabis use disorder are more prevalent in individuals with ADHD, compared to the general population, and there is growing popular perception that cannabis is therapeutic for ADHD. However, the relationship between cannabis use and ADHD symptomology is poorly understood. Further understanding of the role of the ECS in ADHD pathophysiology and the molecular alterations that may be a target for treatment is needed. To further the science on this emerging area of research, this scoping review describes the preclinical and clinical evidence seeking to understand the relationship between the ECS and ADHD. [ABSTRACT FROM AUTHOR]

Context Treatment options for advanced neuroendocrine tumors (NETs), pheochromocytomas and paragangliomas (PPGLs) are still limited. In recent years, antitumor effects of cannabinoids have been reported; however, there are only very limited data available in NETs or PPGLs. Objective Investigation of the effects of cannabidiol (CBD) on patient-derived human NET/PPGL primary cultures and on NET/PPGL cell lines. Methods We established primary cultures derived from 46 different patients with PPGLs (n = 35) or NETs (n = 11) who underwent tumor resection at 2 centers. Treatment of patient primary cultures with clinically relevant doses (5 µM) and slightly higher doses (10 µM) of CBD was performed. Results We found opposing effects of 5 µM CBD: significant antitumor effects in 5/35 (14%) and significant tumor-promoting effects in 6/35 (17%) of PPGL primary cultures. In terms of antitumor effects, cluster 2-related PPGLs showed significantly stronger responsivity to CBD compared to cluster 1-related PPGLs (P =.042). Of the cluster 2-related tumors, NF1 PPGLs showed the strongest responsivity (4/5 PPGL primary cultures with a significant decrease in cell viability were NF1 -mutated). We also found opposing effects of 10 µM CBD in PPGLs and NETs: significant antitumor effects in 9/33 of PPGL (27%) and 3/11 of NET (27%) primary cultures and significant tumor-promoting effects in 6/33 of PPGL (18%) and 2/11 of NET (18%) primary cultures. Conclusion We suggest a potential novel treatment option for some NETs/PPGLs but also provide evidence for caution when applying cannabinoids as supportive therapy for pain or appetite management to cancer patients and possibly as health supplements. [ABSTRACT FROM AUTHOR]

The medicinal plant Cannabis sativa L. (C. sativa) is currently being extensively studied to determine the full extent of its therapeutic pharmacological potential. Δ9-tetrahydocannabinol (THC) and cannabidiol (CBD) are the most thoroughly investigated compounds. We aimed to explore the anticancer activity of cannabinoids mixture isolated from the Lebanese C. sativa plant in ratios comparable to the local medicinal plant, to elucidate its mechanism of action in breast cancer cells in vitro. Cells were subjected to cytotoxicity assay, cell cycle analysis, Annexin V/PI dual staining, cell death ELISA, immunofluorescence, in addition to western blot analysis of apoptotic and autophagy markers. We further evaluated the anti-metastatic effect of cannabinoids on MDA-MB-231 using the scratch wound-healing, trans-well migration and invasion assays. Our results revealed the promising therapeutic benefits of CBD/THC on inhibiting the growth of breast cancer cells by promoting cellular fragmentation, phosphatidylserine translocation to the outer membrane leaflet and DNA fragmentation in both cell lines while inhibiting the motility of the triple negative breast cancer cells. In our study, CBD/THC mixture was found to exhibit a pro-apoptotic activity via the activation of the mitochondrial apoptotic pathway, independent from ROS production while also suggesting the activation of a caspase-dependent apoptotic pathway. Even though autophagy was altered upon exposure to the cannabinoid mixture, our data suggested that it is not the mechanism responsible of inducing cell death. In conclusion, our study demonstrates the promising therapeutic benefits of CBD and THC isolated from the Lebanese C. sativa plant on breast cancer cells in vitro. [ABSTRACT FROM AUTHOR]

