Reticuline

Reticuline at a Glance

Reticuline is a 1-benzyltetrahydroisoquinoline alkaloid, and it is the most important molecule most people have never heard of. Almost every famous alkaloid here — berberine, sanguinarine, papaverine, thebaine, morphine, codeine — is built from it. Plants make reticuline from two molecules of the amino acid tyrosine and then push it down one of several branches; which branch a species takes is most of what determines its alkaloid chemistry ^{3Reference 3Hagel JM · 2013ReviewBenzylisoquinoline alkaloid metabolism — a century of discovery and a brave new world — reviewView study →}.

The molecule exists as two mirror-image forms, and the difference between them is the whole story. (S)-reticuline is the form plants make, and it feeds the protoberberines, the benzophenanthridines and papaverine. (R)-reticuline is made only after an enzymatic inversion, and it is the committed precursor of the morphinans — the opiates. The enzyme that performs that inversion, STORR/REPI, was identified in 2015 and is the step that made engineered-yeast opioid production possible ^{5,6,8Reference 5Winzer T et al. · 2015Morphinan biosynthesis in opium poppy requires a P450-oxidoreductase fusion protein (STORR) — plant geneticsView study →Reference 6Farrow SC et al. · 2015Stereochemical inversion of (S)-reticuline by a cytochrome P450 fusion in opium poppy — identification of reticuline epimerase (REPI)View study →Reference 8Galanie S et al. · 2015Complete biosynthesis of opioids in yeast — metabolic engineeringView study →}.

As a drug in its own right reticuline is genuinely under-studied, and its evidence is entirely preclinical. Its best-measured activity is positive allosteric modulation of GABAA receptors by the (S)-enantiomer, which is the reason California poppy’s sedative reputation is attributed to this alkaloid rather than to the more abundant ones ^{1Reference 1Fedurco M et al. · 2015In vitroModulatory effects of Eschscholzia californica alkaloids on recombinant GABAA receptors — in vitro electrophysiologyView study →}. Beyond that there is a small but consistent animal literature on vasorelaxation and hypotension ^{14,15Reference 14Dias KL et al. · 2004AnimalCardiovascular effects induced by reticuline in normotensive rats — animal studyView study →Reference 15Medeiros MAA et al. · 2009Medeiros MAA, Nunes XP, Barbosa-Filho JM, Lemos VS, Pinho JF, Roman-Campos D, de Medeiros IA, Araújo DAM, Cruz JS. (2009). (S)-reticuline induces vasorelaxation through the blockade of L-type Ca²⁺ channels — patch-clamp and isolated-tissue study. Naunyn-Schmiedeberg’s Archives of Pharmacology, 379(2), 115–125. https://pubmed.ncbi.nlm.nih.gov/18825370/View study →} and on JAK2/STAT3-linked anti-inflammatory activity ^{16,17,18,19Reference 16Yang X et al. · 2018Anti-inflammatory effects of boldine and reticuline isolated from Litsea cubeba through JAK2/STAT3 and NF-κB signaling pathways — animal studyView study →Reference 17Lyu X et al. · 2024AnimalAnti-inflammatory effects of reticuline on the JAK2/STAT3/SOCS3 and p38 MAPK/NF-κB signaling pathway in a mouse model of obesity-associated asthma — animal studyView study →Reference 18Xu S et al. · 2025Reticuline modulates astrocyte and microglial responses to enhance prognosis after traumatic brain injury — animal studyView study →Reference 19Tian J et al. · 2026In vitroReticuline alleviates rheumatoid arthritis by suppressing the JAK/STAT signaling pathway — in vitro and collagen-induced arthritis modelView study →}. There are no human trials, no human pharmacokinetics, and a real neurotoxicity flag from the Annona side ^{23Reference 23Kotake Y et al. · 2004Detection and determination of reticuline and N-methylcoclaurine in the Annonaceae family using liquid chromatography–tandem mass spectrometry — includes SH-SY5Y cytotoxicity and complex-I inhibitionView study →}.

