Preclinical studies have demonstrated that THCV enhances insulin sensitivity, thus promoting glucose uptake in peripheral tissues. This process reduces insulin resistance, which is a hallmark of type 2 diabetes. By improving the efficiency of insulin action, THCV addresses one of the central mechanisms that contributes to hyperglycemia and disease progression [12],[14]. In dietary-induced obesity (DIO) mice, THCV increased the amount of energy used and reduced the glucose intolerance in a dose-dependent manner. In addition, THCV enhanced the tolerance to glucose and the sensitivity to insulin among genetically obese (ob/ob) mice, thereby restoring insulin signaling in hepatocytes and myotubes resistant to insulin [22]. Furthermore, studies have indicated that THCV's effects may involve signaling through GPR55, as shown in experiments that compared a GPR55 knockout and wild-type mice [23]. These findings suggest that GPR55-mediated mechanisms may partially account for THCV's ability to regulate glucose tolerance and energy balance, thus warranting a further investigation into its role in metabolic health.

THCV's dual modulation of CB1 and CB2 receptors allows it to effectively restore glucose homeostasis. By suppressing appetite-driven hyperglycemia through CB1 antagonism and improving insulin sensitivity via CB2 activation, THCV provides a comprehensive approach to glycemic control [12],[18].

While the majority of current evidence comes from preclinical studies, they provide strong support for THCV's potential in diabetes management. Animal models have consistently demonstrated improvements in insulin sensitivity, fasting glucose levels, and systemic inflammation [12],[22],[23]. Limited human trials have reported promising results in glycemic control and appetite regulation, paving the way for further research into its clinical applications. A trial with 62 diabetic human subjects showed promising results and demonstrated a lowered fasting plasma glucose and boosted pancreatic β-cell function [24].

The emerging evidence positions THCV as a novel therapeutic candidate for type 2 diabetes management. Its ability to address insulin resistance, lower fasting glucose levels, and restore glucose homeostasis makes it particularly relevant in a clinical setting. Going forward, studies should focus on randomized controlled trials on a larger scale to confirm the effects of THCV, establish the optimal dosing, and evaluate the long-term safety [8]. Additionally, studies that explore the combined effects of THCV with existing antidiabetic therapies could provide further insights into its potential role in comprehensive diabetes care.

THCV's appetite-suppressing effects are primarily mediated through its antagonistic action on the CB1 receptor. In contrast to THC, which activates CB1 receptors and stimulates appetite (commonly referred to as the “munchies”), THCV inhibits this receptor's activity [14]. This inhibition reduces food intake and prevents excessive caloric consumption, thus making it a promising agent for appetite regulation. Unlike THC, THCV's effects do not produce psychoactive side effects, thus further enhancing its therapeutic potential for weight management [14].

Animal studies have provided strong evidence for THCV's appetite-suppressing and anti-obesity effects. In some rodent models, THCV administration improved the energy expenditure by 30% over a 24-hour period [22]. Maintaining this level of energy expenditure over a longer period would limit weight gain. The experimental data demonstrated that THCV exhibits hypophagic properties, thus significantly reducing the food intake and weight gain in free-feeding mice at doses as low as 3 mg·kg⁻¹. Interestingly, the hypophagic effects persisted without increased feeding on the following day [25]. THCV has demonstrated a possible role in weight management by directly reducing lipid accumulation in vitro, particularly among adipocytes and hepatosteatosis models. Through the use of nuclear magnetic resonance (NMR)-based metabolomics, the effects THCV caused in the metabolism of hepatocytes could be confirmed. These treatments induced post-translational modifications in the CREB, AMPKa2, PRAS40, and STATs proteins, suggesting an enhanced ability to metabolize lipids and the ability to cause an increase in the activity of cellular mitochondria, which are essential for energy expenditure. In vivo studies that used zebrafish and obese mice further demonstrated that THCV enhances yolk lipid utilization and prevents hepatosteatosis. These findings suggest that THCV may contribute to weight management by improving lipid metabolism and preventing fat accumulation, thus addressing key factors in obesity-related metabolic disorders [26]. These effects were observed without any significant adverse events, which supports its safety profile for further investigations as an alternative therapeutic treatment to obesity-related metabolic disorders.

