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A pilot study of the effects of cannabis on appetite hormones in HIV-infected adult men
Abstract
The endocannabinoid system is under active investigation as a pharmacological target for obesity management due to its role in appetite regulation and metabolism. Exogenous cannabinoids such as tetrahydrocannabinol (THC) stimulate appetite and food intake. However, there are no controlled observations directly linking THC to changes of most of the appetite hormones.
We took the opportunity afforded by a placebo-controlled trial of smoked medicinal cannabis for HIV-associated neuropathic pain to evaluate the effects of THC on the appetite hormones ghrelin, leptin and PYY, as well as on insulin.
In this double-blind cross-over study, each subject was exposed to both active cannabis (THC) and placebo.
Compared to placebo, cannabis administration was associated with significant increases in plasma levels of ghrelin and leptin, and decreases in PYY, but did not significantly influence insulin levels.
These findings are consistent with modulation of appetite hormones mediated through endogenous cannabinoid receptors, independent of glucose metabolism.
... Some hormones are also affected by THC administration, affecting signaling pathways related to the food intake (Gatta-Cherifi et al., 2012;Riggs et al., 2012); this is thanks to leptin and insulin that stimulate the arcuate nucleus, carrying information about the state of the energy deposits found in fatty tissue, and as well as by the ghrelin production in the stomach during the fasting state. In this way, the increased release of ghrelin increases appetite by stimulating the arcuate nucleus via humoral, through the vagus Obesity -↑Blood levels of anandamide and 2arachidonylglycerol. -Delay in the maximum peaks of serum 2arachidonylglycerol and 2-oleoylglycerol in response to circadian cycle. ...
... nerve (Fig. 2). This is supported by a study conducted in patients positive for the human immunodeficiency virus (HIV), where the patients received THC for smoking Cannabis, and they presented a significant increase in plasma ghrelin levels, concomitant with a decrease in peptide YY and leptin levels, and without changes in serum insulin levels in compared to controls who received placebo (Riggs et al., 2012). In addition, it was reported that there is a correlation between the THC and leptin levels in human serum, having higher levels of THC and lower levels of leptin (Gatta-Cherifi et al., 2012;Riggs et al., 2012). ...
... This is supported by a study conducted in patients positive for the human immunodeficiency virus (HIV), where the patients received THC for smoking Cannabis, and they presented a significant increase in plasma ghrelin levels, concomitant with a decrease in peptide YY and leptin levels, and without changes in serum insulin levels in compared to controls who received placebo (Riggs et al., 2012). In addition, it was reported that there is a correlation between the THC and leptin levels in human serum, having higher levels of THC and lower levels of leptin (Gatta-Cherifi et al., 2012;Riggs et al., 2012). For their part, Farokhnia et al. observed that in young subjects who smoked Cannabis (6.9 ± 0.95% of THC, corresponding to ~50.6 mg) had decreased plasma levels of insulin and glucagon-like peptide 1 (GLP-1) compared to subjects who received placebo. ...
The objective of this systematic review was to investigate previously published literature that examined the effect of hypercaloric diet on the endocannabinoid system, eating behavior, and the development of obesity. In the present review, we analyzed and described the evidence that suggests that the regulation of the endocannabinoid system through the activation of the receptors for cannabinoid type 1 (CB1R) and type 2 (CB2R) by modulating the production of anandamide, 2-arachidonoylglycerol (2-AG) and oleamide, influence the appetite and satiety centers, inducing or inhibiting the consumption of hypercaloric foods such as Western diet; thereby altering the production of hormones like the ghrelin, insulin, peptide YY and leptin. However, the adequate doses of pure cannabinoids and/or the cannabinoid-enriched Cannabis herbal extracts for the treatment of eating disorders like anorexia and/or obesity, neither for disorders of the mood, have not determined.
... 29 Interestingly, Riggs et al. found a positive association between treatment with cannabis-based medicine and plasma concentrations of ghrelin in patients with HIV. 30 Also, Farokhnia et al. reported that in healthy cannabis users, plasma-GLP-1 concentrations were lower after administration of cannabis compared to placebo. 31 These findings suggest that cannabis-based medicine (e.g. ...
... There are several human studies with cannabis-based medicines in patients with Alzheimer's disease/dementia, cancer, and HIV, and the studies that have investigated appetite stimulation have shown varying effects. 30,[32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51] Brisbois et al. showed that THC increased premeal appetite in cancer patients. 50 Dejesus et al. showed that cannabisbased medicine improved appetite and reversed weight loss in HIV/AIDS-infected patients. ...
Background and aim:
Malnutrition in older patients is linked to poor appetite. Cannabis-based medicine may have orexigenic properties in older patients, but this has to our knowledge never been investigated. In older patients, uncertainty applies to the accuracy of estimated glomerular filtration rate (eGFR) based on creatinine, which is crucial for medication prescribing. In older patients with poor appetite, the study aims 1) to assess the efficacy of Sativex® (8.1 mg delta-9-tetrahydrocannabinol (THC) and 7.5 mg cannabidiol (CBD)) to stimulate appetite and 2) to compare the performance of various GFR-estimates and measured-GFR (mGFR) for determining gentamicin clearance utilising population pharmacokinetic (popPK) modelling methods.
Methods and objectives:
This study is composed of two sub-studies. Sub-study 1 is an investigator-initiated single-center, double-blinded, randomised, placebo-controlled, superiority, cross-over study. Sub-study 1 will recruit 17 older patients with poor appetite, who will also be invited to sub-study 2. Sub-study 2 is a single-dose pharmacokinetics study and will recruit 55 patients. Participants will receive Sativex® and placebo in sub-study 1 and gentamicin with simultaneous measurements of GFR in sub-study 2. The primary endpoints are: sub-study 1) difference in energy intake between Sativex® and placebo conditions, and sub-study 2) accuracy of different eGFR equations compared to mGFR. The secondary endpoints include safety parameters, changes in the appetite hormones, total ghrelin and GLP-1 and subjective appetite sensations and the creation of popPK models of THC, CBD, and gentamicin.
... The ability of low dose THC, which is also prescribed [FDA-approved synthetic THC (Marinol)] as an appetite stimulant in PLWH [130][131][132][133][134] to reprogram BG-EVs and affect their functions is significant. Chronic cannabis use may slow disease progression, prolong survival, reduce viral load, and attenuate infection-induced inflammation/ immune activation in SIV-infected RMs [7,[55][56][57][135][136][137][138] and ART-treated PLWH [139,140]. ...
... The effect of THC is systemic-affecting many organs. As a result, THC and other cannabinoids are recommended for the treatment of digestive disorders [141][142][143][144][145][146] and FDA approved their use for clinical management of wasting and appetite stimulation, in PLWH [130,131,133,134,147]. ...
Background
Early invasion of the central nervous system (CNS) by human immunodeficiency virus (HIV) (Gray et al. in Brain Pathol 6:1–15, 1996; An et al. in Ann Neurol 40:611–6172, 1996), results in neuroinflammation, potentially through extracellular vesicles (EVs) and their micro RNAs (miRNA) cargoes (Sharma et al. in FASEB J 32:5174–5185, 2018; Hu et al. in Cell Death Dis 3:e381, 2012). Although the basal ganglia (BG) is a major target and reservoir of HIV in the CNS (Chaganti et al. in Aids 33:1843–1852, 2019; Mintzopoulos et al. in Magn Reson Med 81:2896–2904, 2019), whether BG produces EVs and the effect of HIV and/or the phytocannabinoid–delta-9-tetrahydrocannabinol (THC) on BG-EVs and HIV neuropathogenesis remain unknown.
Methods
We used the simian immunodeficiency virus (SIV) model of HIV and THC treatment in rhesus macaques (Molina et al. in AIDS Res Hum Retroviruses 27:585–592, 2011) to demonstrate for the first time that BG contains EVs (BG-EVs), and that BG-EVs cargo and function are modulated by SIV and THC. We also used primary astrocytes from the brains of wild type (WT) and CX3CR1+/GFP mice to investigate the significance of BG-EVs in CNS cells.
Results
Significant changes in BG-EV-associated miRNA specific to SIV infection and THC treatment were observed. BG-EVs from SIV-infected rhesus macaques (SIV EVs) contained 11 significantly downregulated miRNAs. Remarkably, intervention with THC led to significant upregulation of 37 miRNAs in BG-EVs (SIV–THC EVs). Most of these miRNAs are predicted to regulate pathways related to inflammation/immune regulation, TLR signaling, Neurotrophin TRK receptor signaling, and cell death/response. BG-EVs activated WT and CX3CR1+/GFP astrocytes and altered the expression of CD40, TNFα, MMP-2, and MMP-2 gene products in primary mouse astrocytes in an EV and CX3CR1 dependent manners.
Conclusions
Our findings reveal a role for BG-EVs as a vehicle with potential to disseminate HIV- and THC-induced changes within the CNS.
... Total ghrelin blood levels were increased in chronic drug smoking HIV patients Chronic THC smokers Riggs et al. [217] Total ghrelin blood levels were increased after oral drug administration in healthy cannabis users Cannabis Farokhnia et al. [218] Total ghrelin blood levels were higher after oral drug administration in comparison to smoked and vaporized drug; no significant effects on acyl-ghrelin were found Cannabis Farokhnia et al. [219] Vaporized drug AUC was positively correlated with total ghrelin AUC and a similar positive correlation between drug AUC and acyl-ghrelin AUC was also indicated THC Farokhnia et al. [219] ...
... Human studies have explored the impact of cannabinoids on ghrelin blood levels. Increased blood levels of total ghrelin were observed in chronic THC-smoking HIV-infected men [217]. Furthermore, increased blood levels of total ghrelin were observed after the oral administration of cannabis in healthy adult cannabis users [218]. ...
Drug addiction causes constant serious health, social, and economic burden within the human society. The current drug dependence pharmacotherapies, particularly relapse prevention, remain limited, unsatisfactory, unreliable for opioids and tobacco, and even symptomatic for stimulants and cannabinoids, thus, new more effective treatment strategies are researched. The antagonism of the growth hormone secretagogue receptor type A (GHS-R1A) has been recently proposed as a novel alcohol addiction treatment strategy, and it has been intensively studied in experimental models of other addictive drugs, such as nicotine, stimulants, opioids and cannabinoids. The role of ghrelin signaling in these drugs effects has also been investigated. The present review aims to provide a comprehensive overview of preclinical and clinical studies focused on ghrelin’s/GHS-R1A possible involvement in these nonalcohol addictive drugs reinforcing effects and addiction. Although the investigation is still in its early stage, majority of the existing reviewed experimental results from rodents with the addition of few human studies, that searched correlations between the genetic variations of the ghrelin signaling or the ghrelin blood content with the addictive drugs effects, have indicated the importance of the ghrelin’s/GHS-R1As involvement in the nonalcohol abused drugs pro-addictive effects. Further research is necessary to elucidate the exact involved mechanisms and to verify the future potential utilization and safety of the GHS-R1A antagonism use for these drug addiction therapies, particularly for reducing the risk of relapse.
... Continuing on the subject of cannabis as medicine, there have been claims that either smoked or ingested cannabis containing the psychoactive component THC, and those that are natural or synthetic in origin (dronabinol), improves the appetites of people with AIDS, increases weight gain and lifts mood, thereby improving the quality of life. In a doubleblind cross-over study [40], compared to placebo, cannabis administration was associated with significant increases in plasma levels of appetite controlling hormones, ghrelin and leptin, but did not significantly influence insulin levels, suggesting that the modulation of appetite hormones is mediated through endogenous cannabinoid receptors, independent of glucose metabolism. In an elegant NIDA-funded randomized, cross-over, double-blind, placebo-controlled study, Farokhnia et al. [41] investigated the effects of cannabis administration, via different routes, on peripheral concentrations of appetitive and metabolic hormones in a sample of cannabis users. ...
... Regarding the impact of cannabis on sexually transmitted infections (STIs), the data show that there were fewer STIs and lower risk of sexual engagement among HIV-infected MSMs who smoked cannabis as compared to those who did not smoke cannabis [72]. On the positive side of cannabis use, research shows that cannabis improves appetite, food intake, and metabolism, possibly via the endocannabinoid system, which, in turn, activates appetite stimulating hormones such as ghrelin and leptin [40,41]. ...
Cannabis continues to be the most used drug in the world today. Research shows that cannabis use is associated with a wide range of adverse health consequences that may involve almost every physiological and biochemical system including respiratory/pulmonary complications such as chronic cough and emphysema, impairment of immune function, and increased risk of acquiring or transmitting viral infections such as HIV, HCV, and others. The review of published research shows that cannabis use may impair immune function in many instances and thereby exerts an impact on viral infections including human immune deficiency virus (HIV), hepatitis C infection (HCV), and human T-cell lymphotropic type I and II virus (HTLV-I/II). The need for more research is also highlighted in the areas of long-term effects of cannabis use on pulmonary/respiratory diseases, immune dysfunction and the risk of infection transmission, and the molecular/genetic basis of immune dysfunction in chronic cannabis users.
... 67 More studies indicated the synergistic effect of endocannabinoids and ghrelin. 68−70 Additionally, Riggs et al. 63 found that administration of medical cannabis by HIV-infected adult men decreased their plasma level of anorexic hormone peptide YY and had no effect on insulin level while another anorexic hormone leptin was increased in this case. One possible explanation of increased leptin is that the level of endogenous cannabinoids is inversely associated with leptin's plasma concentration. ...