Glycine receptors (GlyR) are regulated by small-molecule binding at several allosteric sites. Cannabinoids like tetrahydrocannabinol (THC) and N-arachidonyl-ethanol-amide (AEA) potentiate the GlyR response but their mechanism of action is not fully established. By combining millisecond coarse-grained (CG) MD simulations powered by Martini 3 with backmapping to all-atom representations, we have characterized the cannabinoid-binding site(s) at the zebrafish GlyR-α1 active state with atomic resolution. Based on hundreds of thousand ligand-binding events, we find that cannabinoids bind to the transmembrane domain of the receptor at both intrasubunit and intersubunit sites. For THC, the intrasubunit binding mode predicted in simulation is in excellent agreement with recent cryo-EM structures, while intersubunit binding recapitulates in full previous mutagenesis experiments. Intriguingly, AEA is predicted to bind at the same intersubunit site despite the strikingly different chemistry. Statistical analyses of the ligand-receptor interactions highlight potentially relevant residues for GlyR potentiation, offering experimentally testable predictions. The predictions for AEA have been validated by electrophysiology recordings of rationally designed mutants. The results highlight the existence of multiple cannabinoid-binding sites for the allosteric regulation of GlyR and put forward an effective strategy for the identification and structural characterization of allosteric binding sites. Cannabinoids potentiate responses of brain receptors, but their mechanism of action is unknown. Here, using coarse-grained MD simulations and electrophysiology of mutants, the authors elucidate the allosteric binding sites for two cannabinoids at the glycine receptor. [ABSTRACT FROM AUTHOR]

This review focuses on the recently discovered specific action of two classical endocannabinoids (ECs), 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamide (AEA), in the case of their synthesis and degradation in skeletal muscles; in other words, this review is dedicated to properties and action of the myoendocannabinoid (myoEC) pool. Influence of this pool is considered at three different levels: at the level of skeletal muscles, motor synapses, and also at the level of the whole organism, including central nervous system. Special attention is paid to the still significantly underestimated and intriguing ability of ECs to have positive effect on energy exchange and contractile activity of muscle fibers, as well as on transmitter secretion in motor synapses. Role of muscle contractions in regulation of activity balance between the enzymes catalyzing synthesis and degradation of myoECs and, therefore, in the release of myoECs and exertion of their specific effects is thoroughly considered. Increasingly popular hypotheses about the prominent role of myoECs (AEA and/or 2-AG) in the rise of the overall level of ECs in the blood during muscle exercise and the development of "runner's high" and about the role of myoECs in the correction of a number of psychophysiological conditions (pain syndrome, stress, etc.) are discussed here. Thus, this review presents information about the myoEC pool from a totally new viewpoint, underlining its possible independent and non-trivial regulatory role in the body, in contrast to the traditional and well-known activity of neurogenic ECs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous mast cell tumors (cMCTs) are a common type of tumor in dogs. This study measured blood concentrations of endocannabinoids, namely 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA), and AEA congeners, namely N-palmitoylethanolamine (PEA) and N-oleoylethanolamine (OEA), in 17 dogs with cMCTs and 11 healthy dogs. Dogs with cutaneous mast cell tumors had significantly higher levels of 2-AG and lower levels of AEA and PEA compared to healthy dogs, while OEA levels showed no difference. The ability of these endocannabinoids to serve as differentiators between healthy dogs and those with tumors was evaluated, and 2-AG was found to be a highly accurate (98%) indicator for identifying dogs with cMCTs. Levels of 2-AG above 52.75 pmol/mL had 94% sensitivity and 90% specificity in detecting the tumor. This is the first study to show that endocannabinoid levels are altered in dogs with mast cell tumors, indicating their potential use as biomarkers for diagnosing or monitoring this type of cancer in the future. A cutaneous mast cell tumor (cMCT) is among the most common tumors in dogs. Endocannabinoids (eCBs) belong to the endocannabinoid system (ECS), which involves also cannabinoid receptors and an enzymatic system of biosynthesis and degradation. In this study, plasma levels of N-arachidonoylethanolamine (AEA), 2-arachidonoylglycerol (2-AG), N-palmitoylethanolamine (PEA), and N-oleoylethanolamine (OEA) were evaluated in 17 dogs with MCTs of varying histological grades and clinical stages, as well as in a control group of 11 dogs. Dogs affected by cMCT had higher plasma levels of 2-AG (p = 0.0001) and lower levels of AEA (p = 0.0012) and PEA (p = 0.0075) compared to the control group, while no differences were observed at the OEA level between healthy and cMCT dogs (p = 0.9264). The ability of eCBs to help discriminate between healthy and cMCT dogs was interrogated through the area under the ROC curve (AUC). An accuracy of 0.98 (95% confidence interval [CI], 0.94–1.02) was found for 2-AG, of 0.85 (95% CI, 0.71–0.99) for AEA, and of 0.81% for PEA (95% CI, 0.64–0.69). Values > 52.75 pmol/mL for 2-AG showed 94% sensitivity and 90% specificity in distinguishing cMCT. This is the first study to demonstrate alterations in plasmatic levels of eCBs in dogs affected by MCTs, suggesting the significance of these biomarkers in the tumorigenic process and their potential use as biomarkers in the future. [ABSTRACT FROM AUTHOR]

