Relatório Epidemiológico: casos suspeitos de intoxicação exógena por canabinoides sintéticos - 01/09/2024 a 07/09/2024

O Programa Municipal de Prevenção e Controle de Intoxicações (PMPCI) da Coordenadoria de Vigilância em Saúde da Secretaria Municipal da Saúde de São Paulo (COVISA/SMS-SP) disponibiliza semanalmente o relatório epidemiológico de casos suspeitos de intoxicação exógena por canabinoides sintéticos registrados no Sinan.

Relatório Epidemiológico: casos suspeitos de intoxicação exógena por canabinoides sintéticos - 25/08/2024 a 31/08/2024

O Programa Municipal de Prevenção e Controle de Intoxicações (PMPCI) da Coordenadoria de Vigilância em Saúde da Secretaria Municipal da Saúde de São Paulo (COVISA/SMS-SP) disponibiliza semanalmente o relatório epidemiológico de casos suspeitos de intoxicação exógena por canabinoides sintéticos registrados no Sinan.

Relatório Epidemiológico: casos suspeitos de intoxicação exógena por canabinoides sintéticos - 18/08/2024 a 24/08/2024

O Programa Municipal de Prevenção e Controle de Intoxicações (PMPCI) da Coordenadoria de Vigilância em Saúde da Secretaria Municipal da Saúde de São Paulo (COVISA/SMS-SP) disponibiliza semanalmente o relatório epidemiológico de casos suspeitos de intoxicação exógena por canabinoides sintéticos registrados no Sinan.

The effects of Cannabis sativa and cannabinoids on the inhibition of pancreatic lipase - An enzyme involved in obesity.

INTRODUCTION: Obesity is a chronic noncommunicable disease characterized by excessive body fat that can have negative health consequences. Obesity is a complex disease caused by a combination of genetic, environmental, and lifestyle factors. It is characterized by a discrepancy between caloric intake and expenditure. Obesity increases the risk of acquiring major chronic diseases, including heart disease, stroke, cancer, and Type 2 diabetes mellitus (T2DM). Currently, the inhibition of pancreatic lipases (PL) is a promising pharmacological therapy for obesity and weight management. In this study, the inhibition of pancreatic lipase by Cannabis sativa (C. sativa) plant extract and cannabinoids was investigated. METHODS: The inhibitory effect was assessed using p-nitrophenyl butyrate (pNPB), and the results were obtained by calculating the percentage relative activity and assessed using one-way analysis of variance (ANOVA). Kinetic studies and spectroscopy techniques were used to evaluate the mode of inhibition. Diet-induced; and diabetic rat models were studied to evaluate the direct effects of C. sativa extract on PL activity. RESULTS: Kinetic analyses showed that the plant extracts inhibited pancreatic lipase, with tetrahydrocannabinol (THC) and cannabinol (CBN) being the potential cause of the inhibition noted for the C. sativa plant extract. CBN and THC inhibited the pancreatic lipase activity in a competitive manner, with the lowest residual enzyme activity of 52 % observed at a 10 µg/mL concentration of CBN and 39 % inhibition at a 25 µg/mL concentration of THC. Circular dichroism (CD) spectroscopy revealed that the inhibitors caused a change in the enzyme's secondary structure. At low concentrations, THC showed potential for synergistic inhibition with orlistat. C.sativa treatment in an in vivo rat model confirmed its inhibitory effects on pancreatic lipase activity. CONCLUSION: The findings in this study provided insight into the use of cannabinoids as pancreatic lipase inhibitors and the possibility of using these compounds to develop new pharmacological treatments for obesity.

Inhibition of Myeloma Cell Function by Cannabinoid-Enriched Product Associated With Regulation of Telomere and TP53.