... 71,72 However, the high levels of exogenous cannabinoid stimulation might feedback negatively on endogenous cannabinoid production, leading to increases in leptin. 63 On the contrary, in healthy adults instead of HIV-positive patients, consuming cannabis showed no significant or significant down-regulation effects on plasma leptin. 66,73 In parallel, the plasma concentrations of anorexic hormone GLP-1 in healthy volunteers were lower under cannabis consumption than in placebo condition, while the spike in blood insulin concentrations observed under the placebo condition due to food intake was blunted by cannabis administration. ...
Cannabis is an excellent natural source of fiber and various bioactive cannabinoids. So far, at least 120 cannabinoids have been identified, and more novel cannabinoids are gradually being unveiled by detailed cannabis studies. However, cannabinoids in both natural and isolated forms are especially vulnerable to oxygen, heat, and light. Therefore, a diversity of cannabinoids is associated with their chemical instability to a large extent. The research status of structural conversion of cannabinoids is introduced. On the other hand, the use of drug-type cannabis and the phytocannabinoids thereof has been rapidly popularized and plays an indispensable role in both medical therapy and daily recreation. The recent legalization of edible cannabis further extends its application into the food industry. The varieties of legal edible cannabis products in the current commercial market are relatively monotonous due to rigorous restrictions under the framework of Cannabis Regulations and infancy of novel developments. Meanwhile, patents/studies related to the safety and quality assurance systems of cannabis edibles are still rare and need to be developed. Furthermore, along with cannabinoids, many phytochemicals such as flavonoids, lignans, terpenoids, and polysaccharides exist in the cannabis matrix, and these may exhibit prebiotic/probiotic properties and improve the composition of the gut microbiome. During metabolism and excretion, the bioactive phytochemicals of cannabis, mostly the cannabinoids, may be structurally modified during enterohepatic detoxification and gut fermentation. However, the potential adverse effects of both acute and chronic exposure to cannabinoids and their vulnerable groups have been clearly recognized. Therefore, a comprehensive understanding of the chemistry, metabolism, toxicity, commercialization, and regulations regarding cannabinoid edibles is reviewed and updated in this contribution.
... In the only published human study, to our knowledge, looking at appetitive and metabolic hormones, smoked medicinal cannabis (as a treatment for neuropathic pain) was tested in adult men positive for human immunodeficiency virus (HIV). In this pilot, crossover, double-blind study, cannabis administration increased blood concentrations of ghrelin and leptin, decreased peptide YY (PYY) concentrations, and had no significant effects on insulin 48 . The goal of the present study was to explore the effects of cannabis administration on peripheral concentrations of endocrine markers related to appetite and metabolism in a sample of cannabis users and to build the foundation for future studies in this regard. ...
... A pilot human study found a positive correlation between blood concentrations of an endocannabinoid (2-AG) and ghrelin during hedonic eating 85 . In another pilot human study, administration of smoked medicinal cannabis, compared to placebo, significantly increased blood ghrelin concentrations in HIV-infected adult men 48 . While the aforementioned findings are consistent with our results, it is hard to interpret why the effects on ghrelin in the present study were limited to specific routes of cannabis administration. ...
As perspectives on cannabis continue to shift, understanding the physiological and behavioral effects of cannabis use is of paramount importance. Previous data suggest that cannabis use influences food intake, appetite, and metabolism, yet human research in this regard remains scant. The present study investigated the effects of cannabis administration, via different routes, on peripheral concentrations of appetitive and metabolic hormones in a sample of cannabis users. This was a randomized, crossover, double-blind, placebo-controlled study. Twenty participants underwent four experimental sessions during which oral cannabis, smoked cannabis, vaporized cannabis, or placebo was administered. Active compounds contained 6.9 ± 0.95% (~50.6 mg) ∆9-tetrahydrocannabinol (THC). Repeated blood samples were obtained, and the following endocrine markers were measured: total ghrelin, acyl-ghrelin, leptin, glucagon-like peptide-1 (GLP-1), and insulin. Results showed a significant drug main effect (p = 0.001), as well as a significant drug × time-point interaction effect (p = 0.01) on insulin. The spike in blood insulin concentrations observed under the placebo condition (probably due to the intake of brownie) was blunted by cannabis administration. A significant drug main effect (p = 0.001), as well as a trend-level drug × time-point interaction effect (p = 0.08) was also detected for GLP-1, suggesting that GLP-1 concentrations were lower under cannabis, compared to the placebo condition. Finally, a significant drug main effect (p = 0.01) was found for total ghrelin, suggesting that total ghrelin concentrations during the oral cannabis session were higher than the smoked and vaporized cannabis sessions. In conclusion, cannabis administration in this study modulated blood concentrations of some appetitive and metabolic hormones, chiefly insulin, in cannabis users. Understanding the mechanisms underpinning these effects may provide additional information on the cross-talk between cannabinoids and physiological pathways related to appetite and metabolism.
... In line with this, animal work suggests that ECs may enhance appetitive motivation and food intake by interacting with several metabolic hormones. Human evidence is, however, limited, but a pilot study in HIV-infected men showed that chronically smoked THC increased plasma concentrations of ghrelin and leptin, whereas a decrease in PYY (peptide YY) and no effect on insulin were found (50). Furthermore, hedonic food intake in satiated normal-weight subjects increases plasma concentrations of the orexigenic hormone ghrelin and the EC 2-arachidonoylglycerol, indicating that both may be important in mediating the rewarding effects of palatable foods (12). ...
... However, we verified that baseline ghrelin concentrations were within physiological ranges and did not differ between THC and placebo, and that there were no other potential assay-related methodological issues that could have confounded our results. Moreover, it has to be noted that, to the best of our knowledge, so far no study has assessed the effect of acute cannabinoid administration on ghrelin concentrations to anticipatory food reward and human evidence on the effect of (chronically smoked) THC on plasma ghrelin concentrations is also mixed (more details in the Supplemental Information) (50,56). These divergent findings may be explained by differences in study paradigm (e.g., visual food cues compared with actual intake, a buffet meal compared with a single-drink meal), drug dosing, and route of administration as well as interspecies differences, and thus warrant further investigations. ...
Background:
The endocannabinoid system (ECS) is considered a key player in the neurophysiology of food reward. Animal studies suggest that the ECS stimulates the sensory perception of food, thereby increasing its incentive-motivational and/or hedonic properties and driving consumption, possibly via interactions with metabolic hormones. However, it remains unclear to what extent this can be extrapolated to humans.
Objective:
We aimed to investigate the effect of oral Δ9-tetrahydrocannabinol (THC) on subjective and metabolic hormone responses to visual food stimuli and food intake.
Methods:
Seventeen healthy subjects participated in a single-blinded, placebo-controlled, 2 × 2 crossover trial. In each of the 4 visits, subjective "liking" and "wanting" ratings of high- and low-calorie food images were acquired after oral THC or placebo administration. The effect on food intake was quantified in 2 ways: via ad libitum oral intake (half of the visits) and intragastric infusion (other half) of chocolate milkshake. Appetite-related sensations and metabolic hormones were measured at set time points throughout each visit.
Results:
THC increased "liking" (P = 0.031) and "wanting" ratings (P = 0.0096) of the high-calorie, but not the low-calorie images, compared with placebo. Participants consumed significantly more milkshake after THC than after placebo during oral intake (P = 0.0005), but not intragastric infusion, of milkshake. Prospective food consumption ratings during the food image paradigm were higher after THC than after placebo (P = 0.0039). THC also increased plasma motilin (P = 0.0021) and decreased octanoylated ghrelin (P = 0.023) concentrations before milkshake consumption (i.e., in both oral intake and intragastric infusion test sessions), whereas glucagon-like peptide 1 responses to milkshake intake were attenuated by THC during both oral (P = 0.0002) and intragastric (P = 0.0055) administration.
Conclusions:
These findings suggest that the ECS drives food intake by interfering with anticipatory, cephalic phase, and metabolic hormone responses. This trial was registered at clinicaltrials.gov as NCT02310347.
... In addition, receptor antagonists reduced plasma leptin levels in obese individuals [79]. Thus, it might be expected CBD reduces leptin levels by blocking CB1 receptors, but other studies have found that leptin levels are significantly increased in cannabis smokers [80]. However, in some studies, there was no difference between cannabis smoking and blood leptin levels [81]. ...
Cannabidiol (CBD), a non-psychoactive phytocannabinoid abundant in Cannabis sativa, has gained considerable attention for its anti-inflammatory, antioxidant, analgesic, and neuroprotective properties. It exhibits the potential to prevent or slow the progression of various diseases, ranging from malignant tumors and viral infections to neurodegenerative disorders and ischemic diseases. Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, and viral hepatitis stand as prominent causes of morbidity and mortality in chronic liver diseases globally. The literature has substantiated CBD’s potential therapeutic effects across diverse liver diseases in in vivo and in vitro models. However, the precise mechanism of action remains elusive, and an absence of evidence hinders its translation into clinical practice. This comprehensive review emphasizes the wealth of data linking CBD to liver diseases. Importantly, we delve into a detailed discussion of the receptors through which CBD might exert its effects, including cannabinoid receptors, CB1 and CB2, peroxisome proliferator-activated receptors (PPARs), G protein-coupled receptor 55 (GPR55), transient receptor potential channels (TRPs), and their intricate connections with liver diseases. In conclusion, we address new questions that warrant further investigation in this evolving field.
... Leptin levels have been shown to be lower in cannabis in individuals who identified as cannabis smokers, which was more significant among male smokers [87]. Leptin plays an important role in appetite and energy balance which can impact food intake and body weight [88,89]. Therefore, future work may be able to access leptin and ghrelin as a measure of obesity risks for prenatal THC offspring. ...
... Cannabis has a known effect on appetite hormones [44,45]; nevertheless, the efficacy of cannabis treatment for improving appetite-related symptoms has not been consistently demonstrated in randomized controlled trials [20]. Our results are consistent with most of these studies, showing no net effect of cannabis on appetite: most patients reported no change and a similar number of patients reported an increase or decrease in appetite. ...
The proportion of older adults using medical cannabis is rising. Therefore, we aimed to assess the effects of herbal medical cannabis on the functional status of older adults. We conducted a prospective observational study of patients aged 65 years or older that initiated cannabis treatment for different indications, mostly chronic non-cancer pain, during 2018–2020 in a specialized geriatric clinic. The outcomes assessed were activities of daily living (ADL), instrumental activities of daily living (IADL), pain intensity, geriatric depression scale, chronic medication use, and adverse events at six months. A cohort of 119 patients began cannabis treatment: the mean age was 79.3 ± 8.5 and 74 (62.2%) were female. Of the cohort, 43 (36.1%) experienced adverse effects due to cannabis use and 2 (1.7%) required medical attention. The mean ADL scores before and after treatment were 4.4 ± 1.8 and 4.5 ± 1.8, respectively (p = 0.27), and the mean IADL scores before and after treatment were 4.1 ± 2.6 and 4.7 ± 3, respectively (p = 0.02). We concluded that medical cannabis in older adults has a number of serious adverse events, but was not associated with a decrease in functional status, as illustrated by ADL and IADL scores after six months of continuous treatment.
... It is possible that persistent or prolonged stimulation of cannabinoid receptor 1 may lead to increased disordered eating behavior. Current literature demonstrates a positive correlation between levels of tetrahydrocannabinol and ghrelin, an orexigenic hormone [38]. Furthermore, the effects of cannabis vary based on route of ingestion. ...
... Cannabis use is common among people living with HIV (PLWH), who often use it to manage disease symptoms [11,12]. Both natural and synthetic forms of ∆ 9 -THC (THC) (available as FDA-approved Marinol ® and Syndros ® ), the main psychotropic component of cannabis, have been demonstrated to stimulate appetite and increase body weight, collectively improving the overall well-being of PLWH [13,14]. ...
