Rubiscolin
A delta-opioid peptide released from spinach Rubisco — orally active in mice, with memory, mood and appetite effects. A food-derived research peptide, not a drug
Rubiscolin is an opioid peptide that comes from an unlikely source: Rubisco, the carbon-fixing enzyme in plant leaves and the most abundant protein on Earth. When spinach Rubisco is digested, it releases short peptides — rubiscolin-5 (Tyr-Pro-Leu-Asp-Leu) and rubiscolin-6 (Tyr-Pro-Leu-Asp-Leu-Phe) — that act selectively on the delta-opioid receptor. That makes rubiscolin a food-derived 'exorphin,' in the same broad class as the milk peptide beta-casomorphin, and it was the first bioactive peptide shown to come from plant Rubisco. What makes it unusual among peptides is that it works when given by mouth in mice, not only by injection. Through the delta-opioid receptor, rubiscolin-6 has produced a spread of effects in rodents: pain relief, enhanced memory consolidation, reduced anxiety, an antidepressant-like effect under stress, and complex effects on gut motility and food intake. Its effects are blocked by delta-opioid antagonists, confirming the mechanism. Rubiscolin is studied as a food-derived bioactive peptide; it is not an approved medicine and has not been given to people as a treatment.
No established human dose Details ↓
Recommended Dosing
No established human dose
Rubiscolin is a peptide released from a plant food protein; it has never been given to people as a treatment. The work is in mice, where synthetic peptide is given by injection or by mouth at experimental amounts that do not carry over to people.
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What is it?
Food proteins, when digested, release short peptides, and some of them turn out to be biologically active. Rubiscolin is one of the more surprising examples: it is released from Rubisco (D-ribulose-1,5-bisphosphate carboxylase/oxygenase), the enzyme plants use to fix carbon dioxide and the most abundant protein on the planet. Japanese researchers noticed that part of the spinach Rubisco large subunit matched the pattern of known opioid peptides (an N-terminal tyrosine followed by proline and aliphatic residues), synthesised the fragments, and confirmed opioid activity — naming them rubiscolin-5 (YPLDL) and rubiscolin-6 (YPLDLF).
Both peptides are selective for the delta-opioid receptor, as shown in receptor-binding assays using the delta ligand deltorphin II and in the mouse vas deferens bioassay. This makes rubiscolin a food-derived 'exorphin' — an exogenous opioid peptide from the diet, like the milk-derived beta-casomorphins. It was the first bioactive peptide shown to come from plant Rubisco, raising the idea that leaf protein, not just animal protein, can be a source of opioid peptides.
Most striking is that rubiscolin works orally. In mice, rubiscolin-6 produced antinociception after either injection into the brain ventricles or oral administration, and later studies found it enhances memory consolidation in a passive-avoidance test — an effect seen at amounts smaller than those needed for analgesia and blocked by the delta antagonist naltrindole, confirming a delta-opioid mechanism.
Rubiscolin-6's behavioural reach widened with further work. It had an anxiolytic effect in the elevated plus-maze after injection or oral dosing, mediated by the delta-opioid receptor but requiring sigma-1 and dopamine D1 receptors downstream. In restraint-stressed mice it produced an antidepressant-like effect in the tail-suspension test, again blocked by naltrindole. And it influences eating: rubiscolin-6 rapidly suppressed postprandial motility of the gastric antrum and then increased food intake over the following hours, a delta-opioid-mediated orexigenic effect the authors suggested might be relevant to anorexia and cachexia.
Because Rubisco is so plentiful in green leaves, rubiscolin has also drawn interest as a peptide that could be produced in crops — researchers engineered soybean seeds to accumulate tandem repeats of rubiscolin and other bioactive peptides within a storage protein. Throughout, rubiscolin is a food-derived and research peptide. No published study has given it to people as a treatment, it is approved nowhere, and anything sold online under its name is an unregulated research chemical. Nothing here is a dose or a therapy; this page records what the published science says.