Multiple myeloma is a hematological cancer caused by the uncontrolled proliferation of abnormal plasma cells in the bone marrow, leading to excessive immunoglobulin production. Our study aimed to examine the anticancer properties of BRF1A, a cannabinoid (CBD)-enriched product, on 2 myeloma cell lines: U266 and ARH-7. We treated U266 and ARH-77 myeloma cells with varying doses of BRF1A and measured the production of IgE and IgG antibodies using ELISA. Cell viability was assessed using trypan blue and CCK-8 assays. We measured the expression of genes related to the production of IgE and IgG antibodies, IgEH, and IgGH. We determined its effect on the expression of telomerase and its phosphorylated form as an indicator of telomere stabilization. Furthermore, we determined its effect on other cancer-related targets such as NF-ĸB, c-Myc, and TP53 in U266 cells using reverse transcription polymerase chain reaction (RT-PCR) and western blotting. BRF1A reduced myeloma cell IgE and IgG production in a time and dose-dependent manner. It also suppressed the expression of p-IκBα, p-NFκB (p65), and total NFκB protein, as well as XBP1u and XBP1s. It increased the gene and protein expression of telomere and hTERT and significantly increased cancer suppressor TP53 gene and p53 protein expression. Additionally, BRF1A decreased the c-Myc gene and protein expression. Our study has shown that a CBD-enriched product can reduce the growth of myeloma cells by suppressing the critical functions of IgE- and IgG-producing cells. This study could help bridge the gap in understanding how cannabinoid-containing products affect cancer, aging, telomere, and cancer-suppressor gene activity.

Cannabinoids in the Inflamed Synovium Can Be a Target for the Treatment of Rheumatic Diseases.

The management of rheumatic diseases has noticeably changed in recent years with the development of targeted therapeutic agents, namely, biological disease-modifying antirheumatic drugs. Identifying essential signaling pathways and factors crucial for the development and progression of these diseases remains a significant challenge. Therapy could be used to delay the onset or reduce harm. The endocannabinoid system's presence within the synovium can be identified as a suggested target for therapeutic interventions due to its role in modulating pain, inflammation, and joint metabolism. This review brings together the most pertinent information concerning the actions of the endocannabinoid system present in inflamed synovial tissue and its interaction with phytocannabinoids and synthetic cannabinoids, which can be used from a therapeutic perspective to minimize the inflammatory and pain processes typical of osteoarthritis and rheumatoid arthritis.

Opioid and Cannabinoid Systems in Pain: Emerging Molecular Mechanisms and Use in Clinical Practice, Health, and Fitness.

Pain is an unpleasant sensory and emotional experience. Adequate pain control is often challenging, particularly in patients with chronic pain. Despite advances in pain management, drug addiction, overtreatment, or substance use disorders are not rare. Hence the need for further studies in the field. The substantial progress made over the last decade has revealed genes, signalling pathways, molecules, and neuronal networks in pain control thus opening new clinical perspectives in pain management. In this respect, data on the epigenetic modulation of opioid and cannabinoid receptors, key actors in the modulation of pain, offered new perspectives to preserve the activity of opioid and endocannabinoid systems to increase the analgesic efficacy of opioid- and cannabinoid-based drugs. Similarly, upcoming data on cannabidiol (CBD), a non-psychoactive cannabinoid in the marijuana plant Cannabis sativa, suggests analgesic, anti-inflammatory, antioxidant, anticonvulsivant and ansiolitic effects and supports its potential application in clinical contexts such as cancer, neurodegeneration, and autoimmune diseases but also in health and fitness with potential use in athletes. Hence, in this review article, we summarize the emerging epigenetic modifications of opioid and cannabinoid receptors and focus on CBD as an emerging non-psychoactive cannabinoid in pain management in clinical practice, health, and fitness.

New Psychoactive Substances Toxicity: A Systematic Review of Acute and Chronic Psychiatric Effects.

