# Clinical Study: Gastrointestinal Delivery Reduces Appetite & Food Cravings in Women

**TYPE:** Primary Clinical Research (Peer-Reviewed)
**STATUS:** Published
**TRIAL REGISTRY ID:** ACTRN12622000107729 (Australian New Zealand Clinical Trials Registry)
**ETHICS APPROVAL:** Northern B Health and Disability Ethics Committee (2022 EXP 10995)
**DOI:** [10.1016/j.obpill.2024.100117](https://doi.org/10.1016/j.obpill.2024.100117)
**JOURNAL:** Obesity Pillars (2024, Vol 11)
**AUTHORS:** Walker et al.

---

## Study Summary (TL;DR)
This clinical trial investigated the effect of Amarasate® (a bitter hops extract) on appetite and food cravings in 30 healthy women during a 24-hour water-only fast. Participants received either a Placebo, Low Dose (250mg), or High Dose (500mg) of Amarasate at 16 and 20 hours into the fast.
**Key Findings:** Both doses significantly reduced appetite and food cravings compared to placebo. Specifically, cravings for savory foods were significantly reduced. The study confirms that the appetite-suppressing effects previously seen in men are also present in women.

## Full Text Content

### 1. Introduction
Bitter tasting plants have a long history of use as traditional, health-giving foods and medicine, with recent interest in their application as appetite suppressants [1,2]. The use of bitter foods to suppress appetite and food cravings is reported in several cultures throughout history. Interestingly, two examples of traditional bitter appetite suppressants have recently been rediscovered and considered for commercial development: *Lathyrus linifolius* (heath pea) and *Hoodia gordonii* [3].

The effectiveness of directed GI bitterness for appetite regulation was assessed in a recent 2021 meta-analysis [4]. Klaassen et al. determined that pre-meal treatment with bitter tastants significantly reduce energy intake, concluding that "Bitter stimuli are most potent to influence eating behavior", and suggested their mechanism of action was likely via the stimulation of appetite-suppressing gut peptide hormones released from enteroendocrine cells. Although bioactive, most of the bitter compounds evaluated were either non-dietary, pharmaceutical, or unsuitable for development into a consumer product. The search for a commonly consumed bitter plant extract with a history of medicinal use led to *Humulus lupulus* (hops) [5]. The primary bittering components of hops are the alpha acids, which exhibit limited bioavailability [6], persistent bitterness in epithelial sensory tissue [7], and high viscosity when in extract form. These properties are favorable for producing a potent and persistent bitterness at the gut surface when delivered directly to the GI tract in a highly concentrated capsule-based format.

We have previously shown that capsule-based GI delivery of an extract of bitter hop can reduce food intake, suppress appetite, and stimulate the release of appetite-suppressing gut hormones in healthy males [8,9]. To the best of our knowledge, however, no published work exists that assess the efficacy of bitter hops on appetite in females or on the effect of bitter hops on food cravings. Determining the efficacy of bitter hops in the regulation of food cravings and appetite measures in females is important, as the effect of GI bitterness on appetite may differ between males and females [10], and as food cravings are key determinants in diet compliance [11]. In this study we hypothesis that an extract of New Zealand hops (Amarasate®) will 1) Improve subjective measures of appetite and food craving during the 16–24 h period of a 24 h water-only fast in healthy, normal weight women, and 2) Reduced rebound eating immediately post fast.

### 2. Materials and Methods

**2.1. Participants**
Thirty healthy women (eligibility: age 18–40 y, BMI 18.5–25 kg/m²) were recruited through poster and electronic advertisement in Auckland, New Zealand. Exclusion criteria included current participation in a weight loss program, GI diseases, previous GI surgery, diabetes, or use of medication affecting appetite. Participants were also required to be non-smokers and able to undertake a 24 h water-only fast. All subjects provided written informed consent.

**2.2. Study design, supplements and protocol**
The study design was modified from a previous study examining the effect of the same hop extract on appetite measure in men [8]. Briefly, this was a randomized, double-blind, cross-over treatment study, using Visual Analogue Scales (VAS) to assess the effect of a hop extract on appetite and food craving during the last 8 h of a 24 h water-only fast. It involved two concentrations of the Amarasate hop flower extract suspended in a canola oil excipient and a placebo control, which were protected from gastric acid digestion by encapsulation using a hydroxypropyl methylcellulose (HPMC) DRcap capsule.

**Treatments:**
* **High Dose (HD):** 500 mg Amarasate total daily (250 mg per capsule).
* **Low Dose (LD):** 250 mg Amarasate total daily (125 mg per capsule).
* **Placebo:** Formulation matched control.

All treatment groups received two capsules, one given at 16 h (10:00 AM) and the second given 20 h (2:00 PM) into the 24 h fast, each containing half the total daily treatment dose. Participants were required to attend three study visits.