Mechanism of Action
Rubiscolin is a food-derived delta-opioid-selective peptide released from spinach Rubisco. Through the delta-opioid receptor it produces analgesia, memory enhancement, anxiolytic and antidepressant-like effects and changes in gut motility and appetite in animals; some downstream effects also require sigma-1 and dopamine-D1 receptors.
Food-protein origin
Released by digestion of the spinach Rubisco large subunit as rubiscolin-5 (YPLDL) and rubiscolin-6 (YPLDLF); a dietary 'exorphin' (PMID 11741591).
Delta-opioid agonism
Selective delta-opioid-receptor agonist; its analgesic, memory, anxiolytic and antidepressant effects are blocked by the delta antagonist naltrindole (PMIDs 12668220, 31061291).
Downstream sigma-1 / dopamine-D1
Its anxiolytic effect additionally requires sigma-1 and dopamine-D1 receptors downstream of the delta-opioid receptor (PMID 17766012).
Published Research
These are studies of rubiscolin read from their PubMed records on November 7, 2026: the 2001 discovery paper establishing it as a delta-selective opioid peptide from spinach Rubisco with oral analgesia; mouse studies of its memory-enhancing, anxiolytic, antidepressant-like and appetite/gut effects (all delta-opioid-mediated); and a study producing rubiscolin in genetically modified soybean. All the evidence is in cells and animals; rubiscolin has not been given to people as a treatment.
Discovery: rubiscolin, a delta-selective opioid peptide from spinach Rubisco
Sequences in the spinach Rubisco large subunit matching the opioid-peptide pattern were synthesised and shown to have delta-selective opioid activity in mouse vas deferens and delta receptor-binding assays, and were named rubiscolin-5 (YPLDL) and rubiscolin-6 (YPLDLF); both had antinociceptive activity in mice after brain-ventricle or oral administration — the first bioactive peptide derived from plant Rubisco (a discovery study).
Rubiscolin-6 enhances memory consolidation (mice)
In a passive-avoidance test in mice, rubiscolin-6 enhanced memory consolidation after either brain-ventricle or oral administration, at amounts smaller than those needed for its analgesic effect; the memory enhancement was blocked by the delta-opioid antagonist naltrindole, indicating a delta-opioid-receptor mechanism (a preclinical result).
Rubiscolin-6 has an anxiolytic effect via sigma-1 and dopamine D1 receptors
Rubiscolin-6, given intraperitoneally or orally, had an anxiolytic effect in the mouse elevated plus-maze; the effect was blocked by the delta-opioid antagonist naltrindole and also by sigma-1 and dopamine-D1 (but not D2) antagonists — indicating the anxiolytic action is mediated by sigma-1 and dopamine-D1 receptors downstream of the delta-opioid receptor (a preclinical result).
Rubiscolin-6 has an antidepressant-like effect in stressed mice
In restraint-stressed mice, rubiscolin-6 reduced immobility time in the tail-suspension test without affecting locomotor activity, indicating an antidepressant-like effect; it was blocked by the delta-opioid antagonist naltrindole, confirming the effect is mediated by the delta-opioid receptor (a preclinical result).
Rubiscolin-6 suppresses gastric motility and increases food intake (mice)
In conscious mice, rubiscolin-6 rapidly suppressed postprandial motility of the gastric antrum and subsequently increased cumulative food intake over the following hours; both effects were normalised by co-administration of the delta-opioid antagonist naltrindole — a delta-mediated orexigenic effect the authors suggested could be relevant to anorexia and cachexia (a preclinical result).
Rubiscolin produced in genetically modified soybean seeds
Transgenic soybean lines were engineered to express a seed-storage protein carrying tandem repeats of bioactive peptides including rubiscolin (YPLDLF), which accumulated in the seeds — demonstrating that rubiscolin and related peptides can be produced in a crop (a production / biotechnology study).