Established Uses

Reticuline has no therapeutic use in people. It does, however, have one genuine, deployed real-world application: it is a forensic marker of opium use. Reticuline is a constituent of opium and a metabolic demethylation product of three other opium benzyltetrahydroisoquinolines (codamine, laudanosine and laudanine), and it appears in the urine of opium users — largely as a conjugate, released by acid or β-glucuronidase hydrolysis. Critically, it cannot be detected after heroin use, poppy-seed ingestion or pharmaceutical codeine, so its presence alongside urinary morphine and codeine distinguishes opium consumption from those other sources ^{26Reference 26Al-Amri AM et al. · 2004The GC-MS detection and characterization of reticuline as a marker of opium use — forensic studyView study →}.

Its second real-world role is industrial rather than clinical: reticuline is the target intermediate of essentially every attempt to manufacture benzylisoquinoline alkaloids in microbes, because a cell that can make reticuline is within a few enzymes of berberine, papaverine or thebaine ^{8,9,30Reference 8Galanie S et al. · 2015Complete biosynthesis of opioids in yeast — metabolic engineeringView study →Reference 9DeLoache WC et al. · 2015An enzyme-coupled biosensor enables (S)-reticuline production in yeast from glucose — metabolic engineeringView study →Reference 30Wu Z et al. · 2026ReviewWu Z, Wang P, Chiu TY. (2026). [Recent advances in the application value and biosynthesis of chiral reticuline] — review. Sheng Wu Gong Cheng Xue Bao (Chinese Journal of Biotechnology), 42(3), 1042–1061. https://pubmed.ncbi.nlm.nih.gov/41873066/View study →}.

The Branch Point of the Benzylisoquinoline Alkaloids

Benzylisoquinoline alkaloid (BIA) metabolism is a funnel followed by a fan. Two tyrosine-derived units — dopamine and 4-hydroxyphenylacetaldehyde — are condensed to (S)-norcoclaurine, which is methylated and hydroxylated through coclaurine and N-methylcoclaurine to give (S)-reticuline. Everything upstream is a single narrow channel; everything downstream fans out into the several thousand alkaloids of the family ^{3Reference 3Hagel JM · 2013ReviewBenzylisoquinoline alkaloid metabolism — a century of discovery and a brave new world — reviewView study →}.

From (S)-reticuline the pathway splits along at least four routes:

• To the protoberberines. The berberine bridge enzyme (BBE) — a flavin-dependent oxidase — forges an extra carbon–carbon bond that closes reticuline’s open benzyl arm into the four-ring protoberberine core, giving (S)-scoulerine ^{4Reference 4Bird DA · 2001Berberine bridge enzyme, a key branch-point enzyme in benzylisoquinoline alkaloid biosynthesis, contains a vacuolar sorting determinant — plant biochemistryView study →}. From there the pathway runs to columbamine, palmatine, epiberberine, canadine and berberine, and — on the reduced branch — tetrahydropalmatine.
• To the methylenedioxy and benzophenanthridine alkaloids. Ring closures by CYP719-clan P450 enzymes carry scoulerine on to stylopine, protopine, allocryptopine, coptisine, and finally the benzophenanthridines sanguinarine and chelerythrine ^{4Reference 4Bird DA · 2001Berberine bridge enzyme, a key branch-point enzyme in benzylisoquinoline alkaloid biosynthesis, contains a vacuolar sorting determinant — plant biochemistryView study →}.
• To papaverine. (S)-reticuline is methylated to (S)-laudanine, then laudanosine, then N-demethylated to tetrahydropapaverine and dehydrogenated to papaverine. Stable-isotope feeding of Papaver seedlings settled this route in 2010 and disposed of the older norreticuline hypothesis ^{11Reference 11Han X et al. · 2010The biosynthesis of papaverine proceeds via (S)-reticuline — stable-isotope precursor feedingView study →}.
• To the aporphines. An N-methyltransferase and the phenol-coupling P450 CYP80G2 convert reticuline into magnoflorine and the wider aporphine class ^{3Reference 3Hagel JM · 2013ReviewBenzylisoquinoline alkaloid metabolism — a century of discovery and a brave new world — reviewView study →}.