**Protocol:** On the evening prior to commencement of the 24 h fast, participants were instructed to eat a typical dinner until comfortably full immediately before 1800 h and then fast overnight with the consumption of water allowed. Participants arrived at the clinical facility at 0950 h (15 h 50 min into the fast) and were randomly assigned to one of three treatments. Treatment capsules were given at 1000 h (t=0 min) and at 1400 h (t=240 min). Appetite and food craving measures were taken at 30-min intervals from 1000 h by VAS.

**2.3. Appetite measures**
Subjective measures of appetite (i.e., hunger, fullness, satisfaction, thoughts of food (TOF)), food-type cravings and physical comfort (e.g., nausea) were recorded from 16 h to 24 h of the fast using a 100 mm scale. The Food Craving-related VAS questions included cravings for: food, sugary foods, salty foods, fatty foods, savory foods, and spicy foods [12].

**2.4. Fast breaking ad libitum meal**
A fast-breaking, rice-based ad libitum meal was presented in excess to participants at 1800 h (24h mark). The meal consisted of rice with non-meat additives (4 g protein, 3 g fat, 29 g carbohydrate per 100g). Participants were instructed to "eat until comfortably full". Energy intake was calculated based on the consumed fraction of the presented meal.

### 3. Results

**3.1. Participants**
Twenty-Seven participants completed all three treatments of the appetite trial. All participants were lean healthy females with a mean age of 21 ± 4 years (range 18–39) and a mean body mass index (BMI) of 21 ± 1 kg/m².

**3.2. Appetite ratings (Hunger & Fullness)**
* **Hunger:** The placebo group recorded a 33 mm increase in VAS hunger ratings over the 16–24 h fasting period. Compared with placebo, both treatments reduced hunger. Differences in excess of 10 mm were recorded for hunger for the **High Dose (HD)** treatment group relative to the placebo for all time points taken from t=90 min onwards. This same magnitude difference was evident for all time points post t=150 min for the **Low Dose (LD)** treatment group. These changes in hunger were statistically significant (p < 0.05).
* **Fullness:** Overall, there was a significant Amarasate treatment effect on fullness (p < 0.05). Fullness increases of ≥10 mm relative to the placebo control were observed at time points t=90 min onwards for the HD treatment.

**3.3. Craving ratings**
* **Food Cravings:** Mean changes in VAS food craving ratings were lower compared with the placebo control for both the HD and LD treatments (p < 0.05). Differences in excess of 10 mm were recorded for the HD treatment group relative to the placebo for all time points taken from t=60 min onwards.
* **Savory Food Cravings:** Cravings for savory food exhibited a significant main effect for treatment (p < 0.05). Differences in excess of 10 mm were recorded for all time points post t=90 for the LD and t=60 for the HD treatment relative to the placebo.
* **Other Cravings:** Mean changes in both VAS sugary food craving and fatty food craving ratings did not differ by 10 mm at any pre-meal time points.

**3.4. Energy intake**
Energy intake at the ad libitum meal was **14.3% lower** when taking the HD treatment (p < 0.05) and 8.1% lower when taking the LD treatment relative to the placebo control treatment.

**3.5. Side effects**
Three participants experienced adverse effects that were deemed likely to be treatment related. Liquid, loose bowel movements were reported by two participants after taking the HD treatment, and from one participant after taking the LD treatment. One participant experienced heartburn from the HD treatment.

### 4. Discussion
This current study shows for the first time that a bitter hop supplement can suppress appetite and can reduce cravings for food in females. Favorable changes in several appetite measures reported here are likely to be biologically important and to affect eating behavior [13]. These changes in appetite measures occur over a greater than 6 h period, are in excess of the 10% that is typically targeted for behavioral change, and would be expected to aid fasting compliance [12].

The relative decrease in absolute hunger ratings observed here was a **greater magnitude** than what was previously seen in males [8]. This finding agrees with other studies showing greater sensitivity of females to the appetite-suppressing effects of GI-targeted bitterness [14].

Cravings for food in general, and **savory food** in particular, were seen to be decreased by the bitter hop treatment. Cravings for savory food was the only specific food craving that showed a treatment effect. The greater increase in cravings for savory foods, when compared to fatty or sugary foods, is in line with a previous report of food cravings experienced during fasting [19].

Amarasate, the bioactive hop extract present in the test capsules, has been shown to exhibit appetite-suppressing activity by increasing the blood concentrations of anorexigenic gut peptides glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK) and peptide tyrosine tyrosine (PYY) [20,21].