This review provides an overview of cannabis-based phytocannabinoids, focusing on their mechanisms of action, therapeutic applications, and production processes, along with the environmental factors that affect their quality and efficacy. Phytocannabinoids such as THC (∆9-tetrahydrocannabinol), CBD (cannabidiol), CBG (cannabigerol), CBN (cannabinol), and CBC (cannabichromene) exhibit significant therapeutic potential in treating various physical and mental health conditions, including chronic pain, epilepsy, neurodegenerative diseases, skin disorders, and anxiety. The cultivation of cannabis plays a crucial role in determining cannabinoid profiles, with indoor cultivation offering more control and consistency than outdoor methods. Environmental factors such as light, water, temperature, humidity, nutrient management, CO2, and the drying method used are key to optimizing cannabinoid content in inflorescences. This review outlines the need for broader data transfer between the health industry and technological production, especially in terms of what concentration and cannabinoid ratios are effective in treatment. Such data transfer would provide cultivators with information on what environmental parameters should be manipulated to obtain the required final product. [ABSTRACT FROM AUTHOR]

Herein, we present a comprehensive total synthesis of cannabidiol integrating both batch and continuous flow conditions. Our approach is planned to streamline the synthesis of olivetolic acid derivatives and utilize an enantiomerically pure monoterpene moiety obtained from naturally occurring (R)‐(+)‐limonene by photocatalysis. Key reactions, including the synthesis of olivetolic ester and a Friedel‐Crafts alkylation, are successfully adapted to continuous flow, resulting in improved yields and selectivities. This study not only offers a scalable and efficient route for cannabidiol synthesis but also contributes to the synthetic approaches to access cannabinoids (diversity synthesis), with potential applications in medicinal and industrial contexts. [ABSTRACT FROM AUTHOR]

Migraine is a common and complex neurological disorder that has a high impact on quality of life. Recent advances with drugs that target the neuropeptide calcitonin gene-related peptide (CGRP) have helped, but treatment options remain insufficient. CGRP is released from trigeminal sensory fibers and contributes to peripheral sensitization, perhaps in part due to actions on immune cells in the trigeminovascular system. In this review, we will discuss the potential of cannabinoid targeting of immune cells as an innovative therapeutic target for migraine treatment. We will cover endogenous endocannabinoids, plant-derived phytocannabinoids and synthetically derived cannabinoids. The focus will be on six types of immune cells known to express multiple cannabinoid receptors: macrophages, monocytes, mast cells, dendritic cells, B cells, and T cells. These cells also contain receptors for CGRP and as such, cannabinoids might potentially modulate the efficacy of current CGRP-targeting drugs. Unfortunately, to date most studies on cannabinoids and immune cells have relied on cell cultures and only a single preclinical study has tested cannabinoid actions on immune cells in a migraine model. Encouragingly, in that study a synthetically created stable chiral analog of an endocannabinoid reduced meningeal mast cell degranulation. Likewise, clinical trials evaluating the safety and efficacy of cannabinoid-based therapies for migraine patients have been limited but are encouraging. Thus, the field is at its infancy and there are significant gaps in our understanding of the impact of cannabinoids on immune cells in migraine. Future research exploring the interactions between cannabinoids and immune cells could lead to more targeted and effective migraine treatments. [ABSTRACT FROM AUTHOR]

Introduction: Persistent genital arousal disorder/genitopelvic dysesthesia (PGAD/GPD) is a rare, yet debilitating disease, which has been included in ICD-11. Pharmacotherapy in PGAD/GPD is a mixed blessing – drugs may either alleviate symptoms or worsen/induce them. Therefore, we aim at offering both an overview of pharmacological approaches to treat this disorder, including treatment failures, and to highlight drugs that may induce or worsen symptoms. We include all available data published so far as well as data from an own registry. Areas covered: The international registries have not recorded any completed or ongoing trials on pharmacotherapy of PGAD/GPD. We refer to case reports, case series, online surveys, and data from our own registry that includes 90 subjects with PGAD/GPD. Expert Opinion: There is weak evidence (level 4) that some drugs such as SSRIs, SNRIs, cannabinoids, and anticonvulsants (pregabalin and gapabentin) may alleviate symptoms in PGAD/GPD. However, serotonergic drugs may also induce or worsen PGAD/GPD during administration or termination, as observed in 28% of cases. In conclusion, the pharmacotherapy of PGAD/GPD is still in its infancy just like the etiopathological understanding of the disease. Clinicians should be aware of PGAD/GPD, conduct careful diagnostics, and discuss an individual treatment plan with the patient. [ABSTRACT FROM AUTHOR]