And, after a stereochemical inversion, to the morphinans — which is the next section.

The consequence for this site is direct: when berberine, coptisine, canadine, hydrastine, palmatine and scoulerine each describe themselves as descending from “(S)-reticuline, the branch-point of this whole alkaloid family,” this is the molecule they mean.

The (S)-to-(R) Epimerisation, and Why It Mattered

Salutaridine synthase — the enzyme that performs the phenol coupling opening the morphinan skeleton — is absolutely specific for (R)-reticuline. When the enzyme (identified as CYP719B1 in 2009) was screened against forty-one candidate substrates, only (R)-reticuline and (R)-norreticuline gave any product at all ^{7Reference 7Gesell A et al. · 2009CYP719B1 is salutaridine synthase, the C–C phenol-coupling enzyme of morphine biosynthesis in opium poppy — enzymologyView study →}. But plants make the (S) form. Something had to invert it, and for decades nobody knew what.

Two groups solved it in 2015, within weeks of each other. Characterising high-reticuline opium-poppy mutants, one team found a genetic locus they named STORR — (S)- to (R)-reticuline — encoding a cytochrome P450 module fused to an aldo-keto reductase module on a single polypeptide. The P450 half oxidises (S)-reticuline to the achiral intermediate 1,2-dehydroreticuline; the reductase half then reduces that intermediate to (R)-reticuline, rather than acting as the P450’s redox partner as one would expect ^{5Reference 5Winzer T et al. · 2015Morphinan biosynthesis in opium poppy requires a P450-oxidoreductase fusion protein (STORR) — plant geneticsView study →}. The other team, working independently, characterised the same fusion as reticuline epimerase (REPI), found it in both Papaver somniferum and thebaine-accumulating P. bracteatum, and showed that silencing it collapsed (R)-reticuline and morphinan levels while (S)-reticuline and its O-methylated derivatives piled up. In Papaver rhoeas, which makes no morphinans, the same two activities exist as separate, unfused enzymes ^{6Reference 6Farrow SC et al. · 2015Stereochemical inversion of (S)-reticuline by a cytochrome P450 fusion in opium poppy — identification of reticuline epimerase (REPI)View study →}. Not every BIA plant has it: a transcriptome survey of Sinomenium acutum found no REPI at all, implying epimerase-independent routes to its alkaloids ^{32Reference 32Yang Y et al. · 2022Full-length transcriptome and metabolite analysis reveal reticuline epimerase-independent pathways for benzylisoquinoline alkaloid biosynthesis in Sinomenium acutum — plant genomicsView study →}.

Why it mattered. The epimerisation was the last missing step in morphine biosynthesis, and the last obstacle to reconstructing the pathway outside the plant. Within months, engineered Saccharomyces cerevisiae strains expressing 21–23 heterologous enzyme activities produced thebaine and hydrocodone from sugar ^{8Reference 8Galanie S et al. · 2015Complete biosynthesis of opioids in yeast — metabolic engineeringView study →}; a parallel effort had already demonstrated (S)-reticuline from glucose in yeast via a seven-enzyme route from L-tyrosine ^{9Reference 9DeLoache WC et al. · 2015An enzyme-coupled biosensor enables (S)-reticuline production in yeast from glucose — metabolic engineeringView study →}. Chemists have since built the inversion into a synthetic route, preparing 1,2-dehydroreticuline chemically and reducing it enzymatically to (R)-reticuline at >99% ee and 92% isolated yield before closing it to salutaridine ^{29Reference 29Cigan E et al. · 2023Concise synthesis of (R)-reticuline and (+)-salutaridine by combining early-stage organic synthesis and late-stage biocatalysis — chemo-enzymatic synthesisView study →}. The reverse manipulation is equally instructive: silencing codeinone reductase in opium poppy stalls the pathway seven steps upstream and makes the plant accumulate (S)-reticuline — a non-narcotic alkaloid — instead of morphine ^{10Reference 10Allen RS et al. · 2004RNAi-mediated replacement of morphine with the nonnarcotic alkaloid reticuline in opium poppy — plant biotechnologyView study →}.

