Simmondsin

Simmondsin

1. Identity: Botanical Source, Chemical Name, and Forms

Botanical Source

Simmondsin is derived from Simmondsia chinensis, a desert shrub that grows in the Sonoran Desert of the southwestern United States. The jojoba plant, Simmondsia chinensis (L.) (Caryophyllales: Simmondsiaceae), is a monotypic species native to the Sonoran Desert in North America. Jojoba is currently being cultivated in many parts of the world, including Mexico, Australia, India, Saudi Arabia, Tunisia, and Egypt.

Jojoba seeds consist of about 50 percent jojoba oil, which is not actually an oil but the only naturally occurring wax that is in liquid form at room temperature. The seed meal remaining after oil extraction is the primary source of simmondsin. After oil extraction, the remaining meal commonly known as "defatted jojoba meal" contains 25–30% crude protein and about 50% carbohydrate.

Chemical Identity

Simmondsin has been isolated and identified as a 2-(cyanomethylene)-3-hydroxy-4,5-dimethoxycyclohexyl β-D-glucoside by application of conventional chemical fractionation and animal bioassay techniques. It is a multiple substituted cyclohexane system bearing a cyanomethylene substituent. The compound is classified as a cyanoglycoside — a glucoside with a cyanomethylene side chain — a structural feature that places it within the broader family of cyanogenic glycosides, though its precise toxicological mechanism via hydrogen cyanide release remains debated.

Jojoba seed is a rich source of liquid wax and also contains a group of closely related glycosides: simmondsin (SM), demethylsimmondsin, and didemethylsimmondsin (DDS). Four ferulate derivatives of SM and demethylsimmondsin have been identified and isolated. The term "Simmondsins" (capitalised, plural) is used to indicate three analogues of simmondsin, which include simmondsin, didemethyl simmondsin, and simmondsin ferulate.

The principal molecules are simmondsin [2-(cyanomethylene)-3-hydroxy-4,5-dimethoxycyclohexyl beta-D-glucoside] (up to 10% by weight of defatted jojoba meal), simmondsin 2′-ferulate, and several minor simmondsin derivatives.

Common Names and Synonyms

Simmondsin is referred to in the scientific literature exclusively by this systematic name or as a "jojoba glycoside." The parent plant bears numerous common names: goat nut, deer nut, pignut, quinine nut, coffeeberry, wild hazel, gray box bush, and Simmondsia chinensis are all synonyms encountered in trade and ethnobotanical sources.

Available Forms and Preparations

Simmondsin is not commercially available as a pure isolated compound for dietary supplementation. Preparations described in the research and patent literature include:

• Defatted jojoba meal: the high-protein, high-carbohydrate byproduct remaining after oil extraction from the seed.
• Standardized extracts: When used in the form of dietary supplements, jojoba extracts can be ingested in the form of capsules, softgels, or tablets. The jojoba extract can be formed into a capsule, typically of 0-size (about 500 mg) or 00-size (about 1000 mg).
• Powdered shakes: An unflavored powdered shake form has been described in patent literature for easy compliance.
• Processing considerations: There are documented processes for reducing the odour, bitterness, astringency and pungency of a simmondsin extract.

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2. Traditional and Historical Use

Indigenous Peoples of the Sonoran Desert

The seeds of Simmondsia chinensis have been traditionally used by Indigenous peoples of the Sonoran Desert, including the Seri, O'odham, and Cahuilla tribes, for medicinal, nutritional, and cosmetic purposes.

Native Americans first made use of jojoba. During the early 18th century Jesuit missionaries on the Baja California Peninsula observed indigenous peoples heating jojoba seeds to soften them. They then used a mortar and pestle to create a salve or buttery substance. The latter was applied to the skin and hair to heal and condition. The O'odham people of the Sonoran Desert treated burns with an antioxidant salve made from a paste of the jojoba seed. Native Americans also used the salve to soften and preserve animal hides.

Pregnant women ate jojoba seeds, believing they assisted during childbirth. Hunters and raiders ate jojoba on the trail to keep hunger at bay. The Seri, who utilize nearly every edible plant in their domain, do not regard the seeds as real food and in the past ate it only in emergencies.