Objective: Previous cancer studies have indicated that medical marijuana addresses a significant unmet need, namely chronic pain treatment and conferring oncology supportive care. However, the clinical research evaluating medical marijuana is preliminary and requires further consideration. Data Sources: We conducted a PubMed search primarily comprising retrospective and prospective studies, systematic reviews, and randomized clinical trials (RCTs) from approximately 2020–2023. The search included specific terms that incorporated medical marijuana, cancer treatment, cancer-related symptoms, pain management, and side effects. Data Summary: A total of 40 studies were included in the review, many of which were either of acceptable or good quality. Select investigations indicated that medical marijuana was associated with decreased overall pain levels and improvements in nausea and vomiting. Alternatively, the results from RCTs have found that the benefits from a placebo were equivalent to medical marijuana in both the treatment of cancer-related pain and providing an opioid-sparing effect. Conclusions: Despite the potential cancer-related benefits derived from medical marijuana, the study design and results for many of the investigations on which the evidence is based, were neither uniform nor conducted via RCTs; hence, the efficacy and appropriateness of medical marijuana in treating cancer-related conditions remain indeterminate. [ABSTRACT FROM AUTHOR]

Public laboratories must balance innovative and existing methods to keep up with designer drug trends. This article presents a strategy for handling designer benzodiazepines (DBZDs) in casework from screening to interpretation. The cross-reactivity of 22 DBZDs and metabolites was tested against the Immunalysis™ benzodiazepine (BZD) direct enzyme-linked immunosorbent assay kit. The kit had high intra-analyte precision (coefficients of variation <15%). Inter-analyte performance varied, triggering confirmation testing at concentrations ranging from 35 to 460 μg/L. The Cuyahoga County Regional Forensic Science Laboratory implemented a 40-analyte BZD and Z-drug confirmation method in 2019. Ten additional analytes were later validated for qualitative reporting, and the limits of detection for 13 analytes were lowered by 60%. The method of standard addition was also optimized for as-needed quantitation. Equal and 1/ x weighting factors correlated well with target concentrations (coefficients of determination (r 2) > 0.98), but 1/ x weighting provided the most consistently accurate concentrations. Six computational models were developed to predict γ-aminobutyric acid-A receptor binding affinity to assist in case interpretation (r 2 > 0.70 for cross-validation and test set prediction). These models were used to predict the binding affinity of analytes in the confirmation method. Other public laboratories can use this same practical strategy to adapt to any designer drug class (e.g. BZDs, opioids, cannabinoids and stimulants). [ABSTRACT FROM AUTHOR]

Cannabis sativa is known for producing over 120 distinct phytocannabinoids, with Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) being the most prominent, primarily in their acidic forms. Beyond Δ9-THC and CBD, a wide array of lesser-known phytocannabinoids, along with terpenes, flavonoids, and alkaloids, demonstrate diverse pharmacological activities, interacting with the endocannabinoid system (eCB) and other biological pathways. These compounds, characterized by phenolic structures and hydroxyl groups, possess lipophilic properties, allowing them to cross the blood–brain barrier (BBB) effectively. Notably, their antioxidant, anti-inflammatory, and neuro-modulatory effects position them as promising agents in treating neurodegenerative disorders. While research has extensively examined the neuropsychiatric and neuroprotective effects of Δ9-THC, other minor phytocannabinoids remain underexplored. Due to the well-established neuroprotective potential of CBD, there is growing interest in the therapeutic benefits of non-psychotropic minor phytocannabinoids (NMPs) in brain disorders. This review highlights the emerging research on these lesser-known compounds and their neuroprotective potential. It offers insights into their therapeutic applications across various major neurological conditions. [ABSTRACT FROM AUTHOR]