One postscript worth noting: in 2026 an aldo-keto reductase (AKR1B1) from the darkling beetle Blaps rhynchopetera was shown in vitro to convert (S)- to (R)-reticuline — the first reticuline isomerase reported outside plants ^{31Reference 31Zhang L et al. · 2026Reticuline isomerase AKR1B1 with aldo-keto reductase activity and detoxification function from the insect Blaps rhynchopetera — enzymologyView study →}.

Which Enantiomer Was Tested

This is the discipline the page exists to enforce. “Reticuline” in a paper title can mean either enantiomer or an unspecified sample, and the two are not pharmacologically interchangeable — the single study that tested both found opposite results.

Finding	Enantiomer actually tested	Source
Positive allosteric modulation at α3/α5/α6 GABAA	(S) — commercial (S)-(+)-reticuline hydrochloride	1Reference 1Fedurco M et al. · 2015In vitroModulatory effects of Eschscholzia californica alkaloids on recombinant GABAA receptors — in vitro electrophysiologyView study →
No effect at α1/α3/α5 GABAA at 10 µM	(R) — tested head-to-head in the same study	1Reference 1Fedurco M et al. · 2015In vitroModulatory effects of Eschscholzia californica alkaloids on recombinant GABAA receptors — in vitro electrophysiologyView study →
L-type Ca²⁺ current blockade, vasorelaxation	(S) — explicitly stated	15Reference 15Medeiros MAA et al. · 2009Medeiros MAA, Nunes XP, Barbosa-Filho JM, Lemos VS, Pinho JF, Roman-Campos D, de Medeiros IA, Araújo DAM, Cruz JS. (2009). (S)-reticuline induces vasorelaxation through the blockade of L-type Ca²⁺ channels — patch-clamp and isolated-tissue study. Naunyn-Schmiedeberg’s Archives of Pharmacology, 379(2), 115–125. https://pubmed.ncbi.nlm.nih.gov/18825370/View study →
Negative inotropy in guinea-pig papillary muscle	(S) — as (+)-S-reticuline	27Reference 27Kimura I et al. · 1989Inotropic effects of (±)-higenamine and its chemically related components, (+)-R-coclaurine and (+)-S-reticuline, contained in the traditional medicines “bushi” and “shin-i” in isolated guinea-pig papillary muscle — isolated-tissue studyView study →
Salutaridine synthase substrate (morphine route)	(R) only — (S) is not a substrate	7Reference 7Gesell A et al. · 2009CYP719B1 is salutaridine synthase, the C–C phenol-coupling enzyme of morphine biosynthesis in opium poppy — enzymologyView study →
Berberine bridge enzyme substrate (berberine route)	(S) only	4Reference 4Bird DA · 2001Berberine bridge enzyme, a key branch-point enzyme in benzylisoquinoline alkaloid biosynthesis, contains a vacuolar sorting determinant — plant biochemistryView study →
Endogenous alkaloid in human cells	(S) — configuration determined	24Reference 24Poeaknapo C et al. · 2004Endogenous formation of morphine in human cells — (S)-reticuline identified as an endogenous precursorView study →
Hypotension in rats; CNS depression in rodents	not stated — isolated from Ocotea duckei, whose major benzylisoquinoline is (S)-reticuline 15Reference 15Medeiros MAA et al. · 2009Medeiros MAA, Nunes XP, Barbosa-Filho JM, Lemos VS, Pinho JF, Roman-Campos D, de Medeiros IA, Araújo DAM, Cruz JS. (2009). (S)-reticuline induces vasorelaxation through the blockade of L-type Ca²⁺ channels — patch-clamp and isolated-tissue study. Naunyn-Schmiedeberg’s Archives of Pharmacology, 379(2), 115–125. https://pubmed.ncbi.nlm.nih.gov/18825370/View study →	13,14Reference 13Morais LC et al. · 1998AnimalCentral depressant effects of reticuline extracted from Ocotea duckei in rats and mice — animal studyView study →Reference 14Dias KL et al. · 2004AnimalCardiovascular effects induced by reticuline in normotensive rats — animal studyView study →
Anti-inflammatory animal work; anticancer; D5R	not stated in the source papers	16,17,18,19,21,22Reference 16Yang X et al. · 2018Anti-inflammatory effects of boldine and reticuline isolated from Litsea cubeba through JAK2/STAT3 and NF-κB signaling pathways — animal studyView study →Reference 17Lyu X et al. · 2024AnimalAnti-inflammatory effects of reticuline on the JAK2/STAT3/SOCS3 and p38 MAPK/NF-κB signaling pathway in a mouse model of obesity-associated asthma — animal studyView study →Reference 18Xu S et al. · 2025Reticuline modulates astrocyte and microglial responses to enhance prognosis after traumatic brain injury — animal studyView study →Reference 19Tian J et al. · 2026In vitroReticuline alleviates rheumatoid arthritis by suppressing the JAK/STAT signaling pathway — in vitro and collagen-induced arthritis modelView study →Reference 21Alghamdi HA et al. · 2025In vitroReticuline and coclaurine exhibit vitamin D receptor-dependent anticancer and pro-apoptotic activities in the colorectal cancer cell line HCT116 — in vitroView study →Reference 22Mo J et al. · 2026In vitroVirtual and CMC-based screening identified reticuline, an intermediate of BIA biosynthesis, as a potential agonist of D5R — in vitroView study →