No Established Human Dose
Rubiscolin is a peptide released from a plant food protein; it has never been given to people as a treatment. The work is in mice, where synthetic peptide is given by injection or by mouth at experimental amounts that do not carry over to people. No regulator has approved any dose, and no published human dose exists, so no amount is printed here.
What this rests on: PMID 11741591, PMID 12668220, PMID 17766012.
Educational information, not medical advice. The doses on this page come from approved labels, published studies and, where no study exists, amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
What a Buyer Needs to Know
What is sold, how it is mixed, stored and taken, and what is known about its safety, quality and legal status. Each part names its source. Where we have none, it says unknown.
What is sold
Unknown: we hold no label and no published test that says what forms or vial sizes Rubiscolin is sold in. A vial's own label is a seller's claim, not a source.
Mixing a vial: a worked example
Unknown: no human dose of Rubiscolin has been established (see No Established Human Dose below), so there is no amount to work out. The reconstitution calculator does the arithmetic for any vial, water and dose.
Storage before and after mixing
Unknown: no label or published stability study on file says how to store Rubiscolin, before or after mixing. The mixing guide sets out the general rules, with their sources: keep a mixed vial in the fridge, and use it promptly, as the bacteriostatic water label says of any drug dissolved in it. The 28 days often quoted is the limit for an opened multiple-dose vial from a manufacturer, an outer limit set for sterility, not a time a mixed solution has been shown to keep. Nobody has published how long Rubiscolin stays intact once mixed.
How it is taken
Unknown: with no established human dose, there is no established way of taking Rubiscolin. What the human studies gave and how is set out under No Established Human Dose.
What to expect, and when
How long it stays in the body: a half-life of not established for humans; a small food-derived peptide, unusually active after oral dosing in mice. After about five half-lives almost none is left.
When effects appear: unknown; no source on this page gives a time to effect for Rubiscolin. Results reported in the studies are under Published Research.
Source: half-life: PMID 11741591.
Side effects, and when to stop or get help
From the Side Effects section: No human adverse-event data exist: no published study has administered rubiscolin to people; In animals it is a delta-opioid agonist with behavioural effects (memory, anxiety, mood, appetite), so opioid-type actions are a mechanistic consideration — an inference, not human data for this peptide; Its orexigenic (appetite-increasing) effect in mice suggests effects on eating behaviour that would need study before any use (PMID 36111502); Material sold online as 'rubiscolin' is an unregulated research chemical of unverified content. Full list and cautions ↓
When to stop or get help: unknown; no label or trial on file sets rules for stopping Rubiscolin. Treat a severe or unexpected reaction as a reason to stop and see a doctor.
Source: the Side Effects section below (“Rubiscolin is a food-derived peptide that has not been given to people as a drug, so there is no human safety profile; the points below reflect that research status and its biology”).
Interactions
Unknown: a PubMed search for human interaction studies of Rubiscolin (reviewed 2026-11-07) found none. Unknown is not the same as safe to combine.
Every peptide's record, with its source: the interaction matrix.
Checking what you bought
Unknown: no published independent test of Rubiscolin products is in our lab-results database yet, so how products sold under this name measure up is not known.
To read a certificate of analysis, paste it into the COA decoder. Trust & Verification explains what independent testing can and cannot show.
Legal status
US: Research Chemical (Not a drug: Drugs@FDA and the openFDA label endpoint hold no record, and FDA GSRS and ChEMBL hold no drug record for rubiscolin (searched November 7, 2026)). Sport: Not on the 2026 List.
Country by country ↓ · Regulatory tracker
Source: this entry's approval status and the WADA Prohibited List, as in Legal Status below.
Side Effects & Contraindications
Reported Side Effects
Rubiscolin is a food-derived peptide that has not been given to people as a drug, so there is no human safety profile; the points below reflect that research status and its biology.