Background: Cannabidiol (CBD) is one of the main cannabinoids present in Cannabis sativa female flowers. Previous investigation has already provided insights into the CBD molecular mechanism; however, there is no transcriptome data for CBD effects on hippocampal subfields. Here, we investigate transcriptomic changes in dorsal and ventral CA1 of adult mice hippocampus after 100 mg/kg of CBD administration (i.p.) for one or seven consecutive days. Methods: C57BL/6JUnib mice were treated with either vehicle or CBD for 1 or 7 days. The collected brains were sectioned, and the hippocampal sub-regions were laser microdissected for RNA-Seq analysis. Results: The transcriptome analysis following 7 days of CBD administration indicates the differential expression of 1559 genes in dCA1 and 2924 genes in vCA1. Furthermore, GO/KEGG analysis identified 88 significantly enriched biological process and 26 significantly enriched pathways for dCBD7, whereas vCBD7 revealed 128 enriched BPs and 24 pathways. Conclusion: This dataset indicates a widespread decrease of electron transport chain and ribosome biogenesis transcripts in CA1, while chromatin modifications and synapse organization transcripts were increased following CBD administration for 7 days. [ABSTRACT FROM AUTHOR]

Objective: The transient receptor potential cation channel, subfamily V (vanilloid), member 1 (TRPV1) mediates pain perception to thermal and chemical stimuli in peripheral neurons. The cannabinoid receptor type 1 (CB1), on the other hand, promotes analgesia in both the periphery and the brain. TRPV1 and CB1 have also been implicated in learned fear, which involves the association of a previously neutral stimulus with an aversive event. In this review, we elaborate on the interplay between CB1 receptors and TRPV1 channels in learned fear processing. Methods: We conducted a PubMed search for a narrative review on endocannabinoid and endovanilloid mechanisms on fear conditioning. Results: TRPV1 and CB1 receptors are activated by a common endogenous agonist, arachidonoyl ethanolamide (anandamide), Moreover, they are expressed in common neuroanatomical structures and recruit converging cellular pathways, acting in concert to modulate fear learning. However, evidence suggests that TRPV1 exerts a facilitatory role, whereas CB1 restrains fear responses. Conclusion: TRPV1 and CB1 seem to mediate protective and aversive roles of anandamide, respectively. However, more research is needed to achieve a better understanding of how these receptors interact to modulate fear learning. [ABSTRACT FROM AUTHOR]

Objective: Preclinical studies suggest that cannabidiol (CBD), a non-intoxicating phytocannabinoid, may reduce addiction-related behaviours for various drug classes in rodents, including ethanol, opiates, and psychostimulants. CBD modulates contextual memories and responses to reward stimuli. Nonetheless, research on the impact of CBD on cocaine addiction-like behaviors is limited and requires further clarification. This study tested the hypothesis that CBD administration inhibits the acquisition and retrieval of cocaine-induced conditioned place preference (CPP) in adult male and female C57BL6/J mice. We also ought to characterise a 5-day CPP protocol in these animals. Methods: Male and female C57BL/6J mice were administered CBD (3, 10, and 30 mg/kg) 30 minutes before cocaine (15 mg/kg) acquisition of expression of CPP. Results: Cocaine induces a CPP in both female and male mice in the 5-day CPP protocol. CBD failed to prevent the acquisition or retrieval of place preference induced by cocaine. CBD did not decrease the time spent on the side paired with cocaine at any of the doses tested in male and female mice, in either acquisition or expression of contextual memory. Conclusion: This study found no support for the hypothesis that CBD decreases reward memory involved in the formation of cocaine addiction. Further research is necessary to investigate the involvement of CBD in other behavioural responses to cocaine and other psychostimulant drugs. This study, however, characterised a 5-day CPP protocol for both female and male C57BL/6J mice. [ABSTRACT FROM AUTHOR]

The public is increasingly reporting using cannabis for anxiety relief. Both cannabis use and the endocannabinoid system have been connected with anxiety relief/anxiolytic properties, but these relationships are complex, and the underlying mechanisms for them are unclear. Background/Objectives: Work is needed to understand how the endocannabinoid system, including the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), may be impacted by the main constituents of cannabis, Δ9-tetrahydrocannabinol (THC), and cannabidiol (CBD). Methods: The current study examined how the ab libitum use of products differing in THC and CBD affected AEA and 2-AG among 292 individuals randomly assigned to THC-dominant use (N = 92), CBD-dominant use (N = 97), THC + CBD use (N = 74), or non-use (N = 29). Results: The findings suggest that AEA levels do not change differently based on 4 weeks of cannabis use or by cannabinoid content, as AEA similarly increased across all conditions from study weeks 2 to 4. In contrast, AEA decreased at an acute administration session with product conditions containing any THC having greater AEA levels on average than the non-use condition. With regard to 2-AG, its levels appeared to primarily be affected by THC-dominant use, both acutely and over 4 weeks, when controlling for baseline cannabis use and examining study product use frequency among use conditions. Conclusions: Overall, the results continue to shed light on the complicated relationship between cannabinoid content and endocannabinoid production, and highlight the need for continued research on their interplay in human subjects. [ABSTRACT FROM AUTHOR]