The honest position: the GABAergic and vascular claims are (S)-specific and demonstrated; the anti-inflammatory and receptor-screening claims are for material of unreported configuration and should be read as “reticuline” without a stereochemical assignment.

Endogenous Reticuline in Animals

Reticuline is not only a plant molecule. It was purified and identified from rat brain at 12.7 ± 5.4 ng/g wet tissue, with the same study ruling out dietary and gut-bacterial sources by showing that rat chow, intestine and cultured gut bacteria contained neither reticuline nor morphine ^{25Reference 25Zhu W et al. · 2003AnimalPresence of reticuline in rat brain — a pathway for morphine biosynthesisView study →}. In human cell lines, GC-MS/MS identified norlaudanosoline, reticuline and morphine in neuroblastoma (SH-SY5Y) and pancreatic-carcinoma (DAN-G) cells; growing the cells under an ¹⁸O₂ atmosphere produced ¹⁸O-labelled alkaloids, proving biosynthetic rather than dietary origin, and the reticuline was determined to be the 1-(S) form ^{24Reference 24Poeaknapo C et al. · 2004Endogenous formation of morphine in human cells — (S)-reticuline identified as an endogenous precursorView study →}.

In other words, mammals appear to run an abbreviated version of the poppy pathway, with (S)-reticuline as an intermediate en route to trace endogenous morphine ^{24,25Reference 24Poeaknapo C et al. · 2004Endogenous formation of morphine in human cells — (S)-reticuline identified as an endogenous precursorView study →Reference 25Zhu W et al. · 2003AnimalPresence of reticuline in rat brain — a pathway for morphine biosynthesisView study →}. This is why the page’s origin reads natural (also endogenous). It is a biochemical curiosity rather than a therapeutic argument — the concentrations are nanogram-scale and the physiological function is unresolved — but it is also the reason the GABAA study bothered to test (R)-reticuline, 1,2-tetrahydroreticuline, codeine and morphine as suspected reticuline metabolites in rodent brain ^{1Reference 1Fedurco M et al. · 2015In vitroModulatory effects of Eschscholzia californica alkaloids on recombinant GABAA receptors — in vitro electrophysiologyView study →}.