In this follow-up study, we investigated the abundance and compartmentalization of blood plasma extracellular miRNA (exmiRNA) into lipid-based carriers—blood plasma extracellular vesicles (EVs) and non-lipid-based carriers—extracellular condensates (ECs) during SIV infection. We also assessed how combination antiretroviral therapy (cART), administered in conjunction with phytocannabinoid delta-9-tetrahydrocannabinol (THC), altered the abundance and compartmentalization of exmiRNAs in the EVs and ECs of SIV-infected rhesus macaques (RMs). Unlike cellular miRNAs, exmiRNAs in blood plasma may serve as minimally invasive disease indicators because they are readily detected in stable forms. The stability of exmiRNAs in cell culture fluids and body fluids (urine, saliva, tears, cerebrospinal fluid (CSF), semen, blood) is based on their association with different carriers (lipoproteins, EVs, and ECs) that protect them from the activities of endogenous RNases. Here, we showed that in the blood plasma of uninfected control RMs, significantly less exmiRNAs were associated with EVs compared to the level (30% higher) associated with ECs, and that SIV infection altered the profile of EVs and ECs miRNAome (Manuscript 1). In people living with HIV (PLWH), host-encoded miRNAs regulate both host and viral gene expression, which may serve as indicators of disease or treatment biomarkers. The profile of miRNAs in blood plasma of PLWH (elite controllers versus viremic patients) are different, indicating that HIV may alter host miRNAome. However, there are no studies assessing the effect of cART or other substances used by PLWH, such as THC, on the abundance of exmiRNA and their association with EVs and ECs. Moreover, longitudinal exmiRNA profiles following SIV infection, treatment with THC, cART, or THC+cART remains unclear. Here, we serially analyzed miRNAs associated with blood plasma derived EVs and ECs. Methods: Paired EVs and ECs were separated from EDTA blood plasma of male Indian rhesus macaques (RMs) in five treatment groups, including VEH/SIV, VEH/SIV/cART, THC/SIV, THC/SIV/cART, or THC alone. Separation of EVs and ECs was achieved with the unparalleled nano-particle purification tool ─PPLC, a state-of-the-art, innovative technology equipped with gradient agarose bead sizes and a fast fraction collector that allows high resolution separation and retrieval of preparative quantities of sub-populations of extracellular structures. Global miRNA profiles of the paired EVs and ECs were determined with RealSeq Biosciences (Santa Cruz, CA) custom sequencing platform by conducting small RNA (sRNA)-seq. The sRNA-seq data were analyzed using various bioinformatic tools. Validation of key exmiRNA was performed using specific TaqMan microRNA stem-loop RT-qPCR assays. Results: We investigated the effect of cART, THC, or both cART and THC together on the abundance and compartmentalization of blood plasma exmiRNA in EVs and ECs in SIV-infected RMs. As shown in Manuscript 1 of this series, were in uninfected RMs, ~30% of exmiRNAs were associated with ECs, we confirmed in this follow up manuscript that exmiRNAs were present in both lipid-based carriers—EVs and non-lipid-based carriers—ECs, with 29.5 to 35.6% and 64.2 to 70.5 % being associated with EVs and ECs, respectively. Remarkably, the different treatments (cART, THC) have distinct effects on the enrichment and compartmentalization pattern of exmiRNAs. In the VEH/SIV/cART group, 12 EV-associated and 15 EC-associated miRNAs were significantly downregulated. EV-associated miR-206, a muscle-specific miRNA that is present in blood, was higher in the VEH/SIV/ART compared to the VEH/SIV group. ExmiR-139-5p that was implicated in endocrine resistance, focal adhesion, lipid and atherosclerosis, apoptosis, and breast cancer by miRNA-target enrichment analysis was significantly lower in VEH/SIV/cART compared to VEH/SIV, irrespective of the compartment. With respect to THC treatment, 5 EV-associated and 21 EC-associated miRNAs were significantly lower in the VEH/THC/SIV. EV-associated miR-99a-5p was higher in VEH/THC/SIV compared to VEH/SIV, while miR-335-5p counts were significantly lower in both EVs and ECs of THC/SIV compared to VEH/SIV. EVs from SIV/cART/THC combined treatment group have significant increases in the count of eight (miR-186-5p, miR-382-5p, miR-139-5p and miR-652, miR-10a-5p, miR-657, miR-140-5p, miR-29c-3p) miRNAs, all of which were lower in VEH/SIV/cART group. Analysis of miRNA-target enrichment showed that this set of eight miRNAs were implicated in endocrine resistance, focal adhesions, lipid and atherosclerosis, apoptosis, and breast cancer as well as cocaine and amphetamine addiction. In ECs and EVs, combined THC and cART treatment significantly increased miR-139-5p counts compared to VEH/SIV group. Significant alterations in these host miRNAs in both EVs and ECs in the untreated and treated (cART, THC, or both) RMs indicate the persistence of host responses to infection or treatments, and this is despite cART suppression of viral load and THC suppression of inflammation. To gain further insight into the pattern of miRNA alterations in EVs and ECs and to assess potential cause-and-effect relationships, we performed longitudinal miRNA profile analysis, measured in terms of months (1 and 5) post-infection (MPI). We uncovered miRNA signatures associated with THC or cART treatment of SIV-infected macaques in both EVs and ECs. While the number of miRNAs was significantly higher in ECs relative to EVs for all groups (VEH/SIV, SIV/cART, THC/SIV, THC/SIV/cART, and THC) longitudinally from 1 MPI to 5 MPI, treatment with cART and THC have longitudinal effects on the abundance and compartmentalization pattern of exmiRNAs in the two carriers. As shown in Manuscript 1 where SIV infection led to longitudinal suppression of EV-associated miRNA-128-3p, administration of cART to SIV-infected RMs did not increase miR-128-3p but resulted in longitudinal increases in six EV-associated miRNAs (miR-484, miR-107, miR-206, miR-184, miR-1260b, miR-6132). Furthermore, administration of cART to THC treated SIV-infected RMs resulted in a longitudinal decrease in three EV-associated miRNAs (miR-342-3p, miR-100-5p, miR181b-5p) and a longitudinal increase in three EC-associated miRNAs (miR-676-3p, miR-574-3p, miR-505-5p). The longitudinally altered miRNAs in SIV-infected RMs may indicate disease progression, while in the cART Group and the THC Group, the longitudinally altered miRNAs may serve as biomarkers of response to treatment. Conclusions: This paired EVs and ECs miRNAome analyses provided a comprehensive cross-sectional and longitudinal summary of the host exmiRNA responses to SIV infection and the impact of THC, cART, or THC and cART together on the miRNAome during SIV infection. Overall, our data point to previously unrecognized alterations in the exmiRNA profile in blood plasma following SIV infection. Our data also indicate that cART and THC treatment independently and in combination may alter both the abundance and the compartmentalization of several exmiRNA related to various disease and biological processes.
... 11 Cannabis has been shown to acutely increase appetite, 105,106 but research related to cannabis use and hunger hormones is limited. All empirical human studies on this topic use samples of adults and focus chiefly on insulin, ghrelin, leptin, peptide YY, and glucagon-like peptide 1. 87, 107 Farokhnia and colleagues (2020) conducted a randomized, placebo-controlled trial of the effect of cannabis ingestion on various hunger-related hormones, accounting for different routes of cannabis administration. Their study found that compared to placebo, cannabis intake was associated with a decrease in the normal and expected insulin spike following sugar intake. ...
The current review highlights the available research related to cannabis and indicators of physical health in a variety of domains. Various studies have found associations between cannabis use with pulmonary, cardiovascular, gastrointestinal, and endocrine function as well as body mass index and sleep. At this time, more research is needed to understand the influence of cannabis use on physical health, particularly among adolescent samples.
... With growing rates of eating disorders ranging from anorexia nervosa to obesity (Saper et al., 2002;Zigman & Elmquist, 2003), as well as diseases such as HIV/AIDS and cancer, which are associated with increased energy expenditure resulting in wasting and cachexia (Inui, 2002;Riggs et al., 2012), it is important to understand the pathoneurogenic mechanisms underlying the alterations in food intake and energy expenditure observed in these opposing states. Ample evidence collected over the past 25 years demonstrates that exogenous N/OFQ induces sex-and energy status-dependent inhibition of POMC ARC neurones and accompanying hyperphagia. ...
We tested the hypothesis that N/OFQ neurones in the arcuate nucleus (N/OFQARC) inhibit proopiomelanocortin (POMCARC) neurones in a diet‐ and hormone‐dependent manner to promote a more extensive rebound hyperphagia upon re‐feeding following an 18 h fast. We utilized intact male or ovariectomized (OVX) female mice subjected to ad libitum‐feeding or fasting conditions. N/OFQARC neurones under negative energy balance conditions displayed heightened sensitivity as evidenced by a decreased rheobase threshold, increased firing frequency, and increased burst duration and frequency compared to ad libitum‐feeding conditions. Stimulation of N/OFQARC neurones more robustly inhibited POMCARC neurones under fasting conditions compared to ad libitum‐feeding conditions. N/OFQARC inhibition of POMCARC neurones is hormone dependent as chemostimulation of N/OFQARC neurones from fasted males and OVX females produced a sizable outward current in POMCARC neurones. Oestradiol (E2) markedly attenuated the N/OFQ‐induced POMCARC outward current. Additionally, N/OFQ tonically inhibits POMCARC neurones to a greater degree under fasting conditions than in ad libitum‐feeding conditions as evidenced by the abrogation of N/OFQ–nociceptin opioid peptide (NOP) receptor signalling and inhibition of N/OFQ release via chemoinhibition of N/OFQARC neurones. Intra‐arcuate nucleus application of N/OFQ further elevated the hyperphagic response and increased meal size during the 6 h re‐feed period, and these effects were mimicked by chemostimulation of N/OFQARC neurones in vivo. E2 attenuated the robust N/OFQ‐induced rebound hyperphagia seen in vehicle‐treated OVX females. These data demonstrate that N/OFQARC neurones play a vital role in mitigating the impact of negative energy balance by inhibiting the excitability of anorexigenic neural substrates, an effect that is diminished by E2 in females. image
Key points
Nociceptin/orphanin FQ (N/OFQ) promotes increased energy intake and decreased energy expenditure under conditions of positive energy balance in a sex‐ and hormone‐dependent manner.
Here it is shown that under conditions of negative energy balance, i.e. fasting, N/OFQ inhibits anorexigenic proopiomelanocortin (POMC) neurones to a greater degree compared to homeostatic conditions due to fasting‐induced hyperexcitability of N/OFQ neurones.
Additionally, N/OFQ promotes a sustained increase in rebound hyperphagia and increase in meal size during the re‐feed period following a fast.
These results promote greater understanding of how energy balance influences the anorexigenic circuitry of the hypothalamus, and aid in understanding the neurophysiological pathways implicated in eating disorders promoting cachexia.
... Previous studies find regular marijuana use reduces body weight (Le Strat & Le Foll, 2011;Rodondi et al., 2006). Other research notes recreational marijuana may lead to behavioral changes, which result in weight gain (Pesta et al., 2013;Riggs et al., 2012;Soria-Gómez et al., 2014). With nearly 70% of US adults considered overweight or obese (Flegal et al., 2012) and marijuana's comparatively common use (Rodondi et al., 2006), a more robust understanding of the effects of decriminalizing marijuana use on obesity is strongly needed. ...
Obesity in the US arguably constitutes the most significant health epidemic over the past century. Recent legislative changes allowing for recreational marijuana use further create a need to better understand the relationship between marijuana use and health choices, leading to obesity. We examine this relationship by using a synthetic control approach to examine the impact of legalized recreational marijuana access on obesity rates by comparing Washington State to a synthetically constructed counterfactual. We find that recreational marijuana's introduction did not lead to increased obesity rates and may have led to decreases in obesity.
... Of note, ghrelin and cannabinoid receptor activity interact and promote each other's excretion (Kola et al., 2008;Mazidi et al., 2014;Zbucki et al., 2008). Specifically, in a previous trial, cannabis administration significantly increased serum ghrelin and leptin levels in a sample with HIV infection (Riggs et al., 2012). The bioavailability of ghrelin also depends on the way of cannabis administration in humans (Farokhnia et al., 2020). ...
Background
Aggression and craving are common and important withdrawal symptoms in cannabis use disorder. The present study investigated the association between appetite-regulating hormones, aggression, and craving during cannabis withdrawal syndrome (CWS).
Methods
Fifty-six male subjects diagnosed with cannabis withdrawal and 45 healthy males were included in the study. The Substance Craving Scale, the Buss–Perry Aggression Questionnaire, and the State-Trait Anxiety Inventory were implemented at baseline. Blood samples were drawn to measure ghrelin, leptin, adiponectin, and resistin levels in the serum. Then, the Point Subtraction Aggression Paradigm (PSAP) was applied. Bloodwork and psychometric assessment procedures were re-implemented after the PSAP. At the 7-day follow-up, psychometric assessments and hormone measurements were repeated in the CWS group.
Results
Baseline serum ghrelin and adiponectin levels were lower in the CWS group than controls at baseline. After PSAP, there was a significant increase in ghrelin levels of patients with CWS compared to controls. Patients yielded higher aggression scores, while there was no significant correlation between hormonal changes and PSAP findings. At 7-day follow, ghrelin and resistin levels significantly increased, while serum leptin decreased in patients with CWS. Finally, there was a positive association between craving and resistin levels.
Conclusions
Our results present the changes in appetite-regulating hormones. Long-term follow-up studies are needed to shed light on neuroendocrinological aspects of cannabis withdrawal.
... Studies show that smoked cannabis increase blood levels of ghrelin and leptin, hormones associated with hunger. 47 Small trials of THC supplementation in patients with advanced cancer have shown subjective reports of improved taste and appetite. 48 However, there are minimal studies examining CBD-predominant products in appetite stimulation or weight gain to date. ...
Cannabis use and interest continues to increase among patients with cancer and caregivers. High-quality research remains scant in many areas, causing hesitancy or discomfort among most clinical providers. Although we have limitations on hard outcomes, we can provide some guidance and more proactively engage in conversations with patients and family about cannabis. Several studies support the efficacy of cannabis for various cancer and treatment-related symptoms, such as chemotherapy-induced nausea and cancer pain. Although formulations and dosing guidelines for clinicians do not formally exist at present, attention to tetrahydrocannabinol concentration and understanding of risks with inhalation can reduce risk. Conflicting information exists on the interaction between cannabis and immunotherapy as well as estrogen receptor interactions. Motivational interviewing can help engage in more productive, less stigmatized conversations.
... Two randomized, placebo-controlled trials found that 28% of patients with HIV-SN achieved a clinically and statistically significant pain reduction (≥30% from baseline) with smoked Cannabis products, with a necessary number for treatment (NNT) of 4 [138][139][140]. Studies show that even smoked or ingested Cannabis, containing the THC component, is capable of improving appetite, weight, and mood, thus improving quality of life [142]. Despite this, recent studies have shown that chronic Cannabis smoking weakens the immune system leading to increased symptoms of chronic bronchitis, cough, sputum production, and wheezing [143][144][145]. ...
