The State of Synthetic Cannabinoid Medications for the Treatment of Pain.

Synthetic cannabinoids are compounds made in the laboratory to structurally and functionally mimic phytocannabinoids from the Cannabis sativa L. plant, including delta-9-tetrahydrocannabinol (THC). Synthetic cannabinoids (SCs) can signal via the classical endogenous cannabinoid system (ECS) and the greater endocannabidiome network, highlighting their signalling complexity and far-reaching effects. Dronabinol and nabilone, which mimic THC signalling, have been approved by the Food and Drug Administration (FDA) for treating nausea associated with cancer chemotherapy and/or acquired immunodeficiency syndrome (AIDS). However, there is ongoing interest in these two drugs as potential analgesics for a variety of other clinical conditions, including neuropathic pain, spasticity-related pain, and nociplastic pain syndromes including fibromyalgia, osteoarthritis, and postoperative pain, among others. In this review, we highlight the signalling mechanisms of FDA-approved synthetic cannabinoids, discuss key clinical trials that investigate their analgesic potential, and illustrate challenges faced when bringing synthetic cannabinoids to the clinic.

Can cannabinoids contribute to cholecystitis - a case of gangrenous acalculous cholecystitis.

SUMMARY: Cannabis legalisation continues to grow globally and its effects on the vascular system have been scrutinized.1 Cannabis has become recognised as a contributor to cardiovascular, cerebrovascular and peripheral vascular disease.2,3 This case report highlights the case of a young male patient presenting with atypical symptoms following cannabis use who developed gangrenous cholecystitis (GC) following vasospasm of his cystic artery. We believe that this is the first-ever case, shared with the anticipation of stimulating more research and prompting recognition of vascular events in this group of patients as our knowledge on the effects of cannabis continues to grow.

Neurological Complications of Cannabinoids.

Cannabinoid use, particularly for recreational purposes, is increasing exponentially across all age groups, especially in younger populations, due to its perceived low risk and legalization. While cannabinoids may be largely considered as safe, there is mounting evidence of increased risk of systemic and neurological complications through their interaction with the poorly understood endocannabinoid receptor network within the central nervous system and other organ systems. Acute cannabinoid exposure can cause neuropsychiatric symptoms in addition to altering cerebral blood flow, leading to cerebrovascular complications such as ischemic stroke, subarachnoid hemorrhage, and reversible cerebral vasoconstriction syndrome (RCVS). Chronic use, particularly among adolescents, may be associated with increased risk of long-term cognitive deficits, schizophrenia, and other neuropsychiatric effects. Synthetic cannabinoids have increased potency, with reports of causing profound neurological complications including coma, seizures, posterior reversible encephalopathy syndrome, and RCVS. Despite increasing evidence, the quality of literature describing neurologic complications with cannabinoids remains limited to case series and retrospective cohort studies, with significant confounding factors such as concomitant use of other illicit drugs, limiting interpretation. In this review, we summarize the effect of cannabinoids on the neurologic system and associated neurological complications.

[Toxicology of synthetic cannabinoids]. / Toxicologie des cannabinoïdes de synthèse.

Synthetic cannabinoids (CS), or synthetic endocannabinoid receptor agonists, were initially synthesized for basic research into exocannabinoid signaling pathways, as well as in clinical research for their analgesic properties. The use of CS for recreational purposes is a recent phenomenon, but one that has grown very quickly in recent years, since these molecules now represent the main category of new synthetic products (NPS). This literature review aims to bring together current data regarding the use and effects caused by CS in humans. The relationship between the structure and activity of these CSs, the pharmacology and adverse effects of these CSs and finally the different methods of analyzing CSs. A better understanding of this phenomenon is essential to raise awareness among stakeholders in the health field.

Cannabinoid products for pain management: recommendations from the São Paulo State Society of Anesthesiology.