Triggering receptor expressed on myeloid cells 2 (TREM2) is involved in neuroinflammation and HIV-associated neurocognitive impairment (NCI). People with HIV (PWH) using cannabis exhibit lower inflammation and neurological disorders. We hypothesized that TREM2 dysfunction mediates HIV neuropathogenesis and can be reversed by cannabinoids. EcoHIV-infected wildtype (WT) and TREM2R47H mutant mice were used to study HIV's impact on TREM2 and behavior. TREM2 and related gene expressions were examined in monocyte-derived macrophages (MDMs) from PWH (n = 42) and people without HIV (PWoH; n = 19) with varying cannabis use via RNA sequencing and qPCR. Differences in membrane-bound and soluble TREM2 (sTREM2) were evaluated using immunocytochemistry (ICC) and ELISA. EcoHIV increased immature and C-terminal fragment forms of TREM2 in WT mice but not in TREM2R47H mice, with increased IBA1 protein in TREM2R47H hippocampi, correlating with worse memory test performance. TREM2 mRNA levels increased with age in PWoH but not in PWH. Cannabidiol (CBD) treatment increased TREM2 mRNA alone and with IL1β. RNA-seq showed the upregulation of TREM2-related transcripts in cannabis-using PWH compared to naïve controls. IL1β increased sTREM2 and reduced membrane-bound TREM2, effects partially reversed by CBD. These findings suggest HIV affects TREM2 expression modulated by cannabis and CBD, offering insights for therapeutic strategies. [ABSTRACT FROM AUTHOR]

In parallel to the legalization of cannabis for both medicinal and recreational purposes, cannabinoid use has steadily increased over the last decade in the United States. Cannabinoids, such as tetrahydrocannabinol and anandamide, bind to the central cannabinoid‐1 (CB1) receptor to impact several physiological processes relevant for body weight regulation, including appetite and energy expenditure. The hypothalamus integrates peripheral signals related to energy balance, houses several nuclei that orchestrate eating, and expresses the CB1 receptor. Herein we review literature to date concerning cannabinergic action in the hypothalamus with a specific focus on eating behaviors. We highlight hypothalamic areas wherein researchers have focused their attention, including the lateral, arcuate, paraventricular, and ventromedial hypothalamic nuclei, and interactions with the hormone leptin. This review serves as a comprehensive analysis of what is known about cannabinoid signaling in the hypothalamus, highlights gaps in the literature, and suggests future directions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Pediatric genetic epilepsies, such as CDKL5 Deficiency Disorder (CDD), are severely debilitating, with early-onset seizures occurring more than ten times daily in extreme cases. Existing antiseizure drugs frequently prove ineffective, which significantly impacts child development and diminishes the quality of life for patients and caregivers. The relaxation of cannabis legislation has increased research into potential therapeutic properties of phytocannabinoids such as cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). CBD's antiseizure properties have shown promise, particularly in treating drug-resistant genetic epilepsies associated with Lennox–Gastaut syndrome (LGS), Dravet syndrome (DS), and Tuberous Sclerosis Complex (TSC). However, specific research on CDD remains limited. Much of the current evidence relies on anecdotal reports of artisanal products lacking accurate data on cannabinoid composition. Utilizing model systems like patient-derived iPSC neurons and brain organoids allows precise dosing and comprehensive exploration of cannabinoids' pharmacodynamics. This review explores the potential of CBD, THC, and other trace cannabinoids in treating CDD and focusing on clinical trials and preclinical models to elucidate the cannabinoid's potential mechanisms of action in disrupted CDD pathways and strengthen the case for further research into their potential as anti-epileptic drugs for CDD. This review offers an updated perspective on cannabinoid's therapeutic potential for CDD. [ABSTRACT FROM AUTHOR]

