This randomized placebo-controlled trial evaluated the effects of cannabinoids in a 1:1 ratio of THC to CBD on appetite, body weight, inflammatory markers, and quality of life in patients with SSc. Of the 27 participants, most were female and had the dcSSc subset. The baseline clinical characteristics were generally balanced between the treatment and placebo groups, except for higher transferrin levels and daily calorie intake per kilogram of body weight in the treatment group. This imbalance may have influenced the outcomes.

The treatment group demonstrated trends toward improved appetite, reflected in higher mean differences in VAS scores for hunger, satisfaction with eating, and ability to eat more compared to the placebo group. These findings align with previous studies suggesting cannabinoids may stimulate appetite by modulating the endocannabinoid system (Marzo and Matias 2005; Camilleri and Zheng 2023; Cohen and Neuman 2020). Specifically, THC is known to mediate appetite through activation of CB1 receptors. In addition, endocannabinoids facilitate mesolimbic dopamine signaling, enhance appetite, and promote eating initiation and food seeking (Kirkham 2009). Although cannabinoids in THC-based formulations demonstrated favorable outcomes on appetite in 11 patients with advanced cancer compared to placebo (Brisbois et al. 2011), many studies on cannabinoids for appetite stimulation in patients with cancer reported similar findings to ours, showing no significant differences in VAS scores for appetite between the treatment and placebo groups (Cannabis-In-Cachexia-Study-Group et al. 2006; Côté et al. 2016; Turcott et al. 2018). One study also reported a significant improvement in appetite compared to baseline, consistent with our findings (Turcott et al. 2018). Other appetite-related parameters, such as feelings of fullness and wanting to eat salty foods, showed no significant changes between or within groups, but the VAS seemed to be lower in the treatment group than in the placebo group. This suggests that cannabinoids may not significantly affect the mechanism underlying the feeling of fullness.

Our analysis suggests that cannabinoids may enhance sweet taste. A previous study in an animal model showed that endocannabinoids can increase sweet taste perception by stimulating CB1 receptors in taste cells, counteracting the inhibitory effects of leptin on sweet taste (Yoshida et al. 2010). The results corroborate our observations that patients in the treatment group exhibited an elevation in the VAS score for craving sweet foods following cannabis consumption, relative to baseline measurements. Cannabinoids also trended to increase the VAS score for wanting to eat spicy foods after taking cannabinoids when compared to baseline. No mechanism has been previously shown to corroborate these findings, as spiciness may not constitute a conventional dietary element in daily life, as it does within the Thai population. However, these findings may guide therapeutic approaches for managing appetite and energy homeostasis in the clinical setting. The mechanisms of the spicy taste of cannabinoids require further investigation.

In contrast to the decrease observed in the placebo group, the treatment group showed a slight increase in body weight and BMI mass index, although these differences were not statistically significant. These findings are consistent with evidence indicating cannabinoids can enhance caloric intake in conditions characterized by anorexia or wasting (Haney et al. 2007) but no significant weight gain among patients with cancer (Cannabis-In-Cachexia-Study-Group et al. 2006; Côté et al. 2016; Turcott et al. 2018). In contrast, a previous observational prospective study in 282 malnourished older participants in nursing homes reported that after taking 134 kcal/d more, the mean weight gain was 2.3 kg at 12 weeks (Malafarina et al. 2021). That means body weight might increase at least 0.7 kg in 4 weeks if taking an additional 134 kcal/d. Although our patients had significant increases in daily calorie intake, the rate of weight gain was lower than expected. These results might be explained by other factors affecting BW, such as gastrointestinal (GI) involvement in SSc, which may cause malabsorption or maldigestion. The lack of significant weight gain, despite increased caloric intake in both groups, may be explained by several factors. First, the presence of GI involvement in approximately 20% of our cohort could have led to malabsorption, thereby blunting the impact of increased food consumption on body weight. Second, the short follow-up duration was a key limitation. As weight gain is often a gradual process, our four-week study period may have been insufficient to detect meaningful changes. Future trials should therefore incorporate longer treatment and follow-up periods to more accurately assess this outcome. Finally, given the imbalances in some baseline characteristics, the results must be interpreted with caution as these differences may have confounded the outcomes. To date, the 2016 European Society for Parenteral and Enteral Nutrition has not graded the use of cannabinoids to improve appetite in cancer patients, rating it as having a low level of evidence, with no recommendation provided for other patient groups (Johnson et al. 2021). Further well-designed studies with larger populations are needed.

Markers of inflammation, including ESR and CRP, decreased in the treatment group but increased in the placebo group after treatment. Cannabinoids have been reported to reduce inflammation in inflammatory bowel disease (IBD), as evidenced by improvements in the Crohn’s Disease Activity Index compared to placebo (Naftali et al. 2013). Another study demonstrated that cannabinoids improved quality of life and appetite in IBD patients compared to placebo, although CRP levels did not significantly change (Naftali et al. 2021). Henshaw et al.(2021) conducted a systematic review of 26 studies examining the anti-inflammatory effects of cannabinoids. Two studies specifically evaluated the combined effects of THC and CBD, revealing that this formulation reduced tumor necrotic factor-α (TNF-α) levels in vivo. The anti-inflammatory effects of cannabinoids vary by dose (Henshaw et al. 2021) and have also been reported to decrease levels of interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-12 (IL-12) (Klein 2005). As IL-1, IL-6, IL-12, and TNF-α are not the primary cytokines involved in SSc; therefore, we did not evaluate their levels in our study. While the reductions in ESR and CRP in the treatment group were not statistically significant, they suggest the potential anti-inflammatory effects of cannabinoids. These findings highlight the need for more extensive trials incorporating pro- and anti-inflammatory cytokines to confirm these effects and to better understand their role in SSc management.