There is growing interest in using cannabinoids across various clinical scenarios, including pain medicine, leading to the disregard of regulatory protocols in some countries. Legislation has been implemented in Brazil, specifically in the state of São Paulo, permitting the distribution of cannabinoid products by health authorities for clinical purposes, free of charge for patients, upon professional prescription. Thus, it is imperative to assess the existing evidence regarding the efficacy and safety of these products in pain management. In light of this, the São Paulo State Society of Anesthesiology (SAESP) established a task force to conduct a narrative review on the topic using the Delphi method, requiring a minimum agreement of 60% among panelists. The study concluded that cannabinoid products could potentially serve as adjuncts in pain management but stressed the importance of judicious prescription. Nevertheless, this review advises against their use for acute pain and cancer-related pain. In other clinical scenarios, established treatments should take precedence, particularly when clinical protocols are available, such as in neuropathic pain. Only patients exhibiting poor therapeutic responses to established protocols or demonstrating intolerance to recommended management may be considered as potential candidates for cannabinoids, which should be prescribed by physicians experienced in handling these substances. Special attention should be given to individual patient characteristics and the likelihood of drug interactions.

Guidelines for Reasonable and Appropriate Care in the Emergency Department (GRACE-4): Alcohol use disorder and cannabinoid hyperemesis syndrome management in the emergency department.

The fourth Society for Academic Emergency Medicine (SAEM) Guidelines for Reasonable and Appropriate Care in the Emergency Department (GRACE-4) is on the topic of the emergency department (ED) management of nonopioid use disorders and focuses on alcohol withdrawal syndrome (AWS), alcohol use disorder (AUD), and cannabinoid hyperemesis syndrome (CHS). The SAEM GRACE-4 Writing Team, composed of emergency physicians and experts in addiction medicine and patients with lived experience, applied the Grading of Recommendations Assessment Development and Evaluation (GRADE) approach to assess the certainty of evidence and strength of recommendations regarding six priority questions for adult ED patients with AWS, AUD, and CHS. The SAEM GRACE-4 Writing Team reached the following recommendations: (1) in adult ED patients (over the age of 18) with moderate to severe AWS who are being admitted to hospital, we suggest using phenobarbital in addition to benzodiazepines compared to using benzodiazepines alone [low to very low certainty of evidence]; (2) in adult ED patients (over the age of 18) with AUD who desire alcohol cessation, we suggest a prescription for one anticraving medication [very low certainty of evidence]; (2a) in adult ED patients (over the age of 18) with AUD, we suggest naltrexone (compared to no prescription) to prevent return to heavy drinking [low certainty of evidence]; (2b) in adult ED patients (over the age of 18) with AUD and contraindications to naltrexone, we suggest acamprosate (compared to no prescription) to prevent return to heavy drinking and/or to reduce heavy drinking [low certainty of evidence]; (2c) in adult ED patients (over the age of 18) with AUD, we suggest gabapentin (compared to no prescription) for the management of AUD to reduce heavy drinking days and improve alcohol withdrawal symptoms [very low certainty of evidence]; (3a) in adult ED patients (over the age of 18) presenting to the ED with CHS we suggest the use of haloperidol or droperidol (in addition to usual care/serotonin antagonists, e.g., ondansetron) to help with symptom management [very low certainty of evidence]; and (3b) in adult ED patients (over the age of 18) presenting to the ED with CHS, we also suggest offering the use of topical capsaicin (in addition to usual care/serotonin antagonists, e.g., ondansetron) to help with symptom management [very low certainty of evidence].

Trends of emergency department visits for cannabinoid hyperemesis syndrome in Nevada: An interrupted time series analysis.