Preliminary human studies support the equivalent effects of THCV on appetite and weight regulation. In small-scale clinical trials, THCV has been shown to reduce hunger with patients that recorded a baseline numerical rating scale (NRS) score of 5.4 and a THCV treatment NRS score of 5.0. The NRS score evaluates appetite, with a 0 representing no appetite and a 10 representing the maximum appetite. However, it should be noted that this reduction in appetite was not found to be statistically significant [24]. Nonetheless, these effects are particularly promising for individuals with obesity or metabolic syndrome, where appetite dysregulation plays a significant role in the disease progression. In addition, a single 10 mg dose of THCV enhanced the neural responses to aversive food stimuli, such as moldy foods, thus suggesting a potential mechanism by which THCV may contribute to weight loss through the modulation of food reward and aversion [27]. Larger randomized controlled trials are needed and necessary to strengthen and confirm the significance of these findings and to establish the optimal dosing regimens.

THCV stands out among cannabinoids due to its dual mechanism of action as an antagonist on CB1 and a partial agonist on CB2. Unlike THC, which promotes appetite and can lead to weight gain [29], THCV suppresses appetite and improves the energy balance [14]. Furthermore, THCV's ability to enhance glucose regulation makes it particularly relevant to manage both obesity and type 2 diabetes [22]. Compared to CBD, which primarily exerts anti-inflammatory and neuroprotective effects [31], THCV's targeted metabolic benefits offer a distinct therapeutic advantage for individuals with metabolic disorders [12].

These properties collectively position THCV as a unique and promising candidate to address the multifactorial challenges associated with obesity and type 2 diabetes. Further research will need to fully validate its clinical efficacy and explore its integration with existing treatment strategies.

Despite promising preclinical and limited human studies, the clinical evidence for THCV remains insufficient. Existing human trials are small in scale and often lack the statistical power needed to draw definitive conclusions [24]. Larger, randomized controlled trials (RCTs) with diverse populations are essential to validate THCV's efficacy, determine the optimal dosing, and assess its long-term benefits in managing obesity and type 2 diabetes. Recent advances in gene editing and fermentation technology now allow for the biosynthesis of cannabinoids in heterologous systems such as yeast and microalgae, thus possibly facilitating more meaningful clinical research by providing a cost-effective and reliable source of cannabinoids such as THCV [32],[33].

One of the significant challenges in cannabinoid-based therapies, including THCV, is poor bioavailability. THCV has a low water solubility, which limits its absorption and systemic availability when orally administered [34]. To address this, innovative drug delivery platforms such as nanoformulations, lipid-based carriers, and emulsified preparations need to be developed to improve THCV's pharmacokinetics and therapeutic efficacy.

The long-term safety of THCV remains unclear due to the lack of extended clinical studies. While preclinical studies have shown no significant adverse effects [22],[24], the safety profile of chronic THCV administration in humans must be rigorously evaluated. Additionally, its potential interactions with other metabolic or weight-loss therapies warrant careful investigations to ensure a safe co-administration in clinical settings.

Cannabinoid-based therapies face significant regulatory hurdles that can delay clinical research and approval processes [35]. Standardized guidelines for THCV's production, dosing, and safety testing are required to accelerate its clinical translation and integration into therapeutic protocols. Additionally, regulatory frameworks must address the public concerns surrounding cannabinoids while ensuring that high-quality, evidence-based treatments are accessible to patients.

Therefore, future research efforts should focus on the following:

By addressing these challenges, THCV has the potential to become a widely accepted therapeutic option to manage obesity and type 2 diabetes, thereby offering targeted benefits that complement existing treatment strategies.