Medical case reports suggest that cannabinoids extracted from Cannabis sativa have therapeutic effects; however, the therapeutic employment is limited due to the psychotropic effect of its major component, Δ9-tetrahydrocannabinol (THC). The new scientific discoveries related to the endocannabinoid system, including new receptors, ligands, and mediators, allowed the development of new therapeutic targets for the treatment of several pathological disorders minimizing the undesirable psychotropic effects of some constituents of this plant. Today, FDA-approved drugs, such as nabiximols (a mixture of THC and non-psychoactive cannabidiol (CBD)), are employed in alleviating pain and spasticity in multiple sclerosis. Dronabinol and nabilone are used for the treatment of chemotherapy-induced nausea and vomiting in cancer patients. Dronabinol was approved for the treatment of anorexia in patients with AIDS (acquired immune deficiency syndrome). In this review, we highlighted the potential therapeutic efficacy of natural and synthetic cannabinoids and their clinical relevance in cancer, neurodegenerative and dermatological diseases, and viral infections.
... Welldesigned trials are needed to determine whether researchers can predict patient response and whether cannabis can improve appetite stimulation, improve the enjoyment of food (152), or improve QOL in patients with advanced cancer. Mechanistically, crosstalk of cannabinoids with neuroendocrine effectors such as ghrelin, leptin, and serotonin is warranted (153,154). ...
Cannabis and cannabinoids are increasingly being accessed and used by patients with advanced cancer for various symptoms and general quality of life. Specific symptoms of pain, nausea and vomiting, loss of appetite and cachexia, anxiety, sleep disturbance, and medical trauma are among those that have prompted patients with cancer to use cannabis. This conference report from the National Cancer Institute’s “Cannabis, Cannabinoid and Cancer Research Symposium” on the topic of “Cancer Symptom/Treatment Side Effect Management” is an expert perspective of cannabis intervention for cancer and cancer treatment-related symptoms. The purpose of the symposium was to identify research gaps, describe the need for high-quality randomized prospective studies of medical cannabis for palliative care in patients with cancer, and evaluate the impact of medical cannabis on cancer survivors’ quality of life. Further, education of clinicians and affiliated health-care providers in guiding cancer patients in using cannabis for cancer care would benefit patients. Together, these steps will further aid in refining the use of cannabis and cannabinoids for symptom palliation and improve safety and efficacy for patients.
... This compound, dronabinol, along with smoked cannabis, is effective at stimulating appetite to combat HIV-associated anorexia [45] and improve weight gain [46]. This is likely accomplished by stimulation of the appetite hormones ghrelin and leptin [47]. However, a more recent Cochrane systematic review indicated that longer studies would be necessary to truly evaluate the consistency and significance of dronabinol's reported benefits [48]. ...
The persistence of human immunodeficiency virus-1 (HIV)-associated neurocognitive disorders (HAND) in the era of effective antiretroviral therapy suggests that modern HIV neuropathogenesis is driven, at least in part, by mechanisms distinct from the viral life cycle. Identifying more subtle mechanisms is complicated by frequent comorbidities in HIV+ populations. One of the common confounds is substance abuse, with cannabis being the most frequently used psychoactive substance among people living with HIV. The psychoactive effects of cannabis use can themselves mimic, and perhaps magnify, the cognitive deficits observed in HAND; however, the neuromodulatory and anti-inflammatory properties of cannabinoids may counter HIV-induced excitotoxicity and neuroinflammation. Here, we review our understanding of the cross talk between HIV and cannabinoids in the central nervous system by exploring both clinical observations and evidence from preclinical in vivo and in vitro models. Additionally, we comment on recent advances in human, multi-cell in vitro systems that allow for more translatable, mechanistic studies of the relationship between cannabinoid pharmacology and this uniquely human virus.
... Patricia K y su equipo en un estudio incluyeron a 28 pacientes adultos masculinos portadores de VIH, en ellos se analizaron hormonas de la conducta alimentaria y la influencia que ejerce el cannabis sobre éstas demostrando que la ghrelina aumenta 42% por las mañanas al compararla contra placebo, la leptina aumenta 67.1% comparada contra placebo, con respecto al PPY, éste disminuye en el grupo de intervención y tiende a aumentar en el grupo placebo en 23.2%; la significancia estadística presenta una p < 0.001. Éste es uno de los primeros ensayos clínicos donde se involucran marcadores biológicos de la conducta de la alimentación con respecto a la administración de un derivado cannabinoide (37) . ...
Introducción:
La caquexia es un síndrome asociado al cáncer avanzado, VIH, pacientes en quimioterapia y quienes tienen seguimiento en cuidados paliativos. La prevalencia es de 25% de los pacientes con diagnóstico de cáncer, 26% en quienes reciben quimioterapia y de 14 a 38% de pacientes con VIH. Un pilar para el manejo es el cannabis debido al efecto del delta-9-tetrahidrocanabinol (THC), del cual se derivó el dronabinol, un fármaco desarrollado para estimular apetito y ganancia de peso. El objetivo de esta revisión bibliográfica es obtener la información sobre los cannabinoides y la evidencia más sólida existente con respecto al uso del dronabinol en pacientes que han presentado pérdida de peso y apetito.
Material y métodos:
Revisión de la bibliografía con buscador PubMed con las palabras clave Palliative care (cuidados paliativos), Cannabinoids (cannabinoides), cachexia (caquexia), Dronabinol (dronabinol), Appetite (apetito), de 1990 a 2018, limitado a humanos, obteniendo 259 artículos, eliminando 222 por repetirse o tener poca relevancia, dejando 37 artículos para análisis.
Resultados:
De 37 artículos revisados, nueve fueron estudios experimentales, 10 revisiones sistematizadas, un metaanálisis y 16 artículos de recomendaciones y sugerencias de manejo.
Conclusión:
El manejo del apetito y pérdida de peso en pacientes en cuidados paliativos, VIH, ancianos o en quimioterapia debe ser multidisciplinario, involucrando nutriólogos, psicólogos y médicos, ajustando el manejo a las características individuales que manifiesten. El dronabinol es un fármaco de primera elección para el manejo de dichos síntomas cuando la historia natural de la enfermedad se acompaña de náusea, vómito o dolor.
... 4 Cannabis has been additionally pointed as interacting with opioid receptors, 5 and it present itself as an alternative to opioids. 6 Further, while loss of appetite and anorexia are common troubling symptoms which are common among cancer patients, 7 cannabis is known to boost appetite, 8,9 and observational data additionally supports such benefit among cancer patients. 10 To a certain extent, there is evidence to support the potential of cannabis for additional symptoms that impact cancer patients, such as gastrointestinal distress, 10 peripheral neuropathy, 11,12 as well as depression and anxiety. ...
Objectives
To assess the motivation of cancer survivors to consume medical cannabis and to assess the patterns of use, perceived efficacy, as well as side and adverse effects.
Methods
Cross-sectional survey among 190 Israeli cancer survivors who were licensed to use medical cannabis in a single institution. In addition to demographic information, the questionnaire examined patterns of use (including dosage, type of cannabis and way of administration), motivation for medical cannabis consumption, perceived efficacy, adverse and side effects, motivation for ceasing cannabis consumption, and tobacco smoking.
Results
The mean monthly dosage of cannabis consumed was 42.4 grams; 95.8% of respondents reported not consuming cannabis regularly before being diagnosed with cancer; the most common way of administration was smoking, and most of the participants reported taking cannabis throughout the day. The most common symptoms for which participants took medical cannabis were pain (n = 169, 88.9%), sleeping disorder (n = 144, 75.8%) and anxiety (n = 79, 41.6%). Twenty patients (10.5%) reported on mild side (or adverse) effects.
Conclusions
This study indicates that cancer survivors may indeed consume cannabis for symptom relief, and not merely for recreational purposes. Although our findings point to perceived safety and efficacy of medical cannabis for cancer survivors, more research is needed to study the adequate role that cannabis may have for treating symptoms associated with cancer survivorship.
... Cannabis has been associated with significant increases in ghrelin and leptin, and decreases in PYY, consistent with the modulation of appetite hormones mediated through endocannabinoid receptors. 61 The Endocannabinoid System The endocannabinoid system encompasses a key interface between the gut microbiota, the immune system, and homeostasis of the human host. Two main endogenous cannabinoids, or endocannabinoids, are the brain-derived arachidonoyl ethanolamide, known as anandamide (AEA), and 2-arachidonoylglycerol (2-AG) derived from lipid precursors, such as arachidonic acid, that are synthesized on demand. ...
People living with HIV infection (PWH) disclose that cannabis is an effective strategy for alleviating symptoms associated with HIV disease. However, some medical providers feel ill-informed to engage in evidence-based conversations. HIV leads to alterations in the gut microbiome, gut-brain axis signaling, and chronic inflammation. The endocannabinoid system regulates homeostasis of multiple organ systems. When deficient, dysregulation of the gut-brain axis can result in chronic inflammation and neuroinflammation. Cannabis along with the naturally occurring endocannabinoids has antioxidant and anti-inflammatory properties that can support healing and restoration as an adjunctive therapy. The purpose of this literature review is to report the physiologic mechanisms that occur in the pathology of HIV and discuss potential benefits of cannabinoids in supporting health and reducing the negative effects of comorbidities in PWH.
... Prior to conducting functional studies, we sought to evaluate the tolerance of BEVs by U937 monocytes by assessing cellular viability upon treatment with different concentrations (20,40, and 100 μg) of BEVs. Cells seeded atop collagen-coated 96-well plates were treated with different concentrations of VEH/SIV or THC/SIV BEVs, while PBS-treated cells served as negative controls. ...
Blood extracellular vesicles (BEVs) carry bioactive cargo (proteins, genetic materials, lipids, licit, and illicit drugs) that regulate diverse functions in target cells. The cannabinoid drug delta-9-tetrahydrocannabinol (THC) is FDA approved for the treatment of anorexia and weight loss in people living with HIV. However, the effect of THC on BEV characteristics in the setting of HIV/SIV infection needs to be determined. Here, we used the SIV-infected rhesus macaque model of AIDS to evaluate the longitudinal effects of THC (THC/SIV) or vehicle (VEH/SIV) treatment in HIV/SIV infection on the properties of BEVs. While BEV concentrations increased longitudinally (pre-SIV (0), 30, and 150 days post-SIV infection (DPI)) in VEH/SIV macaques, the opposite trend was observed with THC/SIV macaques. SIV infection altered BEV membrane properties and cargo composition late in infection, since i) the electrostatic surface properties (zeta potential, ζ potential) showed that RM BEVs carried negative surface charge, but at 150 DPI, SIV infection significantly changed BEV ζ potential; ii) BEVs from the VEH/SIV group altered tetraspanin CD9 and CD81 levels compared to the THC/SIV group. Furthermore, VEH/SIV and THC/SIV BEVs mediated divergent changes in monocyte gene expression, morphometrics, signaling, and function. These include altered tetraspanin and integrin β1 expression; altered levels and distribution of polymerized actin, FAK/pY397 FAK, pERK1/2, cleaved caspase 3, proapoptotic Bid and truncated tBid; and altered adhesion of monocytes to collagen I. These data indicate that HIV/SIV infection and THC treatment result in the release of bioactive BEVs with potential to induce distinct structural adaptations and signaling cues to instruct divergent cellular responses to infection.
... Another research revealed that a single intravenous leptin injection in rats decreased the levels of the endocannabinoids, anandamide, and 2-arachidonylglycerol (2-AG) in the hypothalamus 22 . Also, cannabis smoking was associated with significant changes in leptin levels 23 . Moreover, gender differences have been detected on serum leptin levels in response to biological signals of cannabis smoking 24 . ...
... The mechanisms of a proposed marijuana and type 2 diabetes association, suggest that THC stimulates appetite through activation of CB1 (Riggs et al., 2012), and thus may play a role in eating behaviors among persons who use marijuana. Studies have shown significantly higher caloric intake in marijuana users compared with nonusers (Foltin et al., 1988;Ngueta et al., 2015;Rodondi et al., 2006;Smit and Crespo, 2001). ...
Introduction: Marijuana use is common among persons living with HIV, but whether its use increases the risk of type 2 diabetes in this population has not been explored.
Objective: To determine whether self-reported marijuana use is associated with incident type 2 diabetes in women and men living with and at risk for HIV.
Methods: We analyzed data from the Women’s Interagency HIV Study (WIHS) and Multicenter AIDS Cohort Study (MACS), between 2000-2017 (WIHS) and 1999-2017 (MACS). The association between self-reported marijuana use and incident type 2 diabetes was analyzed using time-dependent Cox regression models among 3,578 and 2,682 participants in the WIHS and MACS respectively.
Results: Over the follow-up period, 452 (WIHS) and 326 (MACS) incident type 2 diabetes cases occurred. In multivariable models, the hazard ratios, collectively indicate a reduced risk of type 2 diabetes, in marijuana users compared to none users, although all associations were not statistically significant. The results were similar for HIV-positive and HIV-negative participants in both cohorts.
Conclusions: In this prospective analysis of nearly 20 years of data for women and men with and at risk for HIV in the WIHS and MACS, although we found a pattern of reduced risk of type 2 diabetes among self-reported marijuana users, the associations were not statistically significant. To better inform clinical decisions and legal policy regarding marijuana use in this population, further longitudinal investigations that biologically quantify marijuana use to assess risk for incident diabetes is warranted.
... 12 Patient-reported sleep benefits are likely related to these sedative effects. While cannabis (containing both 9-Δ-THC and CBD) has been indicated for use as an appetite stimulant in HIV-affected patients with cachexia, 22,23 it remains unclear if CBD alone has significant appetite stimulating effects beyond placebo. Long-term side effects were not analysed in this current audit and future study is still needed to clarify chronic effects of CBD administration. ...
Background:
Cannabidiol (CBD) is the non-euphoriant component of cannabis. In 2017, the New Zealand Misuse of Drugs Regulations (1977) were amended, allowing doctors to prescribe CBD. Therapeutic benefit and tolerability of CBD remains unclear.
Aim:
To review the changes in self-reported quality of life measurements, drug tolerability, and dose-dependent relationships in patients prescribed CBD oil for various conditions at a single institution.