Background: In 2020, there were 36.7 million reported falls among older adults (65+) in the United States. Ethanol and other sedating substances may increase fall risk among older adults due to their effect on cognitive and physical function. We estimate the prevalence of these substances in blood specimens of older adults presenting with a fall injury at selected trauma centers. Methods: The initial study collected blood specimens from May 2020 through July 2021 from adults undergoing a trauma team evaluation at selected United States Level 1 trauma centers. We limited our study to older adults evaluated after a fall (n = 1,365) and selected a random sample (n = 300) based on age, sex, and trauma-center quotas. Medical health records and blood specimens obtained at trauma center presentation were analyzed. We estimated the prevalence of ethanol, benzodiazepines, cannabinoids, and opioids in the blood specimens. Two-sample tests of binomial proportions and Chi-square two-tailed tests were used to compare prevalence estimates of substances by demographic characteristics. Results: At least one substance was detected among 31.3% of samples analyzed. Prevalences of specific substances detected were 9.3% (95% CI: 6.0–12.6%) for benzodiazepines, 4.3% (95% CI: 2.0–6.7%) for cannabinoids, 8.0% (95% CI: 5.2–11.7%) for ethanol, and 15.0% (95% CI: 10.9–19.1%) for opioids. There were 18 deaths (6%; 95% CI: 3.6–9.3%). One-third of decedents had at least one substance detected in their blood. Discussion: Opioids were the most frequently detected substance, followed by benzodiazepines, ethanol, and cannabinoids. Substance use prevalence was not uniform across demographics, with differences observed by sex and age. Conclusions: This study provides insight into the frequency of the presence of substances that may contribute to fall risk and serious injury among older adults. Screening older adults for substances that impair cognitive and physical function can enhance clinical fall prevention efforts. [ABSTRACT FROM AUTHOR]

Why you should read this article: • To develop your knowledge of rare epilepsy syndromes • To enhance your understanding of the association between epilepsy and learning disability • To contribute towards revalidation as part of your 35 hours of CPD (UK readers) • To contribute towards your professional development and local registration renewal requirements (non-UK readers). Epilepsy is more prevalent in people with learning disabilities than in the general population and there are a number of rare epilepsy syndromes closely associated with learning disability. These syndromes are challenging to manage, notably because seizures are often refractory, the risk of status epilepticus is high and comorbidities are usually present. People with a rare epilepsy syndrome need high levels of specialist support throughout their lives. Such syndromes are rare, but professionals who care for people with learning disabilities are likely to encounter them at some point in their career. Improved knowledge and understanding of rare epilepsy syndromes can assist learning disability nurses to provide adequate information, care and support to service users, family members and paid carers as well as to other healthcare professionals. This article explains the association between epilepsy and learning disability, describes rare epilepsy syndromes and explores the goals of treatment, additional treatment options and challenges of management. [ABSTRACT FROM AUTHOR]

Introduction: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder affecting about 1% of children. The disorder is characterized by difficulties within three core symptoms: social interactions, communication, and restricted or repetitive behavior. There is currently no approved psychopharmacological treatment; however, it is hypothesized that ASD symptoms might be ameliorated by manipulating the endocannabinoid (eCB) system. This study aims to review the existing research on cannabinoids as a potential effective treatment for the core symptoms of ASD in children and adolescents. Methods: A literature search was conducted on PubMed, Embase, APA PsychInfo, and Cochrane. The available literature was screened, and studies were included if: the study population consisted of children/adolescents, the treatment involved cannabinoids, and the outcome assessed was the impact on core ASD symptoms. Results: The search yielded five studies, two RCTs and three cohort studies. All the included studies reported an effect of the cannabinoid treatment; however, most of these effects were non-significant and not related to core symptoms. Only one study found a significant improvement on all three core symptoms. The risk of bias was rated as "high" or "very high" in four studies and as "low" in one study. Discussion: Although the included studies did not find substantial results regarding core ASD symptoms, they all reported that cannabinoid treatment had other positive effects. However, Long term outcome is unknown, and safety aspects are scarcely discussed. Conclusion: Based on this review, the effect of cannabinoid treatment on ASD core symptoms is not clear; therefore, further studies are required. [ABSTRACT FROM AUTHOR]