New psychoactive substances (NPSs) are a heterogenous group of psychotropic molecules and diverted pharmaceutical drugs sold worldwide as legal substitutes for controlled drugs. The psychiatric consequences of NPS use are relatively unknown, although evidence of related psychotic symptoms has been described in the literature. We sought to summarize the available evidence on NPS-related psychiatric disorders, to facilitate the interpretation of the molecular mechanism underlying their specific pathologies. A literature search of Scopus, PubMed and Google Scholar was conducted including studies published between 2013 and 2024, in which a correlation between NPS consumption and psychiatric symptoms was reported. Furthermore, the short- and long-term psychopathological effects were included. The literature search resulted in 109 NPS-related intoxication cases in which acute or chronic psychiatric symptoms were reported, mostly related to synthetic cannabinoids, followed by synthetic cathinones, hallucinogens, natural NPSs and stimulants. The most common acute symptoms were hallucinations, aggressiveness, and psychotic and bizarre behavior, related to the molecular disbalance of neurotransmitters in the central nervous systems, with different mechanisms. The lack of clear diagnostic criteria and toxicological analyses has resulted in crucial complications in psychiatric diagnoses related to NPS intoxication. Hence, the implementation of toxicological screening procedures in emergency rooms, including the main NPS classes, should support the diagnosis of acute intoxication and its proper therapeutic treatment. Finally, proper follow-up should be implemented to assess the chronic sequelae.

Rational Design and Modification of NphB for Cannabinoids Biosynthesis.

The rapidly growing field of cannabinoid research is gaining recognition for its impact in neuropsychopharmacology and mood regulation. However, prenyltransferase (NphB) (a key enzyme in cannabinoid precursor synthesis) still needs significant improvement in order to be usable in large-scale industrial applications due to low activity and limited product range. By rational design and high-throughput screening, NphB's catalytic efficiency and product diversity have been markedly enhanced, enabling direct production of a range of cannabinoids, without the need for traditional enzymatic conversions, thus broadening the production scope of cannabinoids, including cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerovarin (CBGV), and cannabigerovarinic acid (CBGVA). Notably, the W3 mutant achieved a 10.6-fold increase in CBG yield and exhibited a 10.3- and 20.8-fold enhancement in catalytic efficiency for CBGA and CBGV production, respectively. The W4 mutant also displayed an 9.3-fold increase in CBGVA activity. Molecular dynamics simulations revealed that strategic reconfiguration of the active site's hydrogen bonding network, disulfide bond formation, and enhanced hydrophobic interactions are pivotal for the improved synthetic efficiency of these NphB mutants. Our findings advance the understanding of enzyme optimization for cannabinoid synthesis and lay a foundation for the industrial-scale production of these valuable compounds.

Cannabinol (CBN) Influences the Ion Channels and Synaptic-Related Genes in NSC-34 Cell Line: A Transcriptomic Study.

Neurological disorders such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and schizophrenia are associated with altered neuronal excitability, resulting from dysfunctions in the molecular architecture and physiological regulation of ion channels and synaptic transmission. Ion channels and synapses are regarded as suitable therapeutic targets in modern pharmacology. Cannabinoids have received great attention as an original therapeutic approach for their effects on human health due to their ability to modulate the neurotransmitter release through interaction with the endocannabinoid system. In our study, we explored the effect of cannabinol (CBN) through next-generation sequencing analysis of NSC-34 cell physiology. Our findings revealed that CBN strongly influences the ontologies related to ion channels and synapse activity at all doses tested. Specifically, the genes coding for calcium and potassium voltage-gated channel subunits, and the glutamatergic and GABAergic receptors (Cacna1b, Cacna1h, Cacng8, Kcnc3, Kcnd1, Kcnd2, Kcnj4, Grik5, Grik1, Slc17a7, Gabra5), were up-regulated. Conversely, the genes involved into serotoninergic and cholinergic pathways (Htr3a, Htr3b, Htr1b, Chrna3, Chrnb2, Chrnb4), were down-regulated. These findings highlight the influence of CBN in the expression of genes involved into ion influx and synaptic transmission.