What It's Used For

Reticuline’s own pharmacology is thin relative to its biochemical importance, and it is entirely preclinical. Two threads are reasonably well characterised — GABAergic sedation and vascular relaxation — and both were measured on the isolated (S)-enantiomer. A third, anti-inflammatory signalling, has accumulated four in-vivo models in under a decade but never a stated configuration.

Evidence by IndicationStrength of support · Beta

Support is an experimental score — a composite weighted by study type (human > animal > in vitro) and volume, tempered for isolate-vs-plant match and for whether the enantiomer was specified. A beta, not a validated metric. Every row here is preclinical; reticuline has no human evidence for any application.

01Sedative & CNS Depressant ActivityShaky44%Recombinant-receptor electrophysiology on the defined (S)-enantiomer + rodent behavioural battery on the isolate ^{1,13Reference 1Fedurco M et al. · 2015In vitroModulatory effects of Eschscholzia californica alkaloids on recombinant GABAA receptors — in vitro electrophysiologyView study →Reference 13Morais LC et al. · 1998AnimalCentral depressant effects of reticuline extracted from Ocotea duckei in rats and mice — animal studyView study →}

02Hypotensive & Vasorelaxant ActivityShaky40%Two in-vivo rat studies plus resolved ion-channel mechanism for (S)-reticuline ^{14,15Reference 14Dias KL et al. · 2004AnimalCardiovascular effects induced by reticuline in normotensive rats — animal studyView study →Reference 15Medeiros MAA et al. · 2009Medeiros MAA, Nunes XP, Barbosa-Filho JM, Lemos VS, Pinho JF, Roman-Campos D, de Medeiros IA, Araújo DAM, Cruz JS. (2009). (S)-reticuline induces vasorelaxation through the blockade of L-type Ca²⁺ channels — patch-clamp and isolated-tissue study. Naunyn-Schmiedeberg’s Archives of Pharmacology, 379(2), 115–125. https://pubmed.ncbi.nlm.nih.gov/18825370/View study →}

03Anti-Inflammatory SignallingShaky38%Four independent in-vivo models converging on JAK2/STAT3 + NF-κB, but configuration never stated ^{16,17,18,19Reference 16Yang X et al. · 2018Anti-inflammatory effects of boldine and reticuline isolated from Litsea cubeba through JAK2/STAT3 and NF-κB signaling pathways — animal studyView study →Reference 17Lyu X et al. · 2024AnimalAnti-inflammatory effects of reticuline on the JAK2/STAT3/SOCS3 and p38 MAPK/NF-κB signaling pathway in a mouse model of obesity-associated asthma — animal studyView study →Reference 18Xu S et al. · 2025Reticuline modulates astrocyte and microglial responses to enhance prognosis after traumatic brain injury — animal studyView study →Reference 19Tian J et al. · 2026In vitroReticuline alleviates rheumatoid arthritis by suppressing the JAK/STAT signaling pathway — in vitro and collagen-induced arthritis modelView study →}

04Antifungal & AntimicrobialShaky16%One 1992 screen of four Annona alkaloids; qualitative, no MICs ^{20Reference 20Paulo MQ et al. · 1992In vitroAntimicrobial activity of benzylisoquinoline alkaloids from Annona salzmanii D.C. — in vitroView study →}

05Anticancer Activity In VitroShaky14%Single cell-line study with a clean VDR-knockout control ^{21Reference 21Alghamdi HA et al. · 2025In vitroReticuline and coclaurine exhibit vitamin D receptor-dependent anticancer and pro-apoptotic activities in the colorectal cancer cell line HCT116 — in vitroView study →}

06Dopamine D5 Receptor AgonismShaky12%Single 2026 screening paper — docking plus binding and cAMP assays ^{22Reference 22Mo J et al. · 2026In vitroVirtual and CMC-based screening identified reticuline, an intermediate of BIA biosynthesis, as a potential agonist of D5R — in vitroView study →}

Mechanisms

The two ends of this table are the page in miniature: the bottom third is why reticuline matters to biology, the top third is what it does to a mammal, and the two have almost no overlap.