Design & setting:
An audit including all patients (n = 400) presenting to Cannabis Care, New Zealand, between 7 December 2017 and 7 December 2018 seeking CBD prescriptions METHOD: Indications for CBD use were recorded at baseline. Outcomes included EuroQol quality of life measures at baseline and after 3 weeks of use, patient-reported satisfaction, incidence of side effects, and patient-titrated dosage levels of CBD.
Results:
Four hundred patients were assessed for CBD and 397 received a prescription. Follow-up was completed on 253 patients (63.3%). Patients reported a mean increase of 13.6 points (P<0.001) on the EQ-VAS scale describing overall quality of health. Patients with non-cancer pain and mental-health symptoms achieved improvements to patient-reported pain and depression and anxiety symptoms (P<0.05). There were no major adverse effects. Positive side effects included improved sleep and appetite. No associations were found between CBD dose and patient-reported benefit.
Conclusion:
There may be analgesic and anxiolytic benefits of CBD in patients with non-cancer chronic pain and mental health conditions such as anxiety. CBD is well tolerated, making it safe to trial for non-cancer chronic pain, mental health, neurological, and cancer symptoms.
... It was found also that cannabis smoking had modulated the statistically significant inverse correlation between plasma AgRP concentrations and BMI in non cannabis smokers to be insignificant inversely correlation between them. These findings are consistent with modulation of appetite hormones mediated through endogenous cannabinoid receptors as previously concluded by [30], whose study results showed that cannabis administration was associated with significant increases in plasma levels of ghrelin and leptin, and decreases in PYY, but did not significantly influence insulin levels and these findings are consistent with modulation of appetite hormones mediated through endogenous cannabinoid receptors, independent of glucose metabolism. ...
... 86 Medical cannabis and THC, specifically, are known to boost appetite in humans and laboratory animals. 85,[87][88][89][90][91][92] Overall, studies assessing the effects of cannabis or phytocannabinoids on appetite in cancer patients have shown benefits, although there appears to be a placebo effect, and a 2017 report found insufficient evidence to support or refute its use. 73 In one study in 469 patients with advanced cancer and documented weight loss or reduced food intake, 93 and another in 243 patients with advanced cancer and cancer-related anorexia-cachexia syndrome (CACS), 94 appetite increased in all groups including comparison groups treated with dronabinol (synthetic THC), megestrol acetate, 93 cannabis extract, and placebo, 94 suggesting that cannabis-derived products are no better than a placebo. ...
Cannabis has the potential to modulate some of the most common and debilitating symptoms of cancer and its treatments, including nausea and vomiting, loss of appetite, and pain. However, the dearth of scientific evidence for the effectiveness of cannabis in treating these symptoms in patients with cancer poses a challenge to clinicians in discussing this option with their patients. A review was performed using keywords related to cannabis and important symptoms of cancer and its treatments. Literature was qualitatively reviewed from preclinical models to clinical trials in the fields of cancer, human immunodeficiency virus (HIV), multiple sclerosis, inflammatory bowel disease, post-traumatic stress disorder (PTSD), and others, to prudently inform the use of cannabis in supportive and palliative care in cancer. There is a reasonable amount of evidence to consider cannabis for nausea and vomiting, loss of appetite, and pain as a supplement to first-line treatments. There is promising evidence to treat chemotherapy-induced peripheral neuropathy, gastrointestinal distress, and sleep disorders, but the literature is thus far too limited to recommend cannabis for these symptoms. Scant, yet more controversial, evidence exists in regard to cannabis for cancer- and treatment-related cognitive impairment, anxiety, depression, and fatigue. Adverse effects of cannabis are documented but tend to be mild. Cannabis has multifaceted potential bioactive benefits that appear to outweigh its risks in many situations. Further research is required to elucidate its mechanisms of action and efficacy and to optimize cannabis preparations and doses for specific populations affected by cancer.
An impact of legalization and decriminalization of marijuana is the gradual increase in the use of cannabis for recreational purposes, which poses a potential threat to society and healthcare systems worldwide. However, the discovery of receptor subtypes, endogenous endocannabinoids, and enzymes involved in synthesis and degradation, as well as pharmacological characterization of receptors, has led to exploration of the use of cannabis in multiple peripheral and central pathological conditions. The role of cannabis in the modulation of crucial events involving perturbed physiological functions and disease progression, including apoptosis, inflammation, oxidative stress, perturbed mitochondrial function, and the impaired immune system, indicates medicinal values. These events are involved in most neurological diseases and prompt the gradual progression of the disease. At present, several synthetic agonists and antagonists, in addition to more than 70 phytocannabinoids, are available with distinct efficacy as a therapeutic alternative in different pathological conditions. The present review aims to describe the use of cannabis in neurological diseases and psychiatric disorders.
Cannabinoid use has surged in the past decade, with a growing interest in expanding cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) applications into special populations. Consequently, the increased use of CBD and THC raises the risk of drug–drug interactions (DDIs). Nevertheless, DDIs for cannabinoids, especially in special populations, remain inadequately investigated. While some clinical trials have explored DDIs between therapeutic drugs like antiepileptic drugs and CBD/THC, more potential interactions remain to be examined. This review summarizes the published studies on CBD and THC–drug interactions, outlines the mechanisms involved, discusses the physiological considerations in pharmacokinetics (PK) and DDI studies in special populations (including pregnant and lactating women, pediatrics, older adults, patients with hepatic or renal impairments, and others), and presents modeling approaches that can describe the DDIs associated with CBD and THC in special populations. The PK of CBD and THC in special populations remain poorly characterized, with limited studies investigating DDIs involving CBD/THC in these populations. Therefore, it is critical to evaluate potential DDIs between CBD/THC and medications that are commonly used in special populations. Modeling approaches can aid in understanding these interactions.
The endocannabinoid system (ECs) is composed of multiple signaling compounds and receptors within the central and peripheral nervous system along with various organs, including the gut, liver, and skeletal muscle. The ECs has been implicated in metabolism, gut motility, and eating behaviors. The ECs is altered in disease states such as obesity. Recent studies have clarified the role of the gut microbiome and nutrition on the ECs. Exogenous cannabinoid (CB) use, either organic or synthetic, stimulates the ECs through CB1 and CB2 receptors. However, the role of CBs is unclear in regard to nutrition optimization or to treat disease states. This review briefly summarizes the effect of the ECs and exogenous CBs on metabolism and nutrition. With the increased legalization of cannabis, there is a corresponding increased use in the United States. Therefore, nutrition clinicians need to be aware of both the benefits and harm of cannabis use on overall nutrition status, as well as the gaps in knowledge for future research and guideline development.
Cannabis sativa L. was used for medicinal purposes for millennia, being useful for the treatment of several conditions such as pain, convulsions, insomnia, and lack of appetite, among others. However, due to its psychotropic side effects and the impossibility to prepare standardized formulations it was banned in the late 1930s and removed from therapeutics, being considered as a drug that was solely used for recreational purposes. In the last two decades, this situation has changed, and the therapeutic use of cannabis has resurged again, demonstrating that standardized cannabis preparations can be safe and useful for the treatment of a broad range of pathologies. In fact, several cannabis-based formulations have been approved with medicinal purposes. This chapter analyzes the medicinal use of cannabis, describing their benefits, risks, and current and future perspectives.
Background:
Early invasion of the central nervous system (CNS) by human immunodeficiency virus (HIV) (1, 2), results in neuroinflammation, potentially through extracellular vesicles (EVs) and their micro RNAs (miRNA) cargoes (3, 4). Although the basal ganglia (BG) is a major target and reservoir of HIV in the CNS (5, 6), whether BG produces EVs and the effect of HIV and/or the phytocannabinoid― delta-9-tetrahydrocannabinol (THC) on BG-EVs and HIV neuropathogenesis remain unknown.
Methods:
We used simian immunodeficiency virus (SIV) model of HIV and THC treatment in rhesus macaques (7) to demonstrate for the first time that BG contains EVs (BG-EVs), and that BG-EVs cargo and function are modulated by SIV and THC. We also used primary astrocytes from the brains of wild type (WT) and CX3CR1+/GFP mice to investigate the significance of BG-EVs in CNS cells.
Results:
Significant changes in BG-EV associated miRNA specific to SIV infection and THC treatment were observed. BG-EVs from SIV infected rhesus macaques (SIV EVs) contain 11 significantly downregulated miRNA. Remarkably, intervention with THC led to significant upregulation of 37 miRNAs in BG-EVs (SIV-THC EVs). Most of these miRNAs regulate pathways related to inflammation/immune regulation, TLR signaling, Neurotrophin TRK receptor signaling, and cell death/response. BG-EVs activated WT and CX3CR1+/GFP astrocytes and reprogrammed astrocyte transcriptome in an EV and CX3CR1 dependent manners.
Conclusions:
Our findings reveal a role for BG-EVs as a vehicle with potential to disseminate HIV and THC induced changes within the CNS.
Background:
HIV/SIV-associated periodontal disease (gingivitis/periodontitis) (PD) represents a major comorbidity affecting people living with HIV (PLWH) on combination anti-retroviral therapy (cART). PD is characterized by chronic inflammation and dysbiosis. Nevertheless, the molecular mechanisms and use of feasible therapeutic strategies to reduce/reverse inflammation and dysbiosis remain understudied and unaddressed.
Methods:
Employing a systems biology approach, we report molecular, metabolome and microbiome changes underlying PD and its modulation by phytocannabinoids [delta-9-tetrahydrocannabinol (Δ9-THC)] in uninfected and SIV-infected rhesus macaques (RMs) untreated (VEH-untreated/SIV) or treated with vehicle (VEH/SIV) or Δ9-THC (THC/SIV).
Findings:
VEH- untreated/SIV but not THC/SIV RMs showed significant enrichment of genes linked to anti-viral defense, interferon-β, NFκB, RIG-1, and JAK-STAT signaling. We focused on the anti-microbial DUOX1 and immune activation marker IDO1 that were reciprocally regulated in the gingiva of VEH-untreated/SIV RMs. Both proteins localized to the gingival epithelium and CD163+ macrophages, and showed differential expression in the gingiva of THC/SIV and VEH/SIV RMs. Additionally, inflammation-associated miR-21, miR-142-3p, miR-223, and miR-125a-5p showed significantly higher expression in the gingiva of VEH/SIV RMs. In human primary gingival epithelial cells, miR-125a-5p post-transcriptionally downregulated DUOX1 and THC inhibited IDO1 protein expression through a cannabinoid receptor-2 mediated mechanism. Interestingly, THC/SIV RMs showed relatively reduced plasma levels of kynurenine, kynurenate, and the neurotoxic quinolinate compared to VEH/SIV RMs at 5 months post SIV infection (MPI). Most importantly, THC blocked HIV/SIV-induced depletion of Firmicutes and Bacteroidetes, and reduced Gammaproteobacteria abundance in saliva. Reduced IDO1 protein expression was associated with significantly (p<0.05) higher abundance of Prevotella, Lactobacillus (L. salivarius, L. buchneri, L. fermentum, L. paracasei, L. rhamnosus, L. johnsonii) and Bifidobacteria and reduced abundance of the pathogenic Porphyromonas cangingivalis and Porphyromonas macacae at 5MPI.
Interpretation:
The data provides deeper insights into the molecular mechanisms underlying HIV/SIV-induced PD and more importantly, the anti-inflammatory and anti-dysbiotic properties of THC in the oral cavity. Overall, these translational findings suggest that phytocannabinoids may help reduce gingival/systemic inflammation, salivary dysbiosis and potentially metabolic disease/syndrome in PLWH on cART and those with no access to cART or do not suppress the virus under cART.
Funding:
Research reported in this publication was supported by the National Institutes of Health Award Numbers R01DA052845 (MM and SNB), R01DA050169 (MM and CO), R01DA042524 and R56DE026930 (MM), and P51OD011104 and P51OD011133. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
There is growing momentum to legalize medical cannabis across the United States. Positive public attitudes and permissive policies are based on growing anecdotal experiences and medical evidence that enumerate the health benefits of cannabis. Against this backdrop, Muslim stakeholders are (re)-evaluating their stance on the issue for Muslim patients who may benefit from such novel treatments, Muslim physicians who could incorporate the provision of cannabis into practices, and Muslim entrepreneurs who may seek to engage with the pharmaceutical and business aspects of the growing industry. Given this renewed interest, the Fiqh Council of North America (FCNA), a deliberative body comprised of Islamic jurists and medical consultants, examined the medical as well as religious evidence surrounding medical cannabis in order to furnish Muslim Americans with religious guidance. In 2018, they resolved that, while the use of intoxicating substances is proscribed by Islamic law, medical cannabis was permissible for Muslims to use with the following stipulations: Non-psychoactive preparations of cannabis are permitted to treat illnesses for which therapeutic effects of cannabis are certain, and psychoactive preparations are contingently permissible in cases of dire necessity. In this paper we first discuss the deliberative process and ethico-legal rationale brought to bear in furnishing the ruling, and then proceed to critically examine its conceptual gaps, practical limitations, and future implications. Clarifying the nuances around the religious permissibility of medical cannabis is important for Muslim patients and providers whose attitudes and behaviors may be informed by the ruling, as well for stakeholder groups within pharmaceutical and health policy circles who aim to address the needs of the global Muslim community that may stand to benefit from advances in medical cannabis research and therapeutics.
Background
Observational studies suggested that cannabis use is associated with decreased body fatness; however, observational studies are subject to confounding, making causal inference and determining the direction of these associations difficult. We performed Mendelian randomization (MR) using summary statistics from genome-wide association studies (GWAS) to investigate the potential causal association of cannabis use and obesity-related traits.