Mark Nesbitt, the author of The Cultural History of Plants, cited that the first written mention of the tree is from the early 1700s by a Jesuit Priest exploring the Sonoran desert. The unnamed priest cited that the Southwestern tribes used jojoba extensively as medicine, food, and an appetite suppressant to alleviate hunger; they also used jojoba as a hair growth promoter and as a hairdressing.

Jojoba possesses a long traditional history. It has been used in folklore for treatment of cold, dysuria, and obesity.

Context: Simmondsin as the Active Hunger-Suppressing Constituent

The traditional use of jojoba seeds as a hunger suppressant among hunters and in times of food scarcity is now understood scientifically to be largely attributable to the presence of simmondsin. In large quantities, jojoba seed meal is toxic to many mammals. Later this effect was found to be due to simmondsin, which inhibits hunger. The historical practice of eating whole or lightly processed seeds — not purified simmondsin — means that traditional users encountered the compound alongside the seed's wax, protein, and other antinutritional factors.

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3. Key Constituents and Active Compounds

The Simmondsin Family

Anti-nutritional compounds called simmondsins — specifically 5-demethylsimmondsin, 4,5-didemethylsimmondsin, simmondsin, and simmondsin 2′-ferulate — are present in jojoba meal and are responsible for suppression of appetite and inhibition of feed consumption in different animal species including rats, dogs, cats, and chickens.

Simmondsin 2′-ferulate is notable for its bitter taste. Although there are some suggestions that the anorexia induced by defatted jojoba meal is caused by its bitter taste due to the presence of simmondsin 2′-ferulate and tannins, the facts that simmondsin itself is tasteless and that the food intake inhibition in rats can be reversed by the cholecystokinin receptor antagonist devazepide suggested that the anorexia seen following simmondsin administration is due to stimulation of the cholecystokinin satiation system.

Other Phytochemicals in Jojoba Meal

Jojoba meal is also rich in polyphenols and phytic acid with anticancer and antioxidant activities. Many recent studies have reported its medicinal and pharmacological properties like antioxidant, anti-inflammatory, antimicrobial, anticancer, anti-acne, anti-psoriasis, wound healing, and hepatoprotective activities. Many of these biological activities have been attributed to the presence of several phytochemicals such as simmondsin and phenolic compounds.

Additionally, insecticidal, antifeedant, and antifungal activities of two glucosides isolated from the seeds of jojoba plant have been tested. Bioassay-driven fractionations of the chloroform extract of the plant seeds afforded two glucosides, simmondsin and simmondsin 2′-ferulate. The structure of these glucosides was confirmed by physico-chemical properties and spectroscopic analyses.

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4. Established Mechanisms of Action

Cholecystokinin (CCK) Pathway

The leading proposed mechanism of simmondsin's appetite-suppressing action involves activation of the cholecystokinin (CCK) satiation system. Simmondsin has been reported to produce weight loss and to decrease food intake, an effect that can be blocked by treatment with an inhibitor of cholecystokinin. Specifically, Cokelaere et al. (1995a) reported that this effect is blocked by devazepide, an antagonist of the cholecystokinin A receptor.

Researchers investigated the analogies between the physiological effects of simmondsin, a satiety-inducing glycoside extracted from jojoba seeds, and the gastro-intestinal satiation peptide, cholecystokinin. While it had been considered toxic due to jojoba seed meal causing weight loss in animals, in recent years its appetite suppressant effect has also been researched as a potential treatment for obesity. It is thought to reduce appetite by increasing levels of cholecystokinin.

However, not all studies confirm CCK receptor dependence. In two acute experiments where simmondsin was either added to the diet or injected, there was a dose-related reduction in food intake. The CCKA antagonist lorglumide did not block the acute inhibitory effects of simmondsin on food intake, and simmondsin did not produce conditioned taste aversion. This conflicting evidence means the role of CCK signaling remains an active area of investigation with unresolved mechanistic questions.

Vagal Nerve Mediation

Simmondsin, 2-(cyanomethylene)-3 hydroxy 4,5 dimethoxy cyclohexyl β-D-glucoside, from jojoba meal reduces food intake in rats. Researchers investigated the mechanism of action of simmondsin by studying the effects of fasting or of vagotomy on the food intake reduction. The food intake reduction was significantly less in fasted rats than in non-fasted rats. The reduction of food intake was also significantly diminished after vagotomy. The results suggest that simmondsin reduces intake of food in rats through the augmentation of satiety, in part vagally mediated.

