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Despite centuries of recreational use of cannabis, it is only relatively recently that its mechanisms of action, and the existence of endogenous cannabinoids, have been discovered. In this Timeline article, Raphael Mechoulam and colleagues discuss early research on the plant cannabinoids and speculate on the directions this research might take in the future. Isolation and structure elucidation of most of the major cannabinoid constituents — including Δ 9 -tetrahydrocannabinol (Δ 9 -THC), which is the principal psychoactive molecule in Cannabis sativa — was achieved in the 1960s and 1970s. It was followed by the identification of two cannabinoid receptors in the 1980s and the early 1990s and by the identification of the endocannabinoids shortly thereafter. There have since been considerable advances in our understanding of the endocannabinoid system and its function in the brain, which reveal potential therapeutic targets for a wide range of brain disorders.

For thousands of years cannabis has been valued as a versatile herbal medicine. In the twentieth century, prescription gave way to proscription. Might this ancient remedy be about to regain its healing reputation? By Stephanie Pain

Research into the pharmacology of individual cannabinoids that began in the 1940s, several decades after the presence of a cannabinoid was first detected in cannabis, is concisely reviewed. Also described is how this pharmacological research led to the discovery of cannabinoid CB1 and CB2 receptors and of endogenous ligands for these receptors, to the development of CB1‐ and CB2‐selective agonists and antagonists and to the realization that the endogenous cannabinoid system has significant roles in both health and disease, and that drugs which mimic, augment or block the actions of endogenously released cannabinoids must have important therapeutic applications. Some goals for future research are identified. British Journal of Pharmacology (2006) 147, S163–S171. doi:10.1038/sj.bjp.0706406

Although anandamide (AEA) had been measured in human follicular fluid and is suggested to play a role in ovarian follicle and oocyte maturity, its exact source and role in the human ovary remains unclear. Immunohistochemical examination of normal human ovaries indicated that the endocannabinoid system was present and widely expressed in the ovarian medulla and cortex with more intense cannabinoid receptor 2 (CB2) than CB1 immunoreactivity in the granulosa cells of primordial, primary, secondary, tertiary follicles, corpus luteum and corpus albicans. The enzymes, fatty acid amide hydrolase (FAAH) and N-acyclphosphatidylethanolamine-phospholipase D (NAPE-PLD), were only found in growing secondary and tertiary follicles and corpora lutea and albicantes. The follicular fluid (FF) AEA concentrations of 260 FF samples, taken from 37 infertile women undergoing controlled ovarian hyperstimulation for in vitro fertilisation and intracytoplasmic sperm injection with embryo transfer, were correlated with ovarian follicle size (P = 0.03). Significantly higher FF AEA concentrations were also observed in mature follicles (1.43+/-0.04 nM; mean+/-SEM) compared to immature follicles (1.26+/-0.06 nM), P = 0.0142 and from follicles containing morphologically assessed mature oocytes (1.56+/-0.11 nM) compared to that containing immature oocytes (0.99+/-0.09 nM), P = 0.0011. ROC analysis indicated that a FF AEA level of 1.09 nM could discriminate between mature and immature oocytes with 72.2% sensitivity and 77.14% specificity, whilst plasma AEA levels and FF AEA levels on oocyte retrieval day were not significantly different (P = 0.23). These data suggest that AEA is produced in the ovary, is under hormonal control and plays a role in folliculogenesis, preovulatory follicle maturation, oocyte maturity and ovulation.

The genus Cannabis has a complex history, with great variations in the genus itself, as well as in its current uses worldwide. Today, it is the most commonly used psychoactive substance, with 209 million users in 2020. The legalization of cannabis for medicinal or adult use is complex. From its origins as a therapeutic agent in 2800 bc China, to the current knowledge on cannabinoids and the cannabinoid system, to the complex status of cannabis regulation across continents—knowledge gained from the history of cannabis use can inform research on cannabis-based treatments for patients with medical conditions that remain challenging in 21st century medicine, warranting research and evidence-based policy options. Changes in cannabis-related policymaking, scientific advances, and perceptions may result in increasing patient inquiries about its medicinal usage, regardless of personal opinions, thus meriting education and training of clinicians. This commentary outlines the long history of cannabis use, its current therapeutic potential from a regulatory research perspective, and the continued challenges in research and regulation in the ever-changing era of modern cannabis use. It is crucial to understand the history and complexity of cannabis use as medicine to better understand its potential for clinical therapeutics and the effects of modern-day legalization on other health- and society-related issues.