Cannabis-related emergency department visits have increased after legalization of cannabis for medical and recreational use. Accordingly, the incidence of emergency department visits due to cannabinoid hyperemesis syndrome in patients with chronic cannabis use has also increased. The aim of this study was to examine trends of emergency department visit due to cannabinoid hyperemesis syndrome in Nevada and evaluate factors associated with the increased risk for emergency department visit. The State Emergency Department Databases of Nevada between 2013 and 2021 were used for investigating trends of emergency department visits for cannabinoid hyperemesis syndrome. We compared patients visiting the emergency department due to cannabinoid hyperemesis syndrome with those visiting the emergency department due to other causes except cannabinoid hyperemesis and estimated the impact of cannabis commercialization for recreational use. Emergency department visits due to cannabinoid hyperemesis syndrome have continuously increased during the study period. The number of emergency department visits per 100,000 was 1.07 before commercialization for recreational use. It increased to 2.22 per 100,000 (by approximately 1.1 per 100,000) after commercialization in the third quarter of 2017. Those with cannabinoid hyperemesis syndrome were younger with fewer male patients than those without cannabinoid hyperemesis syndrome. A substantial increase in emergency department visits due to cannabinoid hyperemesis syndrome occurred in Nevada, especially after the commercialization of recreational cannabis. Further study is needed to explore factors associated with emergency department visits.

Reduced fetal cerebral blood flow predicts perinatal mortality in a mouse model of prenatal alcohol and cannabinoid exposure.

BACKGROUND: Children exposed prenatally to alcohol or cannabinoids individually can exhibit growth deficits and increased risk for adverse birth outcomes. However, these drugs are often co-consumed and their combined effects on early brain development are virtually unknown. The blood vessels of the fetal brain emerge and mature during the neurogenic period to support nutritional needs of the rapidly growing brain, and teratogenic exposure during this gestational window may therefore impair fetal cerebrovascular development. STUDY DESIGN: To determine whether prenatal polysubstance exposure confers additional risk for impaired fetal-directed blood flow, we performed high resolution in vivo ultrasound imaging in C57Bl/6J pregnant mice. After pregnancy confirmation, dams were randomly assigned to one of four groups: drug-free control, alcohol-exposed, cannabinoid-exposed or alcohol-and-cannabinoid-exposed. Drug exposure occurred daily between Gestational Days 12-15, equivalent to the transition between the first and second trimesters in humans. Dams first received an intraperitoneal injection of either cannabinoid agonist CP-55,940 (750 µg/kg) or volume-equivalent vehicle. Then, dams were placed in vapor chambers for 30 min of inhalation of either ethanol or room air. Dams underwent ultrasound imaging on three days of pregnancy: Gestational Day 11 (pre-exposure), Gestational Day 13.5 (peri-exposure) and Gestational Day 16 (post-exposure). RESULTS: All drug exposures decreased fetal cranial blood flow 24-hours after the final exposure episode, though combined alcohol and cannabinoid co-exposure reduced internal carotid artery blood flow relative to all other exposures. Umbilical artery metrics were not affected by drug exposure, indicating a specific vulnerability of fetal cranial circulation. Cannabinoid exposure significantly reduced cerebroplacental ratios, mirroring prior findings in cannabis-exposed human fetuses. Post-exposure cerebroplacental ratios significantly predicted subsequent perinatal mortality (p = 0.019, area under the curve, 0.772; sensitivity, 81%; specificity, 85.70%) and retroactively diagnosed prior drug exposure (p = 0.005; AUC, 0.861; sensitivity, 86.40%; specificity, 66.7%). CONCLUSIONS: Fetal cerebrovasculature is significantly impaired by exposure to alcohol or cannabinoids, and co-exposure confers additional risk for adverse birth outcomes. Considering the rising potency and global availability of cannabis products, there is an imperative for research to explore translational models of prenatal drug exposure, including polysubstance models, to inform appropriate strategies for treatment and care in pregnancies affected by drug exposure.

Distinguishing Clinical Features of Cannabinoid Hyperemesis Syndrome and Cyclic Vomiting Syndrome: A Retrospective Cohort Study.