Dose-Dependent Effects on Meal Patterns

Simmondsin supplementation at different doses results in a dose-dependent food intake reduction, which is more pronounced after prior simmondsin experience. The effect of simmondsin on meal patterns — decreased meal size, meal duration and eating rate, increased latency to eat — is most severe at the highest concentration.

Satiety vs. Aversion: A Critical Mechanistic Distinction

A key unresolved issue in simmondsin research concerns whether its appetite-reducing effect is genuine satiety induction or, in part, a learned food aversion. The performed experiments indicate that the simmondsin activity shows some analogy with the satiating molecule cholecystokinin (CCK) at first contact, but shows more analogy with the illness-inducing agent lithium chloride (LiCl) after prior experience with simmondsin.

Behavioral satiety sequence (BSS) studies have been particularly illuminating: at first contact, simmondsin non-significantly reduced food intake by 17% and had little effect on feeding and associated behaviors. The behavioral structure was preserved and a small shift of the onset of resting to the left was observed, suggesting a small satiative action of simmondsin at first contact. Simmondsin given for the second time caused a more pronounced food intake reduction of 52% due to a reduction in eating duration, mean bout intake and mean bout length, and to an increase in latency to eat. At second contact, simmondsin caused a strong switching in active behaviors, disrupting the BSS.

Our results indicate that simmondsin exerts multiple effects. It probably facilitates a small natural process of satiation/satiety at first contact, but creates abnormal physiological effects resulting in aversive reactions from second contact on.

The performed experiments indicate that the simmondsin activity shows some analogy with the satiating molecule CCK at first contact, but shows more analogy with the illness-inducing agent lithium chloride (LiCl) after prior experience with simmondsin. Rats familiar with simmondsin avoid simmondsin-supplemented food by directly monitoring its presence, and by learning to relate it to the postingestive consequences of consumption.

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5. Scientific Evidence by Area of Use

5.1 Appetite Suppression and Food Intake Reduction

Animal Studies (Preclinical)

The vast majority of evidence for simmondsin's anorectic effect comes from animal models. Simmondsin, a glycoside from jojoba meal, decreases food intake after oral administration. The present experiments are designed to clarify the mechanism of simmondsin's anorectic activity. The meal pattern analysis shows that simmondsin supplementation at different doses results in a dose-dependent food intake reduction, which is more pronounced after prior simmondsin experience. The effect of simmondsin on meal patterns — decreased meal size, meal duration and eating rate, increased latency to eat — is most severe at the highest concentration. Rats familiar with simmondsin more seriously postpone their first meal than with first contact, resulting in a decrease of the meal frequency and the day/night feeding ratio.

To investigate the safety and efficacy for weight loss of simmondsin, a dietary supplement extracted from the seed of the jojoba plant, Sprague-Dawley male rats were fed various levels of simmondsin for 8 weeks (lean rats) or 16 weeks (high fat-induced obese rats). Measurements included food intake, body weight and composition, histopathology, and hematology parameters. Simmondsin produced a clear dose-response effect on food intake and body weight. Simmondsin at both the 0.15% level and the 0.25% level significantly reduced food intake and body weight without apparent negative effects.

Evidence strength: Strong and consistent in animal models across multiple independent laboratories, particularly from the Katholieke Universiteit Leuven group (Cokelaere et al.) and others. The preclinical dose-response relationship is well-established. However, the aversion vs. satiety distinction complicates interpretation.

Human/Clinical Evidence

Published peer-reviewed clinical trial evidence specifically for isolated simmondsin in humans is very limited. The most substantive human data comes from a small open-label study described in the patent literature. A group of 20 obese or overweight individuals with BMI higher than 25 were chosen to participate in an outpatient clinical setting. The only intervention was the administration of defatted jojoba seed meal (containing 8–10% simmondsin) at 12.5 g twice a day (one hour before lunch and dinner). The duration of the study was one month. Hunger was significantly reduced and the mean reduction of body weight was 11%. No drop-outs were reported and no side effects were observed. Body weight and BMI were reduced by 8.69% and 11.38%, respectively. Body fat was also dramatically decreased.