Tea Prepared from Dried Cannabis: What Do We Drink?

Besides many other uses, dried Cannabis may be used for "tea" preparation. This study focused on a comprehensive characterization of an aqueous infusion prepared according to a common practice from three fairly different Cannabis cultivars. The transfer of 42 phytocannabinoids and 12 major bioactive compounds (flavonoids) into the infusion was investigated using UHPLC-HRMS/MS. Phytocannabinoid acids were transferred generally in a higher extent compared to their counterparts; in the case of Δ9-THC, it was only in the range of 0.4-1.9% of content in the Cannabis used. A dramatic increase of phytocannabinoids, mainly of the neutral species, occurred when cream was added during steeping, and the transfer of Δ9-THC into "tea" achieved a range of 53-64%. Under such conditions, drinking a 250 mL cup of such tea by a 70 kg person might lead to multiple exceedance of the Acute Reference Dose (ARfD), 1 µg/kg b.w., even in the case when using hemp with a Δ9-THC content below 1% in dry weight for preparation.

[Simultaneous determination of 102 synthetic cannabinoids in electronic cigarette oil by liquid chromatography-tandem mass spectrometry].

Synthetic cannabinoids (SCs), which are among the most widely abused new psychoactive substances, are much more potent and have greater efficacy than natural cannabis. SCs can be disguised in various ways and are commonly sold in the form of electronic cigarette oil. SCs belong to a large family with structures consisting of a core with substituents, linker, ring with substituents, and tail. New SCs can be developed by adding substituents, such as halogen, alkyl, and alkoxy groups, to the aromatic ring system or by changing the alkyl chain length. Since the emergence of so-called first-generation SCs, subsequent developments have led to eighth-generation indole/indazole amide-based SCs. As of July 1, 2021, the entire category of SCs was added to the list of controlled substances, but implementation requires urgent improvements in detection technologies. Typically, each method is limited to a few SCs. Owing to the vast number of chemically diverse SCs and their fast update speed, the determination and identification of various types of SCs using a single method is challenging. Therefore, rapid, sensitive, and accurate quantitative methods that includes various types of SCs must be developed to meet the demand for the qualitative and quantitative analysis of new SCs in seized electronic cigarette oil. In this study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of 102 SCs in electronic cigarette oil. The mass spectrometry and liquid-phase conditions influencing SC separation and determination were optimized. Using the external standard method, 102 SCs were successfully identified in electronic cigarette oil. The samples were extracted using methanol. Target analytes were separated on a Shimadzu Shim-pack GIST-HP C18 AQ column (100 mm×2.1 mm, 1.9 µm) at a column temperature of 40 ℃. The mobile phases consisted of (A) 0.1% formic acid aqueous solution and (B) methanol-acetonitrile (1∶1, v/v). The gradient elution conditions were as follows: 0-8 min, 55%A-15%A; 8-15 min, 15%A; 15-16 min, 15%A-55%A; 16-18 min, 55%A. The flow rate was 0.4 mL/min and the injection volume was 1 µL. Operating in the multiple reaction monitoring mode, the 102 SCs were identified within 18 min. Each SC exhibited a good linear relationship in the range of 1-100.0 µg/L with a correlation coefficient (r)≥0.9915. The limits of detection were 0.01-0.30 µg/L and the limits of quantification were 0.04-0.99 µg/L, which meet the requirements for analyzing SCs in actual samples. Precision was determined using standard solutions with 2, 10, and 50 µg/L of the SCs. The precisions (n=6) were 0.3%-6.0%. The recoveries of the 102 SCs, as evaluated by spiking electronic cigarette oil at low (2 µg/mL), medium (10 µg/mL), and high (50 µg/mL) levels, were 80.1%-119.8%. Good performance was observed for the analysis of real samples. The developed method is accurate, rapid, sensitive, and effective for the determination of the 102 SCs in electronic cigarette oil, satisfying the requirements for practical qualitative and quantitative analysis.