Methods
We used 51 single nucleotide polymorphisms (SNPs) associated with lifetime cannabis use at P 1<× 10⁻⁵ from a GWAS of 184,765 individuals of European descent and 27 SNPs genome-wide associated with cannabis use disorder as instrumental variables. The GWAS for body mass index (BMI) was derived from a meta-analysis of up to 322,154 individuals, and the GWAS for waist circumference (WC) and waist-hip ratio (WHR) included 210,088 participants.
Results
MR showed that lifetime cannabis use (beta = - 0.018, 95% confidence interval (CI): - 0.05-0.015; P-value = 0.279, Q-value = 0.279) and cannabis use disorder (beta = 0.023, 95% CI: 0.023-0.045; P-value = 0.034, Q-value = 0.092) were not associated with BMI. Considering WC and WHR as indicators of obesity, our findings did not support a causal association. Leave-one out analyses and pleiotropy-robust methods did not indicate bias in any of the estimates.
Conclusions
Overall, the MR study provides little evidence that cannabis influences obesity related traits.
Human immunodeficiency virus type 1 (HIV-1) is known to provoke microglial immune responses which likely play a paramount role in the development of chronic neuroinflammatory conditions and neuronal damage related to HIV-1 associated neurocognitive disorders (HAND). In particular, HIV-1 Tat protein is a proinflammatory neurotoxin which predisposes neurons to synaptodendritic injury. Drugs targeting the degradative enzymes of endogenous cannabinoids have shown promise in reducing inflammation with minimal side effects in rodent models. Considering that markers of neuroinflammation can predict the extent of neuronal injury in HAND patients, we evaluated the neurotoxic effect of HIV-1 Tat-exposed microglia following blockade of fatty acid amid hydrolyze (FAAH), a catabolic enzyme responsible for degradation of endocannabinoids, e.g. anandamide (AEA). In the present study, cultured murine microglia were incubated with Tat and/or a FAAH inhibitor (PF3845). After 24 h, cells were imaged for morphological analysis and microglial conditioned media (MCM) was collected. Frontal cortex neuron cultures (DIV 7–11) were then exposed to MCM, and neurotoxicity was assessed via live cell calcium imaging and staining of actin positive dendritic structures. Results demonstrate a strong attenuation of microglial responses to Tat by PF3845 pretreatment, which is indicated by 1) microglial changes in morphology to a less proinflammatory phenotype using fractal analysis, 2) a decrease in release of neurotoxic cytokines/chemokines (MCP-1/CCL2) and matrix metalloproteinases (MMPs; MMP-9) using ELISA/multiplex assays, and 3) enhanced production of endocannabinoids (AEA) using LC/MS/MS. Additionally, PF3845's effects on Tat-induced microglial-mediated neurotoxicity, decreased dysregulation of neuronal intracellular calcium and prevented the loss of actin-positive staining and punctate structure in frontal cortex neuron cultures. Interestingly, these observed neuroprotective effects appeared to be independent of cannabinoid receptor activity (CB1R & CB2R). We found that a purported GPR18 antagonist, CID-85469571, blocked the neuroprotective effects of PF3845 in all experiments. Collectively, these experiments increase understanding of the role of FAAH inhibition and Tat in mediating microglial neurotoxicity in the HAND condition.
Cannabis/cannabinoids are widely used for recreational and therapy purposes, but their risks are largely disregarded. However, cannabinoid-associated use disorders and dependence are alarmingly increasing and an effective treatment is lacking. Recently, the growth hormone secretagogue receptor (GHSR1A) antagonism was proposed as a promising mechanism for drug addiction therapy. However, the role of GHS-R1A and its endogenous ligand ghrelin in cannabinoid abuse remains unclear. Therefore, the aim of our study was to investigate whether the GHS-R1A antagonist JMV2959 could reduce the tetrahydrocannabinol (THC)-induced conditioned place preference (CPP) and behavioral stimulation, the WIN55,212-2 intravenous self-administration (IVSA), and the tendency to relapse. Following an ongoing WIN55,212-2 self-administration, JMV2959 3 mg/kg was administered intraperitoneally 20 min before three consequent daily 120-min IVSA sessions under a fixed ratio FR1, which significantly reduced the number of the active lever-pressing, the number of infusions, and the cannabinoid intake. Pretreatment with JMV2959 suggested reduction of the WIN55,212-2-seeking/relapse-like behavior tested in rats on the twelfth day of the forced abstinence period. On the contrary, pretreatment with ghrelin significantly increased the cannabinoid IVSA as well as enhanced the relapse-like behavior. Co-administration of ghrelin with JMV2959 abolished/reduced the significant efficacy of the GHS-R1A antagonist in the cannabinoid IVSA. Pretreatment with JMV2959 significantly and dose-dependently reduced the manifestation of THC-induced CPP. The THC-CPP development was reduced after the simultaneous administration of JMV2959 with THC during conditioning. JMV2959 also significantly reduced the THC-induced behavioral stimulation in the LABORAS cage. Our findings suggest that GHS-R1A importantly participates in the rewarding/reinforcing effects of cannabinoids.
In the era of combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) is considered a chronic disease with an inflammatory component that specifically targets the brain and causes a high prevalence of HIV-1-associated neurocognitive disorders (HAND). The endocannabinoid (eCB) system has attracted interest as a target for treatment of neurodegenerative disorders, due to the potential anti-inflammatory and neuroprotective properties of cannabinoids, including its potential therapeutic use in HIV-1 neuropathogenesis. In this review, we summarize what is currently known about the structural and functional changes of the eCB system under conditions of HAND. This will be followed by summarizing the current clinical and preclinical findings on the effects of cannabis use and cannabinoids in the context of HIV-1 infection, with specifically focusing on viral load, cognition, inflammation, and neuroprotection. Lastly, we present some potential future directions to better understand the involvement of the eCB system and the role that cannabis use and cannabinoids play in neuroHIV.
Ten years after the successful withdrawal from heroin abuse, a person with diabetes suffered intractable pain and severe muscular emaciation consistent with the syndrome of diabetic neuropathic cachexia. Anti-neuropathic medications failed neither to alleviate suffering and reverse weight loss, nor to stop muscular emaciation. Vigilant evaluation for weight loss aetiologies revealed no responsible aetiology. Prescribing medical cannabis became mandatory, with the intention to alleviate neuropathic pain, regain muscular mass and strengthen legs, enable standing upright and walking normally. Medical cannabis for pain-relief, and the orexigenic properties of tetrahydrocannabinol (THC) ingredient successfully achieved these goals.
Learning points
Medical cannabis can serve to promptly alleviate severe diabetic neuropathic pain.
Past history of heroin abuse was not an absolute contraindication to medical cannabis use.
Medical cannabis increased appetite and reversed muscular emaciation.
Medical cannabis decreased chronic pain and hence, its catabolic consequences.
The identification of the human cannabinoid receptors and their roles in health and disease, has been one of the most significant biochemical and pharmacological advancements to have occurred in the past few decades. In spite of the major strides made in furthering endocannabinoid research, therapeutic exploitation of the endocannabinoid system has often been a challenging task. An impaired endocannabinoid tone often manifests as changes in expression and/or functions of type 1 and/or type 2 cannabinoid receptors. It becomes important to understand how alterations in cannabinoid receptor cellular signaling can lead to disruptions in major physiological and biological functions, as they are often associated with the pathogenesis of several neurological, cardiovascular, metabolic, and inflammatory diseases. This review focusses mostly on the pathophysiological roles of type 1 and type 2 cannabinoid receptors, and it attempts to integrate both cellular and physiological functions of the cannabinoid receptors. Apart from an updated review of pre-clinical and clinical studies, the adequacy/inadequacy of cannabinoid-based therapeutics in various pathological conditions is also highlighted. Finally, alternative strategies to modulate endocannabinoid tone, and future directions are also emphasized.
Objective:
To compile and synthesize the available literature describing medical cannabis use across various disease states.
Data sources:
PubMed, EBSCO, and Google Scholar searches were conducted using MeSH and/or keywords.
Study selection and data extraction:
Studies were included if they described the use of cannabis-based products and medications in the treatment of a predefined list of disease states in humans and were published in English. The extraction period had no historical limit and spanned through April 2019.
Data synthesis:
Evidence was compiled and summarized for the following medical conditions: Alzheimer disease, amyotrophic lateral sclerosis, autism, cancer and cancer-associated adverse effects, seizure disorders, human immunodeficiency virus, inflammatory bowel disease, multiple sclerosis (MS), nausea, pain, posttraumatic stress disorder, and hospice care.
Relevance to patient care and clinical practice:
Based on identified data, the most robust evidence suggests that medical cannabis may be effective in the treatment of chemotherapy-induced nausea and vomiting, seizure disorders, MS-related spasticity, and pain (excluding diabetic neuropathy). Overall, the evidence is inconsistent and generally limited by poor quality. The large variation in cannabis-based products evaluated in studies limits the ability to make direct comparisons. Regardless of the product, a gradual dose titration was utilized in most studies. Cannabis-based therapies were typically well tolerated, with the most common adverse effects being dizziness, somnolence, dry mouth, nausea, and euphoria.
Conclusions:
As more states authorize medical cannabis use, there is an increasing need for high-quality clinical evidence describing its efficacy and safety. This review is intended to serve as a reference for clinicians, so that the risks and realistic benefits of medical cannabis are better understood.
Leptin is an adipocyte-derived hormone that interacts with a putative receptor(s) in the hypothalamus to regulate body weight. The relationship of leptin to metabolic abnormalities associated with obesity together with hormonal and substrate regulation of leptin have not been extensively studied. Therefore, 116 subjects (62 men and 54 women) with a wide range of body weight [body mass index (BMI), 17-54 kg/m2] were characterized on a metabolic ward with regard to body composition, glucose intolerance, insulin sensitivity, energy expenditure, substrate utilization, and blood pressure. Eighty-five of the subjects had normal glucose tolerance (50 men and 35 women), and 31 had noninsulin-dependent diabetes mellitus (12 men and 19 women). In both men and women, fasting leptin levels were highly correlated with BMI (r = 0.87 and r = 0.88, respectively) and percent body fat (r = 0.82 and r = 0.88, respectively; all P < 0.0001). However, men exhibited lower leptin levels at any given measure of obesity. Compared with those in men, leptin levels rose 3.4-fold more rapidly as a function of BMI in women [leptin = 1.815 (BMI)-31.103 in women; leptin = 0.534 (BMI)-8.437 in men] and 3.2 times more rapidly as a function of body fat [leptin = 1.293 (% body fat)-24.817 in women; leptin = 0.402 (% body fat)-3.087 in men]. Hyperleptinemia was associated with insulin resistance (r = -0.57; P < 0.0001) and high waist to hip ratio (r = 0.75; P < 0.0001) only in men. On the other hand, during the hyperinsulinemic euglycemic clamp studies, hyperinsulinemia acutely increased leptin concentrations (20%) only in women. There was no correlation noted between fasting leptin levels and either resting energy expenditure or insulin-induced thermogenesis in men or women (P = NS). In stepwise and multiple regression models with leptin as the dependent variable, noninsulin-dependent diabetes mellitus did not enter the equations at a statistically significant level. The data indicate that there are important gender-based differences in the regulation and action of leptin in humans. Serum leptin levels increase with progressive obesity in both men and women. However, for any given measure of obesity, leptin levels are higher in women than in men, consistent with a state of relative leptin resistance. These findings have important implications regarding differences in body composition in men and women. The observation that serum leptin is not related to energy expenditure rates suggests that leptin regulates body fat predominantly by altering eating behavior rather than calorigenesis.
It has been reported that cannabinoids may cause overeating in humans and in laboratory animals. Although, endogenous cannabinoids and their receptors (CB1) have been found in the hypothalamus, and recently also in gastrointestinal tract, the precise mechanism of appetite control by cannabinoids remains unknown. Recently, ghrelin--a hormone secreted mainly from the stomach X/A-like cells was proposed to be an appetite stimulating agent. The aim of this study was the evaluation of the influence of a single ip injection of a stable analogue of endogenous cannabinoid--anandamide, R-(+)-methanandamide (2.5 mg/kg) and CP 55,940 (0.25 mg/kg), an exogenous agonist of CB1 receptors, on ghrelin plasma concentration and on ghrelin immunoreactivity in the gastric mucosa of male Wistar rats. Four hours after a single injection of both cannabinoids or vehicle, the animals were anaesthetized and blood was taken from the abdominal aorta to determinate plasma ghrelin concentration by RIA. Subsequently, the animals underwent resection of distal part of stomach. Immunohistochemical study of gastric mucosa, using the EnVision method and specific monoclonal antibodies against ghrelin was performed. The intensity of ghrelin immunoreactivity in X/A-like cells was analyzed using Olympus Cell D image analysis system. The attenuation of ghrelin-immunoreactivity of gastric mucosa, after a single injection of R-(+)-methanandamide and CP 55,940 was accompanied by a significant increase of ghrelin plasma concentration. These results indicate that stimulation of appetite exerted by cannabinoids may be connected with an increase of ghrelin secretion from gastric X/A-like cells.