Limitations: This study appeared in a patent filing, not a peer-reviewed journal. It lacked a placebo control group, blinding, and independent verification, rendering its conclusions of limited scientific value without corroboration from independently conducted randomized controlled trials (RCTs).

5.2 Body Weight and Obesity Management

Simmondsin and simmondsin-containing jojoba meal induce food intake inhibition, emaciation, and had been considered toxic before it was found that long-term administration of lower doses of simmondsin or defatted jojoba meal to growing rats induced a sustained food intake inhibition of about 20% without showing any side effects.

Some studies have shown that the food intake reduction induced with lower doses of defatted jojoba meal is due to satiation, and is dose related.

A notable human investigation comes from the context of the supplement IQP-WS-201, a jojoba seed extract standardized for simmondsin content. Note: The IQP-AE-103 trial found in the literature is an okra and inulin product — not a simmondsin-based product — and must not be conflated with simmondsin research. IQP-AE-103 contains a combination of dehydrated okra pod powder and inulin, which has been shown to be a strong fat-binding agent in an in vitro setting; it also exerts high swelling capacity and significantly enhances solution viscosity. This distinction is important: the published double-blind RCT evidence for IQP-AE-103 is not evidence for simmondsin per se.

Evidence strength: For simmondsin specifically in humans, the evidence base is preliminary. Only uncontrolled or patent-filed clinical observations exist. Independent, placebo-controlled RCTs are absent from the peer-reviewed literature as of the time of this writing.

5.3 Insecticidal and Antifeedant Activity

Insecticidal, antifeedant and antifungal activities of two glucosides isolated from the seeds of jojoba plant, Simmondsia chinensis (Link) Schneider, have been tested. Bioassay-driven fractionations of the chloroform extract of the plant seeds over silica gel columns followed by recrystallization afforded two glucosides, simmondsin and simmondsin 2′-ferulate.

Evidence strength: Preliminary in vitro / bioassay data only. No relevance to dietary supplementation in humans.

5.4 COX-2 Inhibition (Anti-inflammatory)

Two new noncyanogenic cyanoglucoside dimers, simmonosides A and B, were identified from the aqueous extract of jojoba leaves. Compounds 1 and 2 are the first examples of noncyanogenic cyanoglucoside dimers containing a unique four-membered ring, representing novel dimerization patterns. Their structures were elucidated based on spectroscopic evidence and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 exhibit promising COX-2 inhibition activity, with IC50 values of 13.5 and 11.4 μM, respectively.

Evidence strength: In vitro, preliminary. These are novel dimers found in jojoba leaves, not the seed meal simmondsin itself; no human data exist.

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6. Body Systems and Health Areas of Association

• Gastrointestinal/Satiety System: Simmondsin's primary investigated activity is modulation of satiety signaling, with proposed involvement of CCK-secreting I-cells in the duodenum and jejunum and vagal afferent pathways.
• Metabolic/Adipose System: Reduction in food intake in animal models translates to loss of body weight and body fat, making it of interest in metabolic obesity research.
• Hematopoietic System: At high doses, simmondsin has been found to be toxic with profound effects on the hematopoietic system.
• Central and Peripheral Nervous System: The involvement of vagal nerve pathways points to peripheral neural mediation of its satiety effects.
• Inflammatory Pathways: Recent studies have reported anti-inflammatory activity associated with jojoba phytochemicals including simmondsin and phenolic compounds.

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7. Dosage Forms and Doses Reported in Studies

All dosages below are reported exactly as stated in the cited sources. No therapeutic dosage has been formally established through approved regulatory processes for simmondsin as a dietary supplement.

Animal Studies

• Sprague-Dawley male rats were fed various levels of simmondsin for 8 weeks (lean rats) or 16 weeks (high fat-induced obese rats). Simmondsin at both the 0.15% and the 0.25% level significantly reduced food intake and body weight without apparent negative effects. At dose levels much higher than therapeutic levels, there seemed to be reversible effects on circulating red and white blood cells.
• Chronic administration of a high dose of simmondsin (0.5% mixed in the food) caused mortality in rats.
• Rats given the choice between a control diet and a simmondsin-supplemented (0.5%) diet, after half an hour, have a significant preference for the control diet.
• Comparison studies used 0.25% simmondsin mixed in food, inducing moderate food intake reduction (65% of normal) in rats.