### 5. References

1. Mithila MV, Khanum F. The appetite regulatory effect of guggulsterones in rats: a repertoire of plasma hormones and neurotransmitters, *J Diet Suppl* 2014;11: 262–71.
2. Sarup P, Bala S, Kamboj S. Pharmacology and Phytochemistry of Oleo-gum resin of commiphora wightii (guggulu). *Sci Tech Rep* 2015;2015:138039.
3. Lee RA, Balick M.J. Indigenous use of Hoodia gordonii and appetite suppression. *Explore* 2007;3:404–6.
4. Klaassen T, Keszthelyi D, Troost FJ, Bast A, Masclee AAM. Effects of gastrointestinal delivery of non-caloric tastants on energy intake: a systematic review and meta-analysis. *Eur J Nutr* 2021;60:2923–47.
5. Meyerhof W, Batram C, Kuhn C, Brockhoff A, Chudoba E, Bufe B, et al. The molecular receptive ranges of human TAS2R bitter taste receptors. *Chem Senses* 2010;35:157–70.
6. Zugravu CA, Bohiltea RE, Salmen T, Pogurschi E, Otelea MR. Antioxidants in hops: bioavailability, health effects and perspectives for New products. *Antioxidants* 2022;11.
7. Intelmann D, Batram C, Kuhn C, Haseleu G, Meyerhof W, Hofmann TF. Three TAS2R bitter taste receptors mediate the psychophysical responses to bitter compounds of hops (Humulus lupulus L.) and beer. *Chemosensory Perception* 2009;2:118–32.
8. Walker E, Lo K, Tham S, Pahl M, Lomiwes D, Cooney J, et al. New Zealand bitter hops extract reduces hunger during a 24 h water only fast. *Nutrients* 2019;11.
9. Walker EG, Lo KR, Pahl MC, Shin HS, Lang C, Wohlers MW, et al. An extract of hops (Humulus lupulus L.) modulates gut peptide hormone secretion and reduces energy intake in healthy-weight men: a randomized, crossover clinical trial. *Am J Clin Nutr* 2022;115:925–40.
10. Andreozzi P, Sarnelli G, Pesce M, Zito FP, Alessandro AD, Verlezza V, et al. The bitter taste receptor agonist quinine reduces calorie intake and increases the postprandial release of cholecystokinin in healthy subjects. *J Neurogastroenterol Motil* 2015;21:511–9.
11. Sayer RD, Peters JC, Pan Z, Wyatt HR, Hill JO. Hunger, food cravings, and diet satisfaction are related to changes in body weight during a 6-month behavioral weight loss intervention: the beef WISE study. *Nutrients* 2018;10.
12. Flint A, Raben A, Blundell JE, Astrup A. Reproducibility, power and validity of visual analogue scales in assessment of appetite sensations in single test meal studies. *Int J Obes Relat Metab Disord* 2000;24:38–48.
13. Blundell J, de Graaf C, Hulshof T, Jebb S, Livingstone B, Lluch A, et al. Appetite control: methodological aspects of the evaluation of foods. *Obes Rev* 2010;11: 251–70.
14. Deloose E, Janssen P, Corsetti M, Biesiekierski J, Masuy I, Rotondo A, et al. Intragastric infusion of denatonium benzoate attenuates interdigestive gastric motility and hunger scores in healthy female volunteers. *Am J Clin Nutr* 2017;105: 580–8.
15. Bedard A, Hudon AM, Drapeau V, Corneau L, Dodin S, Lemieux S. Gender differences in the appetite response to a satiating diet. *J Obes* 2015;2015:140139.
16. Drazen DL, Vahl TP, D'Alessio DA, Seeley RJ, Woods SC. Effects of a fixed meal pattern on ghrelin secretion: evidence for a learned response independent of nutrient status. *Endocrinology* 2006;147:23–30.
17. Hagemann CA, Zhang C, Hansen HH, Jorsal T, Rigbolt KTG, Madsen MR, et al. Identification and metabolic profiling of a novel human gut-derived LEAP2 fragment. *J Clin Endocrinol Metab* 2021;106:2966–81.
18. Reents J, Seidel AK, Wiesner CD, Pedersen A. The effect of hunger and satiety on mood-related food craving. *Front Psychol* 2020;11:568908.
19. Zajac I, Herreen D, Hunkin H, James-Martin G, Doyen M, Kakoschke N, et al. Modified fasting compared to true fasting improves blood glucose levels and subjective experiences of hunger, food cravings and mental fatigue, but not cognitive function: results of an acute randomised cross-over trial. *Nutrients* 2020;13.
20. Li M, Tan HE, Lu Z, Tsang KS, Chung AJ, Zuker CS. Gut-brain circuits for fat preference. *Nature* 2022;610:722–30.
21. Eren-Yazicioglu CY, Yigit A, Dogruoz RE, Yapici-Eser H. Can glp-1. Be a target for reward system related disorders? A qualitative synthesis and systematic review analysis of studies on palatable food, drugs of abuse, and alcohol. *Front Behav Neurosci* 2020;14:614884.