Despite management with opioids and other pain modifying therapies, neuropathic pain continues to reduce the quality of life and daily functioning in HIV-infected individuals. Cannabinoid receptors in the central and peripheral nervous systems have been shown to modulate pain perception. We conducted a clinical trial to assess the impact of smoked cannabis on neuropathic pain in HIV. This was a phase II, double-blind, placebo-controlled, crossover trial of analgesia with smoked cannabis in HIV-associated distal sensory predominant polyneuropathy (DSPN). Eligible subjects had neuropathic pain refractory to at least two previous analgesic classes; they continued on their prestudy analgesic regimens throughout the trial. Regulatory considerations dictated that subjects smoke under direct observation in a hospital setting. Treatments were placebo and active cannabis ranging in potency between 1 and 8% Delta-9-tetrahydrocannabinol, four times daily for 5 consecutive days during each of 2 treatment weeks, separated by a 2-week washout. The primary outcome was change in pain intensity as measured by the Descriptor Differential Scale (DDS) from a pretreatment baseline to the end of each treatment week. Secondary measures included assessments of mood and daily functioning. Of 127 volunteers screened, 34 eligible subjects enrolled and 28 completed both cannabis and placebo treatments. Among the completers, pain relief was greater with cannabis than placebo (median difference in DDS pain intensity change, 3.3 points, effect size = 0.60; p = 0.016). The proportions of subjects achieving at least 30% pain relief with cannabis versus placebo were 0.46 (95% CI 0.28, 0.65) and 0.18 (0.03, 0.32). Mood and daily functioning improved to a similar extent during both treatment periods. Although most side effects were mild and self-limited, two subjects experienced treatment-limiting toxicities. Smoked cannabis was generally
Leptin is an adipocyte-derived hormone that interacts with a putative receptor(s) in the hypothalamus to regulate body weight. The relationship of leptin to metabolic abnormalities associated with obesity together with hormonal and substrate regulation of leptin have not been extensively studied. Therefore, 116 subjects (62 men and 54 women) with a wide range of body weight [body mass index (BMI), 17-54 kg/m2] were characterized on a metabolic ward with regard to body composition, glucose intolerance, insulin sensitivity, energy expenditure, substrate utilization, and blood pressure. Eighty-five of the subjects had normal glucose tolerance (50 men and 35 women), and 31 had noninsulin-dependent diabetes mellitus (12 men and 19 women). In both men and women, fasting leptin levels were highly correlated with BMI (r = 0.87 and r = 0.88, respectively) and percent body fat (r = 0.82 and r = 0.88, respectively; all P < 0.0001). However, men exhibited lower leptin levels at any given measure of obesity. Compared with those in men, leptin levels rose 3.4-fold more rapidly as a function of BMI in women [leptin = 1.815 (BMI)-31.103 in women; leptin = 0.534 (BMI)-8.437 in men] and 3.2 times more rapidly as a function of body fat [leptin = 1.293 (% body fat)-24.817 in women; leptin = 0.402 (% body fat)-3.087 in men]. Hyperleptinemia was associated with insulin resistance (r = -0.57; P < 0.0001) and high waist to hip ratio (r = 0.75; P < 0.0001) only in men. On the other hand, during the hyperinsulinemic euglycemic clamp studies, hyperinsulinemia acutely increased leptin concentrations (20%) only in women. There was no correlation noted between fasting leptin levels and either resting energy expenditure or insulin-induced thermogenesis in men or women (P = NS). In stepwise and multiple regression models with leptin as the dependent variable, noninsulin-dependent diabetes mellitus did not enter the equations at a statistically significant level. The data indicate that there are important gender-based differences in the regulation and action of leptin in humans. Serum leptin levels increase with progressive obesity in both men and women. However, for any given measure of obesity, leptin levels are higher in women than in men, consistent with a state of relative leptin resistance. These findings have important implications regarding differences in body composition in men and women. The observation that serum leptin is not related to energy expenditure rates suggests that leptin regulates body fat predominantly by altering eating behavior rather than calorigenesis.
Using a pre-feed paradigm, the effects of orally-administered delta9-tetrahydrocannabinol (THC) on low baseline levels of nocturnal feeding were assessed. Following 2-h access to a palatable wet mash diet at dark onset, adult male Lister hooded rats (Charles River) were treated with either sesame seed oil vehicle or delta9- tetrahydrocannabinol (0.063, 0.12, 0.25, 0.5, 1.0, or 2.0 mg/kg). One hour later, rats were allowed ad libitum access to standard chow, and intakes were monitored over the subsequent 24 h. Doses of 0.5, 1.0, and 2.0 mg/kg produced substantial hyperphagia during the first hour of testing. Subsequently, rats compensated for their overconsumption so that 24-h intakes were similar in all conditions. The data confirm anecdotal reports of the orexigenic actions of exogenous cannabinoids and suggest a critical role for endogenous cannabinoid systems in the regulation of appetite.
Leptin is the primary signal through which the hypothalamus senses nutritional state and modulates food intake and energy balance. Leptin reduces food intake by upregulating anorexigenic (appetite-reducing) neuropeptides, such as alpha-melanocyte-stimulating hormone, and downregulating orexigenic (appetite-stimulating) factors, primarily neuropeptide Y. Genetic defects in anorexigenic signalling, such as mutations in the melanocortin-4 (ref. 5) or leptin receptors, cause obesity. However, alternative orexigenic pathways maintain food intake in mice deficient in neuropeptide Y. CB1 cannabinoid receptors and the endocannabinoids anandamide and 2-arachidonoyl glycerol are present in the hypothalamus, and marijuana and anandamide stimulate food intake. Here we show that following temporary food restriction, CB1 receptor knockout mice eat less than their wild-type littermates, and the CB1 antagonist SR141716A reduces food intake in wild-type but not knockout mice. Furthermore, defective leptin signalling is associated with elevated hypothalamic, but not cerebellar, levels of endocannabinoids in obese db/db and ob/ob mice and Zucker rats. Acute leptin treatment of normal rats and ob/ob mice reduces anandamide and 2-arachidonoyl glycerol in the hypothalamus. These findings indicate that endocannabinoids in the hypothalamus may tonically activate CB1 receptors to maintain food intake and form part of the neural circuitry regulated by leptin.
The recently discovered orexigenic peptide ghrelin is produced primarily by the stomach and circulates in blood at levels that increase during prolonged fasting in rats. When administered to rodents at supraphysiological doses, ghrelin activates hypothalamic neuropeptide Y/agouti gene-related protein neurons and increases food intake and body weight. These findings suggest that ghrelin may participate in meal initiation. As a first step to investigate this hypothesis, we sought to determine whether circulating ghrelin levels are elevated before the consumption of individual meals in humans. Ghrelin, insulin, and leptin were measured by radioimmunoassay in plasma samples drawn 38 times throughout a 24-h period in 10 healthy subjects provided meals on a fixed schedule. Plasma ghrelin levels increased nearly twofold immediately before each meal and fell to trough levels within 1 h after eating, a pattern reciprocal to that of insulin. Intermeal ghrelin levels displayed a diurnal rhythm that was exactly in phase with that of leptin, with both hormones rising throughout the day to a zenith at 0100, then falling overnight to a nadir at 0900. Ghrelin levels sampled during the troughs before and after breakfast correlated strongly with 24-h integrated area under the curve values (r = 0.873 and 0.954, respectively), suggesting that these convenient, single measurements might serve as surrogates for 24-h profiles to estimate overall ghrelin levels. Circulating ghrelin also correlated positively with age (r = 0.701). The clear preprandial rise and postprandial fall in plasma ghrelin levels support the hypothesis that ghrelin plays a physiological role in meal initiation in humans.
Delta9-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-delta9-tetrahydrocannabinol (THCA) in human plasma can be simultaneously detected using solid-phase extraction with gas chromatography and negative ion chemical ionization mass spectrometry. THC-d3 and THCA-d3 are added as internal standards; protein is precipitated with acetonitrile and the resulting supernatants diluted with 0.1 M sodium acetate (pH 7.0) prior to application to the solid-phase extraction columns. THC and THCA were eluted separately and then pooled, dried under air, and derivatized with trifluoroacetic anhydride and hexafluoroisopropanol. The derivatized THC-d0 gives abundant molecular anions (m/z 410), and the derivatized THCA-d0 gives abundant fragment ions (m/z 422) formed by loss of (CF3)2CHOH from its molecular anion. The recoveries of THC and THCA were 74% and 17%, respectively. The lower and upper limits of quantitation were 0.5 and 100 ng/mL for THC and 2.5 ng/mL and 100 ng/mL for THCA. The within-run accuracy and precision for THC (measured at 0.5, 1, 10 and 75 ng/mL) ranged from 98 to 106% (% target) and 4.1 to 9.5 (%CV), respectively. For THCA, the within-run accuracy and precision (measured at 2.5, 5, 10, and 75 ng/mL) ranged from 89 to 101% and 4.3 to 7.5%, respectively. The between-run accuracy and precision for THC ranged from 92 to 110% and 0.4 to 12.4%, respectively. The between-run accuracy and precision for THCA ranged from 97 to 103% and 6.5 to 12.3%, respectively. In processed samples stored in reconstituted form at -20 degrees C, THC and THCA were stable for at least three days. THC and THCA stored in plasma were stable following three freeze/thaw cycles. THC and THCA in whole blood at room temperature for 6 h, or in plasma stored at room temperature for 24 h, did not show significant change. Storage in polypropylene containers for 7 days at -20 degrees C and the presence of 1% sodium fluoride or the cannabinoid receptor antagonist, SR141716, at 1 microg/mL did not interfere with the quantitation of THC and THCA. In three individuals who smoked marijuana under controlled dosing conditions, peak THC concentrations of 151, 266, and 99 ng/mL were seen in the first plasma samples drawn immediately after the end of smoking, and corresponding peak THCA concentrations of 41, 52, and 17 ng/mL occurred at 0.33 to 1 h after cessation of smoking.
Arcuate nucleus neurons are known to be responsive to a wide array of hormones and nutrients, including leptin, insulin, gonadal steroids and glucose. In addition to potential transport mechanisms, peripheral substances may access these neurons via arcuate cell bodies in and projections to the median eminence, a region considered to be a circumventricular organ. The arcuate is a potent site of leptin action, probably mediating a component of leptin's effects via arcuate neuropeptide Y/agouti-related peptide (NPY/AgRP) and pro-opiomelanocortin (POMC) neurons, and implicating this structure in the long-term control of energy stores. However, ghrelin, the endogenous ligand of the growth hormone secretagogue receptor, may also stimulate feeding and weight gain, in part through action on receptors in arcuate NPY neurons. Since ghrelin is secreted by the stomach upon content depletion, with a half-life of no more than an hour, the arcuate nucleus may also be important in sensing and responding to acute changes in nutrients. We have developed a system for recording from arcuate POMC neurons using a mouse containing a transgene in which the POMC promoter is driving expression of the green fluorescent protein (GFP). In these mice, 99% of the beta-endorphin positive neurons express GFP, making whole cell patch clamp recordings from the sparsely distributed POMC neurons facile. All of the POMC neurons appear to be activated by leptin, via two different mechanisms, while approximately 30-50% of the neurons appear to be inhibited by a gamma-melanocyte stimulating hormone (MSH) specific agonist. The latter result suggests that the melanocortin-3 receptor (MC3-R) may act as an autoinhibitory receptor on some POMC neurons. This hypothalamic slice preparation also confirms the responsiveness of arcuate POMC neurons to a wide variety of nutrients and hormones. Thus the arcuate melanocortin system is best described as a conduit of many diverse signals involved in energy homeostasis, with leptin acting tonically to regulate the responsiveness of the circuit to a wide variety of hormones and nutrients.
Ghrelin is an orexigenic hormone that is implicated in meal initiation, in part because circulating levels rise before meals. Because previous human studies have examined subjects fed on known schedules, the observed preprandial ghrelin increases could have been a secondary consequence of meal anticipation. A causal role for ghrelin in meal initiation would be better supported if preprandial increases occurred before spontaneously initiated meals not prompted by external cues. We measured plasma ghrelin levels among human subjects initiating meals voluntarily without cues related to time or food. Samples were drawn every 5 min between a scheduled lunch and a freely requested dinner, and hunger scores were obtained using visual analog scales. Insulin, glucose, fatty acids, leptin, and triglycerides were also measured. Ghrelin levels decreased shortly after the first meal in all subjects. A subsequent preprandial increase occurred over a wide range of intermeal intervals (IMI; 320-425 min) in all but one subject. Hunger scores and ghrelin levels showed similar temporal profiles and similar relative differences in magnitude between lunch and dinner. One subject displayed no preprandial ghrelin increase and was also the only individual whose insulin levels did not return to baseline between meals. This finding, along with a correlation between area-under-the-curve values of ghrelin and insulin, suggests a role for insulin in ghrelin regulation. The preprandial increase of ghrelin levels that we observed among humans initiating meals voluntarily, without time- or food-related cues, and the overlap between these levels and hunger scores are consistent with a role for ghrelin in meal initiation.
Ghrelin and cannabinoids stimulate appetite, this effect possibly being mediated by the activation of hypothalamic AMP-activated protein kinase (AMPK), a key enzyme in appetite and metabolism regulation. The cannabinoid receptor type 1 (CB1) antagonist rimonabant can block the orexigenic effect of ghrelin. In this study, we have elucidated the mechanism of the putative ghrelin-cannabinoid interaction.
The effects of ghrelin and CB1 antagonist rimonabant in wild-type mice, and the effect of ghrelin in CB1-knockout animals, were studied on food intake, hypothalamic AMPK activity and endogenous cannabinoid content. In patch-clamp electrophysiology experiments the effect of ghrelin was assessed on the synaptic inputs in parvocellular neurons of the hypothalamic paraventricular nucleus, with or without the pre-administration of a CB1 antagonist or of cannabinoid synthesis inhibitors.