Severe poisoning with semi-synthetic cannabinoids.

Recently, semi-synthetic cannabinoids have entered the illegal market and are produced to mimic the psychoactive effects of tetrahydrocannabinol (THC). This is a case report of a 19-year-old man, who was hospitalized due to severe sedation, hypotension and tachy- and bradycardia after ingestion of the semi-synthetic cannabinoids hexahydrocannabinol (HHC) and hexahydrocannabiphorol (HHC-P) mixed in food. HHC-P, HHC and metabolites were identified in blood samples. The amount of semi-synthetic cannabinoids in illegal products can be high, which can explain the described prolonged clinical effects.

The endocannabinoid system as a therapeutic target in neuropathic pain: a review.

INTRODUCTION: This review highlights the critical role of the endocannabinoid system (ECS) in regulating neuropathic pain and explores the therapeutic potential of cannabinoids. Understanding the mechanisms of the ECS, including its receptors, endogenous ligands, and enzymatic routes, can lead to innovative treatments for chronic pain, offering more effective therapies for neuropathic conditions. This review bridges the gap between preclinical studies and clinical applications by emphasizing ECS modulation for better pain management outcomes. AREAS COVERED: A review mapped the existing literature on neuropathic pain and the effects of modulating the ECS using natural and synthetic cannabinoids. This analysis examined ECS components and their alterations in neuropathic pain, highlighting the peripheral, spinal, and supraspinal mechanisms. This review aimed to provide a thorough understanding of the therapeutic potential of cannabinoids in the management of neuropathic pain. EXPERT OPINION: Advances in cannabinoid research have shown significant potential for the management of chronic neuropathic pain. The study emphasizes the need for high-quality clinical trials and collaborative efforts among researchers, clinicians, and regulatory bodies to ensure safe and effective integration of cannabinoids into pain management protocols. Understanding the mechanisms and optimizing cannabinoid formulations and delivery methods are crucial for enhancing therapeutic outcomes.

Cannabinoid combination targets NOTCH1-mutated T-cell acute lymphoblastic leukemia through the integrated stress response pathway.

In T-cell acute lymphoblastic leukemia (T-ALL), more than 50% of cases display autoactivation of Notch1 signaling, leading to oncogenic transformation. We have previously identified a specific chemovar of Cannabis that induces apoptosis by preventing Notch1 maturation in leukemia cells. Here, we isolated three cannabinoids from this chemovar that synergistically mimic the effects of the whole extract. Two were previously known, cannabidiol (CBD) and cannabidivarin (CBDV), whereas the third cannabinoid, which we termed 331-18A, was identified and fully characterized in this study. We demonstrated that these cannabinoids act through cannabinoid receptor type 2 and TRPV1 to activate the integrated stress response pathway by depleting intracellular Ca2+. This is followed by increased mRNA and protein expression of ATF4, CHOP, and CHAC1, which is hindered by inhibiting the upstream initiation factor eIF2α. The increased abundance of CHAC1 prevents Notch1 maturation, thereby reducing the levels of the active Notch1 intracellular domain, and consequently decreasing cell viability and increasing apoptosis. Treatment with the three isolated molecules resulted in reduced tumor size and weight in vivo and slowed leukemia progression in mice models. Altogether, this study elucidated the mechanism of action of three distinct cannabinoids in modulating the Notch1 pathway, and constitutes an important step in the establishment of a new therapy for treating NOTCH1-mutated diseases and cancers such as T-ALL.

Cannabis sativa in veterinary medicine: Foundations and therapeutic applications.