Contraindications & Cautions
Rubiscolin has no approved use and no label. These points reflect its research status.
Legal Status
Rubiscolin is a food-derived opioid peptide studied as a research compound; it is not a drug and is not approved in any country.
Frequently Asked Questions
?What is rubiscolin?
A short opioid peptide (rubiscolin-6 is Tyr-Pro-Leu-Asp-Leu-Phe) released when spinach Rubisco — the plant carbon-fixing enzyme — is digested. It selectively activates the delta-opioid receptor.
?What does it do?
In mice it produces analgesia and, via the delta-opioid receptor, enhances memory consolidation and has anxiolytic and antidepressant-like effects, plus effects on gut motility and appetite (PMIDs 12668220, 17766012, 31061291, 36111502).
?Why is it notable?
It was the first bioactive peptide found to come from plant Rubisco, and unusually it is active when given by mouth in mice, not only by injection (PMID 11741591).
?Is it approved or available to buy?
No. Rubiscolin is not a medicine, has no FDA application or label, and is approved nowhere. Material sold online as rubiscolin is an unregulated research chemical. Grey Peptides lists no sellers and recommends no source; this page records the published science.
References
- [mechanism] Yang S, et al. "Rubiscolin, a delta selective opioid peptide derived from plant Rubisco." FEBS Lett, 2001;509(2):213-7. PMID: 11741591.
- [animal] Yang S, et al. "Effect of rubiscolin, a delta opioid peptide derived from Rubisco, on memory consolidation." Peptides, 2003;24(2):325-8. PMID: 12668220.
- [animal] Hirata H, et al. "Rubiscolin-6, a delta opioid peptide derived from spinach Rubisco, has anxiolytic effect via activating sigma1 and dopamine D1 receptors." Peptides, 2007;28(10):1998-2003. PMID: 17766012.
- [animal] Mitsumoto Y, et al. "Rubiscolin-6, a δ-Opioid Peptide from Spinach RuBisCO, Exerts Antidepressant-Like Effect in Restraint-Stressed Mice." J Nutr Sci Vitaminol (Tokyo), 2019;65(2):202-204. PMID: 31061291.
- [animal] Ataka K, et al. "Rubiscolin‑6 rapidly suppresses the postprandial motility of the gastric antrum and subsequently increases food intake via δ‑opioid receptors in mice." Mol Med Rep, 2022;26(5). PMID: 36111502.
- [mechanism] Nishizawa K, et al. "Accumulation of the bioactive peptides, novokinin, LPYPR and rubiscolin, in seeds of genetically modified soybean." Biosci Biotechnol Biochem, 2008;72(12):3301-5. PMID: 19060385.
- [other] Rubiscolin is released by enzymatic (pepsin) digestion of the large subunit of spinach D-ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco); the sequences Tyr-Pro-Leu-Asp-Leu (rubiscolin-5) and Tyr-Pro-Leu-Asp-Leu-Phe (rubiscolin-6) were identified and named in the discovery paper carded on this page (read November 7, 2026). It was the first bioactive peptide found to derive from plant Rubisco.
- [other] US FDA, Drugs@FDA and the openFDA label endpoint, searched November 7, 2026: no application and no label record for rubiscolin. It is a food-derived peptide studied in research, not a drug; FDA GSRS and ChEMBL hold no drug record for it.
Sources & Citations
The six studies carded above were read from their PubMed records on November 7, 2026. Rubiscolin's sequences (YPLDL, YPLDLF), its origin from spinach Rubisco, its delta-opioid selectivity, its oral activity, and its memory, anxiolytic, antidepressant-like and appetite/gut effects in mice are from the discovery paper and animal studies carded here; the production of rubiscolin in GM soybean is from the biotechnology study, and the absence of US approval or a drug record from Drugs@FDA, openFDA, FDA GSRS and ChEMBL was checked the same day. Grey Peptides sells nothing and links to no vendor.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.