Human Studies / Patent-Based Evidence

• The only intervention in one reported human study was the administration of defatted jojoba seed meal (containing 8–10% simmondsin) at 12.5 g twice a day (one hour before lunch and dinner). The duration of the study was one month.
• As an example from patent literature, 3 capsules each containing 1000 mg of jojoba extract containing about 12 weight percent simmondsin compounds ingested daily by a 90 kg individual can provide a daily ingestion of about 4 mg simmondsin compounds per kilogram of that individual.

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8. Safety Considerations

Established Toxicity in Animals

The presence of toxic factor simmondsin as a cyanogenic glycoside restricts the application of jojoba meal and has caused researchers to seek alternative methods for its detoxification.

The meal byproduct remaining after wax extraction cannot be used as animal feed because of the presence of several cyanide-containing glycosides, such as simmondsin, simmondsin 2′-ferulate, and several minor simmondsin derivatives. Simmondsin and simmondsin-containing jojoba meal induce food intake inhibition, emaciation and, occasionally, mortality; because of this, simmondsins have been considered toxic.

Preliminary rat and mouse toxicological data implicates the benzyl cyanide derivative of simmondsin as the toxicant.

In two chronic feeding studies, the high dose of simmondsin (0.5%) in the diet produced profound weight loss and death in rats. At autopsy, the kidney, heart, and liver of the treated animals were larger than those of pair-fed animals and there was a marked suppression of the bone marrow elements with severe anemia.

Dose-Dependency and Reversibility

Simmondsin at both the 0.15% and the 0.25% levels significantly reduced food intake and body weight without apparent negative effects. At dose levels much higher than therapeutic levels, there seemed to be reversible effects on circulating red and white blood cells. Future studies should determine long-term effects of lower doses on blood cell parameters.

No major toxic effects were described after long-term administration of low doses of simmondsin inducing a sustained food intake and growth reduction in growing rats.

Hematological Effects

Simmondsin produced a clear dose-response effect on food intake and body weight. No remarkable histopathologic changes were noted in the liver, kidney, and spleen at lower doses. One lean animal in the 0.5% group had approximately a 20% depression in red bone marrow cells.

Conditioned Taste Aversion

The ability of simmondsin to induce conditioned taste aversion (CTA) was investigated. Rats receiving simmondsin at concentrations of 0.15%, 0.25%, or 0.5% during their conditioning develop significant taste aversions to saccharin solutions. This raises the concern that part of its anorectic effect in both animals and potentially humans may involve an aversive, illness-like signal rather than true satiety.

Palatability and Behavioral Concerns

The typical flavor of simmondsin seems to have a role in the anorexia. Both flavor and aversion clearly influence or even overrule the possible satiating/satiety action of simmondsin, especially when simmondsin is given for the second time.

Detoxification of Jojoba Meal

Given the established toxicity of simmondsin at higher concentrations, researchers have explored detoxification methods for jojoba meal. Studies were conducted to compare the effect of different detoxification methods on the composition and safety of defatted jojoba meal (DJM). Solvents, microwave, and microbiological treatments (lactic acid bacteria and bifidobacteria) were used to detoxify and reduce the antinutritional factors in DJM. Results indicated that treatment of DJM with isopropanol and Lactobacillus acidophilus was able to reduce antinutritional factors and simmondsin. Several methods can be used to remove the simmondsin toxin from jojoba seed meal, but more research is needed to make it more suitable for animal consumption.

Detoxified defatted jojoba meal that contained lower levels of antinutritional factors and simmondsin was further evaluated by feeding studies using experimental animals. After 8 weeks of feeding studies, there were no statistically significant differences between animal groups fed on basal diet, isopropanol-treated DJM, and Lactobacillus acidophilus-treated DJM in terms of body weight gain and relative organ weights.