This article summarizes our early work with Viswanathan Natarajan in the 1980s at the University of Minnesota’s Hormel Institute, when he was at the beginning of his brilliant academic career. At that time most metabolic pathways for the biosynthesis and degradation of phospholipids were well established and known in considerable detail. Hence, it was exciting to discover a novel sequence of biochemical reactions, first in dog heart and later in various other vertebrate cells and tissues that became known as the transacylation-phosphodiesterase pathway of phospholipid metabolism. Because one of the metabolites, N-arachidonoylethanolamine, produced by this reaction sequence, was later found to bind to and activate cannabinoid receptors, investigations of this pathway became part of the rapidly growing field of endocannabinoid research. This is briefly summarized here as well.

dated about 12000 years ago in two domestication centers situated in Europe and Central Asia.Through the years cannabis spread to the Middle East and Africa (2000-500 yr BP) and then to the Americas from Europe (1545-1800 CE) and Asia (1800Asia ( -1945) ) (Warf, 2014;Crocq, 2020;Rull, 2022). Through these years cannabis varied uses and was associated with alleviating illnesses (Mirzaei et al., 2020), rituals and recreational practices (Kovalchuk et al., 2020;Mirzaei et al., 2020), and as a source of fiber for textiles, food, and oil (van Bakel et al., 2011;Salami et al., 2020).In its recent history, stigma, and prohibition, particularly during the 20th century, have complicated cannabis research and use, despite its importance (Russo, 2007;Maida and Daeninck, 2016). The identification of cannabinoids, especially delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), represented a pivotal moment in cannabinoid research. This was particularly significant following the discovery of the endocannabinoid system in the 1990s, which established a biological foundation for comprehending the effects of these compounds (Zuardi, 2006;Appendino, 2020).Many countries' recent legalization movement has sparked interest in its therapeutic uses, which has revived scientific research and public acceptance. Research on the active elements of cannabis has strengthened the present view of marijuana as a medicinal tool. In the past decades, the therapeutic potential of cannabinoids has been explored in several research areas.In the present research topic \"Therapeutic Potential of Cannabinoids: From Health to Disease\", the journal aimed to shed light on the local and systemic effects of cannabis and cannabinoids on cognitive function, and their implications in neurodegenerative and age-related diseases. In the manuscript \"The effects of standardized cannabis products in healthy volunteers and patients: a systematic literature review\", Leen and colleagues review the effects of standardized cannabis products, especially those made by Bedrocan, on patients and healthy volunteers (Leen et al., 2024). The authors emphasize how crucial consistent cannabis formulations are for successful therapy, pointing to dose-dependent acute effects in healthy volunteers, like anxiety and impaired cognition. With few minor adverse effects, medicinal cannabis has been shown to help individuals with chronic pain. In order to evaluate cannabis dosage, composition, and other variables including age and gender to determine safety and efficacy, the review recommends additional randomized clinical trials.Yndart et al., also discuss the importance of standardized formulations and consistent dosing to ensure reliability (Yndart Arias et al., 2024). The authors discuss the need for more thorough research to determine the best dosage, formulations, and therapeutic efficacy for neurocognitive disorders while reviewing randomized trials assessing cannabidiol (CBD) as a possible treatment for cognitive impairments. By demonstrating the advantages of CBD for anxiety and cognition and emphasizing the need for more carefully planned research to confirm its use in treating neurocognitive impairments like Alzheimer's disease, this manuscript has the potential to further our understanding of CBD as a therapeutic option for cognitive disorders. Also focusing on clinical research, in their review \"Implications for blinding in clinical trials with THC-containing cannabinoids based on the CANNA-TICS trial\", Müller-Vahl and colleagues discuss the issue of unblinding clinical trials using THC-containing cannabinoids, specifically examining the unblinding rates in the CANNA-TICS trial (Muller-Vahl et al., 2022).It states that 17% of individuals unblinded themselves on purpose or by mistake, and that some participants were not aware that they could do so. Due to the potential impact of growing public awareness of THC testing on trial integrity, the study emphasizes the significance of addressing unblinding concerns in subsequent randomized controlled trials utilizing THC-containing cannabinoids.Using an animal model, Melkumyan et al. investigated how mice's anxiety-like behaviors and neuroimmune function were affected by cannabidiol (CBD) and a CBD: THC (3:1) mixture during alcohol withdrawal (Melkumyan et al., 2024). It reveals that whereas CBD and CBD: THC enhanced anxiety during the first four hours of withdrawal, CBD by itself decreased anxiety throughout the next twenty-four hours. According to the study, using cannabis during alcohol withdrawal may have different impacts on anxiety depending on when it is used. These effects may be related to modifications in the central amygdala's neuroimmune function. This manuscript contributes to understanding the potential therapeutic effects of cannabinoids, specifically CBD and CBD: THC, on neuroimmune function modulation in the central amygdala. These results may help guide future studies and therapeutic strategies for treating alcohol withdrawal and related anxiety.The present research topic offers a comprehensive perspective on cannabis research and highlights that effectiveness of medicinal cannabis treatments and patient results are largely dependent on the dosage and formulation evaluation of cannabinoids. Accurate dosage reduces the possibility of side effects while guaranteeing that patients get the right quantity of cannabinoids to produce therapeutic benefits. Inhalants, oils, and foods are examples of formulations that alter the bioavailability and commencement of action, which can have a substantial impact on clinical results (Bhandari et al., 2024). Moreover, personalized dosing based on factors like patient age, weight, metabolism, and the specific condition being treated can enhance treatment efficacy.Without proper assessment and standardization, variations in dosing and formulation can lead to inconsistent results and undermine the potential benefits of medical cannabis for patients.Research on these issues is essential to establish clear guidelines and best practices for cannabinoid use in clinical settings. Investigating optimal dosing regimens and formulation types can provide evidence-based recommendations, ensuring patients receive safe and effective treatments. Furthermore, research can help identify the most suitable formulations for various conditions, refine therapeutic protocols, and reduce the risks of misuse or adverse effects. Understanding the entourage effect, the phenomenon where cannabinoids work synergistically with other compounds in the cannabis plant, also plays a crucial role in maximizing therapeutic outcomes (Baban et al., 2021). Understanding how the entourage effect boosts the effectiveness of cannabinoids may help improve treatment plans and provide patients with more individualized and thorough care. In the end, a better comprehension of these factors will promote the therapeutic use of medical cannabis, enhancing patient outcomes and leading to more potent therapies.The field of cannabinoid research is characterized by considerable deficiencies in mechanistic understanding. Cannabinoids, for instance, have shown promise in treating pain and stiffness, but little is understood about the underlying molecular pathways (Lu and Anderson, 2017;Cintosun et al., 2020). The same is seen in cancer, an area in which cannabinoids have shown in vitro and in vivo effects on cell proliferation (Kalenderoglou et al., 2017;Kim et al., 2019) and tumor progression (Salles et al., 2023;Wang et al., 2024). However, we still need to understand these mechanisms in different types of cancer at the molecular level.In summary, cannabinoids' history is intimately linked to human culture and medicine, having developed from their traditional ceremonial, recreational, and therapeutic applications to their status as a major study area with great promise. Even though these chemicals show great potential, there are still a lot of unanswered questions regarding their underlying processes and best uses. To resolve these scientific ambiguities and fully realize the medicinal promise of cannabis, future research-including well-planned clinical trials-is crucial. With more research, cannabis could become an essential tool for the treatment and prevention of a wide array of health conditions.