Ghrelin did not induce an orexigenic effect in CB1-knockout mice. Correspondingly, both the genetic lack of CB1 and the pharmacological blockade of CB1 inhibited the effect of ghrelin on AMPK activity. Ghrelin increased the endocannabinoid content of the hypothalamus in wild-type mice and this effect was abolished by rimonabant pre-treatment, while no effect was observed in CB1-KO animals. Electrophysiology studies showed that ghrelin can inhibit the excitatory inputs on the parvocellular neurons of the paraventricular nucleus, and that this effect is abolished by administration of a CB1 antagonist or an inhibitor of the DAG lipase, the enzyme responsible for 2-AG synthesis. The effect is also lost in the presence of BAPTA, an intracellular calcium chelator, which inhibits endocannabinoid synthesis in the recorded parvocellular neuron and therefore blocks the retrograde signaling exerted by endocannabinoids. In summary, an intact cannabinoid signaling pathway is necessary for the stimulatory effects of ghrelin on AMPK activity and food intake, and for the inhibitory effect of ghrelin on paraventricular neurons.
Cannabinoid-1 (CB(1)) receptor antagonists exhibit pharmacological properties favorable to treatment of obesity, caused by both centrally mediated effects on appetite and peripherally mediated effects on energy metabolism. However, the relative contribution of these effects to the weight loss produced by CB(1) receptor antagonists remains unclear. Here, we compare food intake-related and independent effects of the CB(1)-selective antagonist 1-(7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)-3-(methylamino) azetidine-3-carboxamide (PF-95453) in obese cynomolgus monkeys. Monkeys were divided into three study groups (n = 10 each) and treated once daily for 8 weeks with either vehicle or PF-95453 as follows: 1, fed ad libitum and dosed orally with vehicle; 2, fed ad libitum and dosed orally with PF-95453 (0.5 mg/kg weeks 1-3, 1.0 mg/kg weeks 4-8); and 3, fed an amount equal to the amount consumed by the drug-treated group and dosed orally with vehicle (pair-fed). PF-95453 treatment significantly reduced food consumption by 23%, body weight by 10%, body fat by 39%, and leptin by 34% while increasing adiponectin by 78% relative to vehicle-treated controls. Pair-fed animals did not exhibit reductions in body weight or leptin but did show significantly reduced body fat (11%) and increased adiponectin (15%) relative to vehicle-treated controls but markedly less than after PF-95453 treatment. Indeed, significant differences were noted between the drug-treated and pair-fed groups with respect to body weight reduction, body fat reduction, increased adiponectin, and leptin reduction. Similar to humans, monkeys treated with the CB(1) receptor antagonist exhibited decreased body weight and body fat, a substantial portion of which seemed to be independent of the effects on food intake.
Leptin regulates energy homeostasis and reproductive, neuroendocrine, immune, and metabolic functions. In this review, we describe the role of leptin in human physiology and review evidence from recent "proof of concept" clinical trials using recombinant human leptin in subjects with congenital leptin deficiency, hypoleptinemia associated with energy-deficient states, and hyperleptinemia associated with garden-variety obesity. Since most obese individuals are largely leptin-tolerant or -resistant, therapeutic uses of leptin are currently limited to patients with complete or partial leptin deficiency, including hypothalamic amenorrhea and lipoatrophy. Leptin administration in these energy-deficient states may help restore associated neuroendocrine, metabolic, and immune function and bone metabolism. Leptin treatment is currently available for individuals with congenital leptin deficiency and congenital lipoatrophy. The long-term efficacy and safety of leptin treatment in hypothalamic amenorrhea and acquired lipoatrophy are currently under investigation. Whether combination therapy with leptin and potential leptin sensitizers will prove effective in the treatment of garden-variety obesity and whether leptin may have a role in weight loss maintenance is being greatly anticipated.
Ghrelin, a peptide hormone predominantly produced by the stomach, was isolated as the endogenous ligand for the growth hormone secretagogue receptor. Ghrelin is a potent stimulator of growth hormone (GH) secretion and is the only circulatory hormone known to potently enhance feeding and weight gain and to regulate energy homeostasis following central and systemic administration. Therapeutic intervention with ghrelin in catabolic situations may induce a combination of enhanced food intake, increased gastric emptying and nutrient storage, coupled with an increase in GH thereby linking nutrient partitioning with growth and repair processes. These qualities have fostered the idea that ghrelin-based compounds may have therapeutic utility in treating malnutrition and wasting induced by various sub-acute and chronic disorders. Conversely, compounds that inhibit ghrelin action may be useful for the prevention or treatment of metabolic syndrome components such as obesity, impaired lipid metabolism or insulin resistance. In recent years, the effects of ghrelin on glucose homeostasis, memory function and gastrointestinal motility have attracted considerable amount of attention and revealed novel therapeutic targets in treating a wide range of pathologic conditions. Furthermore, discovery of ghrelin O-acyltransferase has also opened new research opportunities that could lead to major understanding of ghrelin physiology. This review summarizes the current knowledge on ghrelin synthesis, secretion, mechanism of action and biological functions with an additional focus on potential for ghrelin-based pharmacotherapies.
Leptin plays a vital role in the regulation of energy balance in rodent models of obesity. However, less information is available about its homeostatic role in humans. The aim of this study was to determine whether leptin serves as an indicator of short-term energy balance by measuring acute effects of small manipulations in energy intake on leptin levels in normal individuals. The 12-day study was composed of four consecutive dietary-treatment periods of 3 days each. Baseline (BASE) [100% total energy expenditure (TEE)] feeding, followed by random crossover periods of overfeeding (130% TEE) or underfeeding (70% TEE) separated by a eucaloric (100% TEE) washout (WASH) period. The study participants were six healthy, nonobese subjects. Leptin levels serially measured throughout the study period allowed a daily profile for each treatment period to be constructed and a 24-h average to be calculated; ad libitum intake during breakfast "buffet" following each treatment period was also measured. Average changes in mesor leptin levels during WASH, which were sensitive to energy balance effected during the prior period, were observed. After underfeeding, leptin levels during WASH were 88 +/- 16% of those during BASE compared with 135 +/- 22% following overfeeding (P = 0.03). Leptin levels did not return to BASE during WASH when intake returned to 100% TEE, but instead were restored (104 +/- 21% and 106 +/- 16%; not significant) only after subjects crossed-over to complementary dietary treatment that restored cumulative energy balance. Changes in ad libitum intake from BASE correlated with changes in leptin levels (r2 = 0.40; P = 0.01). Leptin levels are acutely responsive to modest changes in energy balance. Because leptin levels returned to BASE only after completion of a complementary feeding period and restoration of cumulative energy balance, leptin levels reflect short-term cumulative energy balance. Leptin seems to maintain cumulative energy balance by modulating energy intake.
Ghrelin is an orexigenic hormone secreted by the stomach. Increased plasma ghrelin concentration was reported during diet-induced weight loss in obese humans, suggesting that ghrelin contributes to adaptive increment in appetite associated with caloric restriction. Leptin reduces spontaneous food intake and body weight in rodents. The current study tested the hypothesis that increased plasma leptin prevents the potential increase in plasma ghrelin concentration during moderate caloric restriction in lean rats.
Six-month-old male rats (body weight, 367 +/- 9 grams) were randomly assigned to one of the following treatments (8 rats each) for 1 week: (1) leptin subcutaneous infusion to induce moderate hyperleptinemia and moderate caloric restriction (-26% of ad libitum), (2) vehicle infusion and pair feeding, and (3) vehicle infusion and ad libitum feeding.
Leptin-treated (-19 +/- 5 grams) and pair-fed (-19 +/- 2) rats lost weight compared with ad libitum-fed rats (-3 +/- 1, P < 0.05). Compared with control (6.8 +/- 0.7 ng/mL), plasma leptin was higher in leptin-treated (18.6 +/- 0.9 ng/mL, P < 0.01) rats and lower in pair-fed rats (4.3 +/- 0.4 ng/mL, P < 0.05). Plasma ghrelin was substantially higher in calorie-restricted than control rats (2505 +/- 132 pg/mL vs. 1790 +/- 134 pg/mL, P < 0.01), and leptin treatment (1625 +/- 117 pg/mL) completely prevented this change. Plasma ghrelin concentration was negatively correlated with body weight changes in calorie-restricted and control (r = -0.75, P < 0.01) but not in leptin-treated rats (P > 0.8).
Moderate hyperleptinemia prevents an increase of plasma ghrelin during moderate short-term caloric restriction. Satiety-inducing effects of leptin include suppression of gastric orexigenic signals and disruption of a potential feedback mechanism between body weight changes and plasma ghrelin in lean adult rats.
The paraventricular nucleus (PVN) of the hypothalamus plays a key role in the control of appetite and energy balance. Both ghrelin and cannabinoid receptor agonists increase food intake when administered into this nucleus: this study investigated possible interactions between the two systems in relation to eating. The orexigenic effect of ghrelin (100 pmol) when infused in to the PVN was reversed by a small, systemic dose of the CB1 cannabinoid receptor antagonist SR141716 (1 mg kg−1). This is the first demonstration of a functional relationship between brain ghrelin and endocannabinoid systems, and, although it needs to be further investigated, the effect of ghrelin on food intake when injected into the PVN seems to be mediated by stimulation of cannabinoid release.
British Journal of Pharmacology (2004) 143, 520–523. doi:10.1038/sj.bjp.0705968
Obesity represents the most prevalent nutritional problem worldwide which in the long run predisposes to development of diabetes mellitus, hypertension, endometrial carcinoma, osteoarthritis, gall stones and cardiovascular diseases. Despite significant reductions in dietary fat consumption, the prevalence of obesity is on a rise and is taking on pandemic proportions. Obesity develops when energy intake exceeds energy expenditure over time. Recently, a close evolutionary relationship between the peripheral and hypothalamic neuropeptides has become apparent. The hypothalamus being the central feeding organ mediates regulation of short-term and long-term dietary intake via synthesis of various orexigenic and anorectic neuropeptides. The structure and function of many hypothalamic peptides (neuropeptide Y (NPY), melanocortins, agouti-related peptide (AGRP), cocaine and amphetamine regulated transcript (CART), melanin concentrating hormone (MCH), orexins have been characterized in rodent models The peripheral neuropeptides such as cholecystokinin (CCK), ghrelin, peptide YY (PYY3-36), amylin, bombesin regulate important gastrointestinal functions such as motility, secretion, absorption, provide feedback to the central nervous system on availability of nutrients and may play a part in regulating food intake. The pharmacological potential of several endogenous peripheral peptides released prior to, during and/or after feeding are being explored. Long-term regulation is provided by the main circulating hormones leptin and insulin. These systems implicated in hypothalamic appetite regulation provide potential targets for treatment of obesity which could potentially pass into clinical development in the next 5 years. This review summarizes various effects and interrelationship of these central and peripheral neuropeptides in metabolism, obesity and their potential role as targets for treatment of obesity.
Appetite is regulated by a complex system of central and peripheral signals which interact in order to modulate the individual response to nutrient ingestion. Peripheral regulation includes satiety signals and adiposity signals, while central control is accomplished by several effectors, including the neuropeptidergic, monoaminergic and endocannabinoid systems. Satiety signals, including cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), originate from the gastrointestinal (GI) tract during a meal and, through the vagus nerve, reach the nucleus tractus solitarius (NTS) in the caudal brainstem. From NTS afferents fibers project to the arcuate nucleus (ARC), where satiety signals are integrated with adiposity signals, namely leptin and insulin, and with several hypothalamic and supra-hypothalamic inputs, thus creating a complex network of neural circuits which finally elaborate the individual response to a meal. As for the neuropeptidergic system, ARC neurons secrete orexigenic substances, such as neuropeptide Y (NPY) and agouti-related peptide (AGRP), and anorexigenic peptides such as pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). Other brain areas involved in the control of food intake are located downstream the ARC: among these, the paraventricular nucleus (PVN), which produces anorexigenic peptides such as thyrotropin releasing hormone (TRH), corticotrophin releasing hormone (CRH) and oxytocin, the lateral hypothalamus (LHA) and perifornical area (PFA), secreting the orexigenic substances orexin-A (OXA) and melanin concentrating hormone (MCH). A great interest in endocannabinoids, important players in the regulation of food intake, has recently developed. In conclusion, the present work reviews the most recent insights into the complex and redundant molecular mechanisms regulating food intake, focusing on the most encouraging perspectives for the treatment of obesity.
Neurobiology Component
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- M D Annese
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- Taylor
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Leptin-regulated endocannabinoids are involved in maintaining food intake
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Neurobiology Component Neurovirology Component International Component
- M A Archibald
- John Hesselink
- M D Jacopo Annese
- Ph D Michael
- J Taylor
- Ph D Douglas Richman
- David M Smith
Archibald, M.A., John Hesselink, M.D., Jacopo Annese, Ph.D.,
Michael J. Taylor, Ph.D.; Neurobiology Component: Eliezer
Masliah, M.D. (P.I.), Ian Everall, FRCPsych., FRCPath., Ph.D.,
Cristian Achim, M.D., Ph.D.; Neurovirology Component:
Douglas Richman, M.D., (P.I.), David M. Smith, M.D.; International Component: J. Allen McCutchan, M.D.,(P.I.); Developmental Component: Ian Everall, FRCPsych., FRCPath., Ph.D.
(P.I.), Stuart Lipton, M.D.,Ph.D.; Participant Accrual and Retention Unit: J. Hampton Atkinson, M.D. (P.I.), Rodney von
Jaeger,M.P.H.; Data Management Unit: Anthony C. Gamst,
Ph.D. (P.I.), Clint Cushman (Data Systems Manager); Statistics
Unit: Ian Abramson, Ph.D. (P.I.), Florin Vaida, Ph.D., Reena
Deutsch, Ph.D., Tanya Wolfson, M.A.
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