An increase in products containing phytocannabinoids, particularly cannabidiol, is often observed in human and veterinary markets following the legalization of hemp (cannabis) for industrial purposes. In veterinary medicine, derivatives of Cannabis sativa are used for managing pain (osteoarticular, oncological, and neuropathic), epilepsy, and behavioral disorders, as well as oncological, immune-mediated, cardiovascular, and respiratory diseases. In addition, there is growing interest in incorporating C. sativa into livestock feed. To elucidate the mechanisms of action of phytocannabinoids, a thorough understanding of the endocannabinoid system and its role in maintaining homeostasis is essential. Short-term use of phytocannabinoid products appears generally safe, but further research is required to understand the routes of administration, pharmacokinetics, and pharmacodynamics across various species. Although literature on phytocannabinoids in veterinary patients is limited, the available data suggest significant therapeutic potential.

Cannabis sativa en médecine vétérinaire : fondements et applications thérapeutiquesUne augmentation des produits contenant des phytocannabinoïdes, notamment du cannabidiol, est souvent observée sur les marchés humains et vétérinaires à la suite de la légalisation du chanvre (cannabis) à des fins industrielles. En médecine vétérinaire, les dérivés du Cannabis sativa sont utilisés pour gérer la douleur (ostéoarticulaire, oncologique et neuropathique), l'épilepsie et les troubles du comportement, ainsi que les maladies oncologiques, immunitaires, cardiovasculaires et respiratoires. En outre, l'incorporation de C. sativa dans l'alimentation du bétail suscite un intérêt croissant. Pour élucider les mécanismes d'action des phytocannabinoïdes, une compréhension approfondie du système endocannabinoïde et de son rôle dans le maintien de l'homéostasie est essentielle. L'utilisation à court terme de produits phytocannabinoïdes semble généralement sécuritaire, mais des recherches supplémentaires sont nécessaires pour comprendre les voies d'administration, la pharmacocinétique et la pharmacodynamique chez diverses espèces. Bien que la littérature sur les phytocannabinoïdes chez les patients vétérinaires soit limitée, les données disponibles suggèrent un potentiel thérapeutique important.(Traduit par Dr Serge Messier).

Relatório Epidemiológico: casos suspeitos de intoxicação exógena por canabinoides sintéticos - 11/08/2024 a 17/08/2024

O Programa Municipal de Prevenção e Controle de Intoxicações (PMPCI) da Coordenadoria de Vigilância em Saúde da Secretaria Municipal da Saúde de São Paulo (COVISA/SMS-SP) disponibiliza semanalmente o relatório epidemiológico de casos suspeitos de intoxicação exógena por canabinoides sintéticos registrados no Sinan.

Relatório Epidemiológico: casos suspeitos de intoxicação exógena por canabinoides sintéticos - 04/08/2024 a 10/08/2024

O Programa Municipal de Prevenção e Controle de Intoxicações (PMPCI) da Coordenadoria de Vigilância em Saúde da Secretaria Municipal da Saúde de São Paulo (COVISA/SMS-SP) disponibiliza semanalmente o relatório epidemiológico de casos suspeitos de intoxicação exógena por canabinoides sintéticos registrados no Sinan.

Relatório Epidemiológico: casos suspeitos de intoxicação exógena por canabinoides sintéticos - 21/07/2024 a 27/07/2024

O Programa Municipal de Prevenção e Controle de Intoxicações (PMPCI) da Coordenadoria de Vigilância em Saúde da Secretaria Municipal da Saúde de São Paulo (COVISA/SMS-SP) disponibiliza semanalmente o relatório epidemiológico de casos suspeitos de intoxicação exógena por canabinoides sintéticos registrados no Sinan.

Relatório Epidemiológico: casos suspeitos de intoxicação exógena por canabinoides sintéticos - 28/07/2024 a 03/08/2024

O Programa Municipal de Prevenção e Controle de Intoxicações (PMPCI) da Coordenadoria de Vigilância em Saúde da Secretaria Municipal da Saúde de São Paulo (COVISA/SMS-SP) disponibiliza semanalmente o relatório epidemiológico de casos suspeitos de intoxicação exógena por canabinoides sintéticos registrados no Sinan.