Recurrent myelitis is one of the predominant characteristics in patients with neuromyelitis optica (NMO). While paresis, visual loss, sensory deficits, and bladder dysfunction are well known symptoms in NMO patients, pain has been recognized only recently as another key symptom of the disease. Although spinal cord inflammation is a defining aspect of neuromyelitis, there is an almost complete lack of data on altered somatosensory function, including pain. Therefore, eleven consecutive patients with NMO were investigated regarding the presence and clinical characteristics of pain. All patients were examined clinically as well as by Quantitative Sensory Testing (QST) following the protocol of the German Research Network on Neuropathic Pain (DFNS). Additionally, plasma endocannabinoid levels and signs of chronic stress and depression were determined. Almost all patients (10/11) suffered from NMO-associated neuropathic pain for the last three months, and 8 out of 11 patients indicated relevant pain at the time of examination. Symptoms of neuropathic pain were reported in the vast majority of patients with NMO. Psychological testing revealed signs of marked depression. Compared to age and gender-matched healthy controls, QST revealed pronounced mechanical and thermal sensory loss, strongly correlated to ongoing pain suggesting the presence of deafferentation-induced neuropathic pain. Thermal hyperalgesia correlated to MRI-verified signs of spinal cord lesion. Heat hyperalgesia was highly correlated to the time since last relapse of NMO. Patients with NMO exhibited significant mechanical and thermal dysesthesia, namely dynamic mechanical allodynia and paradoxical heat sensation. Moreover, they presented frequently with either abnormal mechanical hypoalgesia or hyperalgesia, which depended significantly on plasma levels of the endogenous cannabinoid 2-arachidonoylglycerole (2-AG). These data emphasize the high prevalence of neuropathic pain and hyperalgesia in patients with NMO. The degree of mechanical hyperalgesia reflecting central sensitization of nociceptive pathways seems to be controlled by the major brain endocannabinoid 2-AG.