Cannabinoids may not directly influence TGF-β, a key cytokine in fibrosis. Our findings showed no significant differences in TGF-β levels between the treatment and placebo groups and notable changes after treatment. Gonzalez et al. reported antifibrotic effects in SSc-induced mice treated with ajulemic acid, a synthetic cannabinoid with a higher binding affinity for CB2 than for CB1 (Gonzalez et al. 2012). Among cannabinoids, CBD has potential immunomodulatory and anti-inflammatory effects. At the same time, THC is known for its effects on appetite stimulation, antiemesis, and analgesia (Zurier and Burstein 2016). The antifibrotic effect of ajulemic acid may be explained by its activation of peroxisome proliferator-activated receptor-γ (PPARγ), which subsequently disrupts the signaling of TGF-β, a major fibrogenic cytokine (Gonzalez et al. 2012). However, the exact mechanism of both anti-inflammatory and antifibrotics of cannabinoids, particularly those with predominant activity on CB2, remains poorly understood.

Improvements in quality of life, measured by the EQ-5D health VAS, were observed in the treatment group post-treatment, although the change was not statistically significant. These findings are consistent with studies suggesting cannabinoids may have positive effects on health perception and overall well-being in chronic disease patients (Whiting et al. 2015).

While cannabinoids have many potential benefits, safety and tolerability data are essential for balanced interpretation. Acute toxicity is a known risk and depends on the dose, patient tolerance, and route of administration. Cannabis can also influence brain functions, including memory and cognition, and increases the risk of psychosis in individuals with prolonged use (Vadivelu et al. 2018). The symptoms of central nervous system (CNS) toxicity can include euphoria, panic, agitation, mood alterations, perceptual changes, loss of social inhibition, muscle incoordination, myoclonic jerking, ataxia, slurred speech, and suicidal ideation. Furthermore, prolonged, high-dose cannabis use can lead to cannabinoid hyperemesis syndrome, which causes cyclic hyperemesis (Allen et al. 2004) and can ultimately result in electrolyte disturbances and impaired kidney function (Vadivelu et al. 2018). The criticality of this was highlighted when one patient in our study experienced a serious adverse event after a single drop of cannabis oil, necessitating immediate withdrawal from treatment and emergency care. This incident validates our study’s rigorous safety protocol, which included close clinical and laboratory monitoring for emergent toxicities, even after the first dose. Our management strategy for such events ranged from dose reduction to immediate treatment discontinuation to always ensure patient safety.

None of the patients developed neuropsychological complications related to the psychotropic effects of cannabinoids, particularly from THC, and all tolerated the daily dose of 2.9 mg THC and 3.2 mg CBD, except for one case with a serious adverse reaction after a single drop of cannabinoid. This may be attributed to the low doses of cannabinoids used in our study. Brisbois et al. (2011) found that THC in a dose of 2.5 mg twice daily had a more significant effect on food taste, quality of life, and sleep quality than placebo treatment in cancer patients. Another study revealed that the effect of increasing appetite by THC at a dose of 2.5 mg twice daily was not more significant than that of megestrol 800 mg daily, and there was no additional benefit when THC was combined with megestrol (Vadivelu et al. 2018). In our study, the doses of THC (1.5 mg twice daily) and CBD (1.6 mg twice daily) were lower than those reported in previous studies but still led to improved appetite in SSc patients. Although the effects of cannabinoids can vary with dosage, we cannot conclude whether a higher dose results in more significant improvements in appetite, quality of life, transferrin levels, or reduction in inflammatory markers and cytokines.

The study drug was administered by transmucosal route (sublingual drop), which is claimed to have good absorption and high bioavailability route when compared to oral ingestion because of direct uptake of the drug by the highly vascularized oral mucosa and does not pass the digestive system, so the drug is not interfering with absorption by gastric acid and does not metabolize via the liver (Stella et al. 2021). Our patients administered cannabis sublingually at a reduced dosage and still achieved efficacy. However, the sublingual route may be more difficult to administer than oral ingestion because absorption is influenced by eating, drinking, or smoking. Patients should be advised to take the drug while fasting. To overcome the limitation, the production of cannabinoids with new technology, such as nanotechnology, may help improve the bioavailability of oral route administration and increase physical stability when compared to conventional formulations (Stella et al. 2021).

The limitations of this study include: (a) a small sample size, which likely left the study underpowered to detect significant differences and increased the risk of a Type II error. Consequently, our findings have limited generalizability and require validation in larger, multicenter randomized controlled trials; (b) baseline imbalances in transferrin levels and calorie intake, which may have introduced bias, although we adjusted for calorie intake per kilogram daily; c) a short follow-up period, which may have limited the detection of changes in parameters, requiring more time to show significant effects, such as serum albumin and body composition; (d) body composition was not included in our study for the reasons mentioned; and (e) the use of an unconventional dose in daily practice due to limitations in extracting plant-derived exogenous cannabinoids. The strengths of this study include being the first to investigate the efficacy of cannabinoids on appetite in SSc patients and to analyze the quality of life, key cytokine levels, inflammatory markers, and daily caloric intake. Future studies should involve larger cohorts and stratify patients according to disease subtype or severity to better understand the heterogeneity of the responses.