Human Safety: State of Evidence

Formal human toxicological data for isolated simmondsin are absent from the peer-reviewed literature. The small, uncontrolled human study reported in the patent literature observed no adverse effects at a dose equivalent to approximately 1–1.25 g of pure simmondsin per day (derived from 12.5 g of meal containing 8–10% simmondsin, twice daily), but this is not a controlled study and cannot establish safety. The absence of published, placebo-controlled human safety trials represents a significant gap in the evidence base.

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9. Summary of Evidence Strength

The table below summarizes the current state of evidence for simmondsin across its investigated areas of use:

• Appetite suppression / food intake reduction (animals): Strong, consistent, replicated preclinical evidence across multiple animal species and study designs at the Katholieke Universiteit Leuven and elsewhere.
• Appetite suppression / food intake reduction (humans): Preliminary and uncontrolled only. No peer-reviewed, blinded, placebo-controlled human RCTs have been published for simmondsin as an isolated compound.
• Mechanism of action (CCK pathway and vagal mediation): Mechanistically plausible and partially supported by pharmacological blockade experiments in animals; contested by findings showing CCK antagonists do not always block simmondsin's effect.
• Satiety vs. aversion: The behavioral evidence strongly indicates that a significant part of simmondsin's food intake–reducing effect at repeated doses is mediated through conditioned aversion rather than true physiological satiety.
• Anti-inflammatory activity: Very preliminary (in vitro only), involving related leaf compounds rather than seed simmondsin directly.
• Safety: Established dose-dependent toxicity in animals at higher concentrations, particularly hematopoietic suppression and organ enlargement; reversible at lower doses in rats. Human safety data are essentially absent from the peer-reviewed record.

References

• Lievens S, Verbaeys I, Flo G, Briers R, Decuypere E, Cokelaere M. Disruption of the behavioral satiety sequence by simmondsin. Appetite. 2009;52(3):703–710.
• Lievens S et al. Simmondsin: effects on meal patterns and choice behavior in rats. Physiology & Behavior. 2003.
• York DA, Singer L, Oliver J, et al. The detrimental effect of simmondsin on food intake and body weight of rats. Industrial Crops and Products. 2000.
• Cokelaere M et al. The vagus nerve is involved in the anorexigenic effect of simmondsin in the rat. Appetite. 2000.
• Barnett RC et al. Simmondsin for weight loss in rats. Journal of Veterinary Pharmacology and Therapeutics. 2006.
• Booth AN, Elliger CA, Waiss AC Jr. Isolation of a toxic factor from jojoba meal. Life Sciences. 1974;15:1115–1120.
• Alotaibi SS et al. Transcriptome Analysis of Jojoba (Simmondsia chinensis) during Seed Development and Liquid Wax Ester Biosynthesis. Plants. 2020;9(5):588.
• ResearchGate: Structure of simmondsin (SM) and SM analogues present in jojoba meal. Capillary electrophoresis: Novel tool for simmondsins analysis and its application to jojoba breeding.
• El Gendy SN et al. A review of the desert gold jojoba (Simmondsia chinensis) whole plant, oil, and meal: Phytochemical composition, medicinal uses, and detoxification. Journal of the American Oil Chemists' Society. 2023;100(8):591–614.
• Elsanhoty RM, Al-Soqeer A, Ramadan MF. Effect of detoxification methods on the quality and safety of jojoba (Simmondsia chinensis) meal. Journal of Food Biochemistry. 2017.
• Cokelaere MM et al. Food Intake Inhibitory Activity of Simmondsin and Defatted Jojoba Meal: Dose-Response Curves in Rats. In: Progress in New Crops, ASHS Press, 1996.
• Wikipedia: Simmondsin.
• Wikipedia: Jojoba (Simmondsia chinensis).
• US Patent 8,673,343: Preparation and administration of jojoba product for reducing weight, fat and blood lipid levels and for the prevention and treatment of cancer.
• US Patent 6,852,342: Compounds for altering food intake in humans.
• US Patent 6,620,442: Simmondsin processing methods and products.
• Uebelhack R et al. Double-Blind, Randomized, Three-Armed, Placebo-Controlled, Clinical Investigation to Evaluate the Benefit and Tolerability of Two Dosages of IQP-AE-103 in Reducing Body Weight in Overweight and Moderately Obese Subjects. Journal of Obesity. 2019.
• USDA Forest Service: Native Plant Oils — Ethnobotany of Jojoba.