Background/Objectives: Chronic pain remains a pervasive and challenging public health issue, often resistant to conventional treatments such as opioids, which carry substantial risks of dependency and adverse effects. Cannabinoids, bioactive compounds derived from the Cannabis sativa plant and their synthetic analogs, have emerged as a potential alternative for pain management, leveraging their interaction with the endocannabinoid system to modulate pain and inflammation. Methods: The current, evolving literature regarding the history, efficacy, applications, and safety of cannabinoids in the treatment of chronic pain was reviewed and summarized to provide the most current review of cannabinoids. Results: Evidence suggests that cannabinoids provide moderate efficacy in managing neuropathic pain, fibromyalgia, cancer-related pain, and multiple sclerosis-related spasticity. Patient-reported outcomes further indicate widespread perceptions of cannabinoids as a safer alternative to opioids, with potential opioid-sparing effects. However, the quality of existing evidence is limited by small sample sizes and methodological inconsistencies. Regulatory barriers, including the classification of cannabis as a Schedule I substance in the United States, continue to hinder robust research and clinical integration. Moreover, the risks associated with cannabinoids, such as psychiatric effects, addiction potential, and drug interactions, necessitate cautious application. Conclusions: Cannabinoids represent a promising, albeit complex, alternative for chronic pain management, particularly given the limitations and risks of traditional therapies such as opioids. However, significant deficiencies remain in the research. While smaller trials and systematic reviews indicate therapeutic potential, the quality of evidence is often low due to limited sample sizes, short study durations, and methodological inconsistencies. Large-scale, randomized controlled trials with long-term follow-up are urgently needed to confirm efficacy and safety across diverse patient populations and pain etiologies.

Objectives. The purpose of this study is to investigate the relationship between plasma endocannabinoids and insulin resistance (IR) in patients with obstructive sleep apnea (OSA). Methods. A population of 64 with OSA and 24 control subjects was recruited. Body mass index (BMI), waist circumference, lipids, blood glucose and insulin, homeostasis model of assessment for insulin resistance index (HOMA-IR), anandamide (AEA), 1/2-arachidonoylglycerol (1/2-AG), and apnea-hypopnea index (AHI) were analyzed. Results. Fasting blood insulin (22.9 ± 7.8 mIU/L versus 18.5 ± 7.2 mIU/L, P<0.05), HOMA-IR (2.9 ± 1.0 versus 2.4 ± 0.9, P<0.01), AEA (3.2 ± 0.7 nmol/L versus 2.5 ± 0.6 nmol/L, P<0.01), and 1/2-AG (40.8 ± 5.7 nmol/L versus 34.3 ± 7.7 nmol/L, P<0.01) were higher in OSA group than those in control group. In OSA group, AEA, 1/2-AG, and HOMA-IR increase with the OSA severity. The correlation analysis showed significant positive correlation between HOMA-IR and AHI (r=0.44, P<0.01), AEA and AHI (r=0.52, P<0.01), AEA and HOMA-IR (r=0.62, P<0.01), and 1/2-AG and HOMA-IR (r=0.33, P<0.01). Further analysis showed that only AEA was significantly correlated with AHI and HOMA-IR after adjusting for confounding factors. Conclusions. The present study indicated that plasma endocannabinoids levels, especially AEA, were associated with IR and AHI in patients with OSA.