OBJECTIVE: To identify clinical characteristics that distinguish cannabinoid hyperemesis syndrome (CHS) from cyclic vomiting syndrome (CVS), 2 conditions marked by episodes of nausea, vomiting, and abdominal pain. STUDY DESIGN: We performed a retrospective chart review of patients admitted to a large children's health care system from 2015 through 2022. Patients with CHS and CVS were identified by the electronic medical record using International Classification of Diseases, Ninth and Tenth Revision codes. RESULTS: Of 201 patients screened, 125 were included. Patients with CHS were older than those with CVS (mean [SD] 18.06 [1.41] vs 14.50 [2.91] years, P < .001). There were no significant differences in sex, race, ethnicity, or hospital length of stay between groups. Patients with CHS were more likely to have a positive urine drug screen (86% vs 2.9%, P < .001), lower mean (SD) serum potassium (3.62 [0.77] vs 3.88 [0.49], P < .001), and greater mean (SD) serum creatinine (0.83 (0.41) vs 0.63 (0.17), P < .001). The average (SD) systolic blood pressure was significantly greater in patients with CHS (systolic blood pressure 124.46 [10.66] vs 118.55 [10.99], P = .032) compared with children of comparable age range with CVS. Imaging was obtained in 36% of all patients, and only 2.4% had abnormalities. CONCLUSIONS: Clinical features including older age, greater systolic blood pressure, positive urine drug screen, and select electrolyte findings might distinguish CHS from CVS. Abdominal imaging in both conditions is of low yield. These findings may allow for early recognition and appropriate therapy in CHS patients.

Cannabinoid hyperemesis syndrome.

SummaryCannabis use is legalised in many countries. We present a patient in their 40s who complained of recurrent abdominal pain and associated nausea and vomiting. The patient was previously seen in various hospitals, treated symptomatically, and discharged with a diagnosis of non-specific abdominal pain. The patient had a chronic history of smoking cannabis and nicotine and drinking alcohol. Abdominal examination revealed no masses, and abdominal X-ray was normal. Blood tests and gastroduodenoscopy revealed no obvious aetiology. Intravenous fluids, together with antiemetics and proton pump inhibitors, were administered. The patient also received counselling and was advised to stop cannabis use. At discharge, the patient was well and asked to come back for review in 2 weeks, and, thereafter monthly for a period of 6 months after stopping cannabis use. The patient reported no recurrent symptoms despite continued cigarette and alcohol use. A suspected cannabinoid hyperemesis syndrome (CHS) became a consideration. Awareness of cannabis-related disorders such as CHS may assist in avoiding costly hospital workups.

The Impact of Cannabis Use on Cognition in People with HIV: Evidence of Function-Dependent Effects and Mechanisms from Clinical and Preclinical Studies.

PURPOSE OF REVIEW: Cannabis 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 FINDINGS: Results 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.

Cannabis and Cannabinoids in Adults With Cancer: ASCO Guideline Q&A.

@JCO_ASCO guideline on #cannabis in cancer with @JCOOP_ASCO companion Q&A addressing key clinical questions.

Exploring the Possible Role of Cannabinoids in Managing Post-cardiac Surgery Complications: A Narrative Review of Preclinical Evidence and a Call for Future Research Directions.

ABSTRACT: Open-heart surgery with cardiopulmonary bypass often leads to complications including pain, systemic inflammation, and organ damage. Traditionally managed with opioids, these pain relief methods bring potential long-term risks, prompting the exploration of alternative treatments. The legalization of cannabis in various regions has reignited interest in cannabinoids, such as cannabidiol, known for their anti-inflammatory, analgesic, and neuroprotective properties. Historical and ongoing research acknowledges the endocannabinoid system's crucial role in managing physiological processes, suggesting that cannabinoids could offer therapeutic benefits in postsurgical recovery. Specifically, cannabidiol has shown promise in managing pain, moderating immune responses, and mitigating ischemia/reperfusion injury, underscoring its potential in postoperative care. However, the translation of these findings into clinical practice faces challenges, highlighting the need for extensive research to establish effective, safe cannabinoid-based therapies for patients undergoing open-heart surgery. This narrative review advocates for a balanced approach, considering both the therapeutic potential of cannabinoids and the complexities of their integration into clinical settings.