Rationale: Recent reports have shown increased cannabis use among women, leading to growing concerns about cannabis use disorder (CUD). While there is preclinical evidence suggesting biological sex influences cannabinoid effects, human research remains scant. We investigated sex differences in the acute response to oral tetrahydrocannabinol (THC) in humans. Methods: 56 healthy men and women with prior exposure to cannabis but no history of CUD participated in a randomized, placebo-controlled, human laboratory study where they received a single 10 mg dose of oral THC (dronabinol). Subjective psychoactive effects were assessed by the visual analog scale of "high", psychotomimetic effects by the Clinician-Administered Dissociative Symptoms Scale and Psychotomimetic States Inventory, verbal learning and memory by Rey Auditory Verbal Learning Test (RAVLT), and physiological effects by heart rate. Outcomes were regularly measured on the test day, except for the RAVLT, which was assessed once. Peak differences from baseline were analyzed using a nonparametric method for repeated measures. Results: Oral THC (10 mg) demonstrated significant dose-related effects in psychotomimetic and physiological domains, but not in RAVLT outcomes. A notable interaction between THC dose and sex emerged concerning the subjective "high" scores, with women reporting heightened sensations (p = 0.05). No other significant effects of sex and THC dose interaction were observed. Conclusion: Oral THC (10 mg) yields similar acute psychotomimetic and physiological effects across sexes, but women may experience a pronounced subjective psychoactive effect. Further research is needed to identify individual vulnerabilities and facilitate tailored interventions addressing CUD. Clinicaltrials.gov registration: https://clinicaltrials.gov/study/NCT02781519?term=Ranganathan&intr=THC&rank=3. [ABSTRACT FROM AUTHOR]

Italy legalized cannabis oil for specific medical conditions (neuropathic pain, refractory epilepsy and other established pathologies) in 2015, but mandates titration of principal cannabinoids before marketing each batch using iphenated techniques coupled with mass spectrometry. To assess reliability of laboratories from the Italian National Health Service in charge of titrating the batches, the Italian National Institute of Health set up an quality control program on determination of Δ9-tetrahydrocannabinol l (THC), cannabidiol (CBD), Δ9-tetrahydrocannabinolic acid A (THCA-A) and cannabidiolic acid (CBDA) in cannabis oil preparations. Two rounds of exercises have been carried out since 2019, involving sixteen Italian laboratories. Five different cannabis oil samples (19-1A and 19-1B for the first round and 22-1A, 22-1B and 22-1C for the second one were prepared and 1 mL amount of each sample was sent to the laboratories. The quantitative performance of each laboratory was assessed calculating the Z-score value, a statistical measurement for value's relationship to the mean of a group of values. In the first round, eight out of fourteen laboratories employed an LC-MS while the remaining six used GC-MS. Differently, in the second round, six out of eleven laboratories employed a GC-MS while the remaining five used LC-MS. In the first round, only 28.6 % laboratories achieved an acceptable performance (Z-score±2), and all of them used LC-MS as analytical method. In the second round, none of the laboratories achieved an acceptable performance. Satisfactory results, based on Z-scores, were generally low (0.0–75.0 %), with only one exception of 100 % for THCA-A determination in sample 22-1B. In the second round, three false negatives (two THC and one CBD by GC-MS determination) were reported while no false positives were described in the blank sample. The two rounds yielded a mean ERR% of 42 % approximately and a mean CV% around 70 % in GC-MS determination. When applying LC-MS determination, the two rounds yielded a mean ERR% of 36 % approximately and a mean CV% around 33 %. The obtained results underline the need for a clear and consistent protocol to be adopted by all laboratories intending to include the titration of oily cannabis-based products into their routinely analytical techniques. This emphasis on methodology standardization and participation to quality control schemes is essential for ensuring reliable and accurate measurements, ultimately enhancing the overall effectiveness and reliability of medical cannabis treatments. [ABSTRACT FROM AUTHOR]

Natural non-psychoactive cannabinoids such as cannabigerol (CBG), cannabidiol (CBD), cannabichromene (CBC), cannabidivarin (CBDV), and cannabinol (CBN) are increasingly consumed as constituents of dietary products because of the health benefits claims. Cannabinoids may reduce certain types of pain, nausea, and anxiety. Anti-inflammatory and even anti-carcinogenic properties have been discussed. However, there are insufficient data available regarding their potential (geno-)toxic effects. Therefore, we tested CBG, CBD, CBC, CBDV, and CBN for their genotoxic potential and effects on mitosis and cell cycle in human lymphoblastoid TK6 cells. The selected cannabinoids (except CBDV) induced increased micronuclei formation, which was reduced with the addition of a metabolic activation system (S9 mix). CBDV induced micronuclei only after metabolic activation. Mitotic disturbances were observed with all tested cannabinoids, while G1 phase accumulation of cells was observed for CBG, CBD and CBDV. The genotoxic effects occurred at about 1000-fold higher concentrations than are reported as blood levels from human consumption. However, the results clearly indicate a need for further research into the genotoxic effects of cannabinoids. The mechanism of the mitotic disturbance, the shape of the dose–response curves and the possible effects of mixtures of cannabinoids are aspects which need clarification. [ABSTRACT FROM AUTHOR]