Cannabis and Cannabinoids in Adults With Cancer: ASCO Guideline.

PURPOSE: To guide clinicians, adults with cancer, caregivers, researchers, and oncology institutions on the medical use of cannabis and cannabinoids, including synthetic cannabinoids and herbal cannabis derivatives; single, purified cannabinoids; combinations of cannabis ingredients; and full-spectrum cannabis. METHODS: A systematic literature review identified systematic reviews, randomized controlled trials (RCTs), and cohort studies on the efficacy and safety of cannabis and cannabinoids when used by adults with cancer. Outcomes of interest included antineoplastic effects, cancer treatment toxicity, symptoms, and quality of life. PubMed and the Cochrane Library were searched from database inception to January 27, 2023. ASCO convened an Expert Panel to review the evidence and formulate recommendations. RESULTS: The evidence base consisted of 13 systematic reviews and five additional primary studies (four RCTs and one cohort study). The certainty of evidence for most outcomes was low or very low. RECOMMENDATIONS: Cannabis and/or cannabinoid access and use by adults with cancer has outpaced the science supporting their clinical use. This guideline provides strategies for open, nonjudgmental communication between clinicians and adults with cancer about the use of cannabis and/or cannabinoids. Clinicians should recommend against using cannabis or cannabinoids as a cancer-directed treatment unless within the context of a clinical trial. Cannabis and/or cannabinoids may improve refractory, chemotherapy-induced nausea and vomiting when added to guideline-concordant antiemetic regimens. Whether cannabis and/or cannabinoids can improve other supportive care outcomes remains uncertain. This guideline also highlights the critical need for more cannabis and/or cannabinoid research.Additional information is available at www.asco.org/supportive-care-guidelines.

Cardiotoxic effects of common and emerging drugs: role of cannabinoid receptors.

Drug-induced cardiotoxicity has become one of the most common and detrimental health concerns, which causes significant loss to public health and drug resources. Cannabinoid receptors (CBRs) have recently achieved great attention for their vital roles in the regulation of heart health and disease, with mounting evidence linking CBRs with the pathogenesis and progression of drug-induced cardiotoxicity. This review aims to summarize fundamental characteristics of two well-documented CBRs (CB1R and CB2R) from aspects of molecular structure, signaling and their functions in cardiovascular physiology and pathophysiology. Moreover, we describe the roles of CB1R and CB2R in the occurrence of cardiotoxicity induced by common drugs such as antipsychotics, anti-cancer drugs, marijuana, and some emerging synthetic cannabinoids. We highlight the 'yin-yang' relationship between CB1R and CB2R in drug-induced cardiotoxicity and propose future perspectives for CBR-based translational medicine toward cardiotoxicity curation and clinical monitoring.

Cannabinoid hyperemesis and pheochromocytoma hypertensive urgency: a case report.

BACKGROUND: This report presents a case of cannabinoid-induced hyperemesis syndrome causing repeated violent retching in a patient with a large (8 cm) adrenal pheochromocytoma resulting in hypertensive urgency. CASE PRESENTATION: A 69-year-old white male patient with a previously diagnosed pheochromocytoma presented to the emergency department with nausea and vomiting and was found to have hypertensive urgency. Computed tomography scan did not show any acute abdominal pathology and history was inconsistent with a gastrointestinal etiology. Patient had a history of daily cannabinoid use for many years and repeated self-limited hyperemesis episodes, and thus a diagnosis of cannabinoid-induced hyperemesis syndrome was made. It was concluded that the likely explanation for the hypertensive urgency was from physical compression of his adrenal tumor during the episodes of retching resulting in a catecholamine surge. The patient was given antiemetics and admitted to the intensive care unit for blood pressure management. Blood pressure was initially controlled with phentolamine and a clevidipine infusion, then transitioned to oral doxazosin and phenoxybenzamine. Hyperemesis and abdominal pain resolved after 24 hours, and his blood pressure returned to baseline. The patient was discharged with the recommendation to stop all cannabis use. On follow-up, his blood pressure remained well controlled, and he subsequently underwent adrenalectomy for tumor removal. CONCLUSION: Hyperemesis can cause hypertensive events in patients with pheochromocytoma by increasing abdominal pressure, leading to catecholamine release.

New-Onset Prolonged Psychosis Following Synthetic Cannabinoid Use in an Older Patient: A Case Report.

Synthetic cannabinoids (SCs), a class of new psychoactive substances (NPS) commonly known as "spice," has rapidly gained popularity and become the most ubiquitous NPS on the illegitimate drug market. SCs, unlike natural cannabis (NC), are not controlled by international drug conventions, posing a significant risk to public health. These substances are easily accessible, relatively inexpensive, and challenging to detect in routine drug screenings. The existing literature provides strong evidence of an association between NC use and psychosis, but there is significantly less data on SC psychosis. We present a clinical case report of a 51-year-old African American female with no known psychiatric history who was admitted to the inpatient psychiatric unit after reported paranoia and altered mental status for the preceding six days. During hospitalization, she exhibited disorganization, persecutory delusions, extreme agitation, and bizarre behaviors that included the concealment of a set of stolen keys in her vagina, necessitating an ethics consult. After consideration of differentials, the patient was diagnosed with substance-induced psychotic disorder secondary to SC. The patient was stabilized on 3 mg Risperidone at bedtime. After 16-day hospitalization, she reached her baseline and later revealed that she had recently smoked SC for the first time. The primary goal of this case is to highlight the sequelae of SC-associated psychosis. A SC-associated psychosis could drastically vary from NC and is often undetectable on a typical UDS, which may result in a lifelong primary psychotic disorder misdiagnosis.

AGA Clinical Practice Update on Diagnosis and Management of Cannabinoid Hyperemesis Syndrome: Commentary.

DESCRIPTION: The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update (CPU) is to review the available evidence and provide expert advice regarding diagnosis and management of cannabinoid hyperemesis syndrome. METHODS: This CPU was commissioned and approved by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. This expert commentary incorporates important as well as recently published studies in this field, and it reflects the experiences of the authors.

Medical cannabis use in oncology and associated outcomes: A scoping review.

BACKGROUND: Natural and synthetic cannabinoids are being used worldwide to treat various symptoms in cancer patients. This study aims to map the therapeutic benefits and adverse effects associated with the use of cannabis-based drugs in these outcomes. METHODS: Following Joanna Briggs Institute guidelines a scoping review was conducted. The study protocol was available in the Open Science Framework public repository. An extensive search strategy involving databases like Cochrane Library, Embase, CINAHL, Medline/PubMed, Lilacs, Google Scholar, and Open Gray for gray literature analysis was executed by a skilled librarian. The inclusion criteria were primary studies (observational and randomized) that evaluated the efficacy and safety of cannabinoids in cancer patients. The review encompassed studies of diverse designs, publication years, and types, as long as they addressed cannabinoids' impact in oncology. RESULTS: Twenty-nine (82.86%) out of total of 35 were randomized and 6 (14.14%) were non-randomized. About 57.1% of studies utilized registered products as interventions, with THC being the most natural cannabinoid cited in variable doses and administration routes. Moreover, 62.85% of studies specified the cancer types (breast, lung, sarcomas, hematological and reproductive system), while only one study detailed cancer staging. The evaluated outcomes encompassed nausea and vomiting (77.14%), appetite (11.43%), pain (8.57%), and tumor regression (2.86%) across different proportions of studies. CONCLUSION: Cannabinoids show promise in managing pain, emesis, and anorexia/cachexia linked to cancer progression. New randomized clinical trials with a larger number of participants and observational studies on long-term safety are crucial to affirm their medicinal utility for cancer patients unresponsive to conventional drugs.