Pharmacokinetics

Essentially unstudied. No oral bioavailability figure, plasma half-life, volume of distribution or metabolite map exists for reticuline in humans or, so far as could be established here, in any animal. Three fragments are worth stating and no more:

• It is excreted conjugated. Reticuline is detectable in the urine of opium users only after acid or β-glucuronidase hydrolysis, which places glucuronidation as a major clearance route in people ^{26Reference 26Al-Amri AM et al. · 2004The GC-MS detection and characterization of reticuline as a marker of opium use — forensic studyView study →}.
• It is brain-accessible. Reticuline occurs endogenously in rat brain tissue ^{25Reference 25Zhu W et al. · 2003AnimalPresence of reticuline in rat brain — a pathway for morphine biosynthesisView study →}, and the Annonaceae neurotoxicity hypothesis explicitly proposes uptake and accumulation of dietary reticuline in the brain ^{23Reference 23Kotake Y et al. · 2004Detection and determination of reticuline and N-methylcoclaurine in the Annonaceae family using liquid chromatography–tandem mass spectrometry — includes SH-SY5Y cytotoxicity and complex-I inhibitionView study →} — consistent with a lipophilic tertiary amine, and in sharp contrast to quaternary berberine (oral bioavailability <1%).
• It is a metabolic intermediate, not an endpoint. In plants reticuline is consumed within one or two enzymatic steps, and in mammals it appears to sit on a route toward trace endogenous morphine ^{24Reference 24Poeaknapo C et al. · 2004Endogenous formation of morphine in human cells — (S)-reticuline identified as an endogenous precursorView study →}. Whether ingested reticuline is similarly transformed in vivo is unknown.

The practical consequence: the in-vivo anti-inflammatory doses of 0.25–1 mg/kg ^{16,17,19Reference 16Yang X et al. · 2018Anti-inflammatory effects of boldine and reticuline isolated from Litsea cubeba through JAK2/STAT3 and NF-κB signaling pathways — animal studyView study →Reference 17Lyu X et al. · 2024AnimalAnti-inflammatory effects of reticuline on the JAK2/STAT3/SOCS3 and p38 MAPK/NF-κB signaling pathway in a mouse model of obesity-associated asthma — animal studyView study →Reference 19Tian J et al. · 2026In vitroReticuline alleviates rheumatoid arthritis by suppressing the JAK/STAT signaling pathway — in vitro and collagen-induced arthritis modelView study →} are unusually low for an oral alkaloid with no measured absorption, and until an exposure study exists those results should be held loosely.

Clinical Trials

None. No registered or published human clinical trial of reticuline as an isolated agent was identified. The only human-adjacent evidence is at the herb level — the California poppy combination trial on the California poppy monograph — where reticuline is one alkaloid among many.

Last checked: July 2026.

Isolate vs. Plant Studies

Almost all of reticuline’s pharmacology is isolate work, which for once is the right design — and the transferability problem runs in the usual direction anyway.

The GABAA electrophysiology used a commercial (S)-(+)-reticuline hydrochloride standard, not plant material, and tested (R)-reticuline in the same experiment ^{1Reference 1Fedurco M et al. · 2015In vitroModulatory effects of Eschscholzia californica alkaloids on recombinant GABAA receptors — in vitro electrophysiologyView study →} — the cleanest single piece of evidence here. The cardiovascular work used reticuline purified from Ocotea duckei stem ^{14,15Reference 14Dias KL et al. · 2004AnimalCardiovascular effects induced by reticuline in normotensive rats — animal studyView study →Reference 15Medeiros MAA et al. · 2009Medeiros MAA, Nunes XP, Barbosa-Filho JM, Lemos VS, Pinho JF, Roman-Campos D, de Medeiros IA, Araújo DAM, Cruz JS. (2009). (S)-reticuline induces vasorelaxation through the blockade of L-type Ca²⁺ channels — patch-clamp and isolated-tissue study. Naunyn-Schmiedeberg’s Archives of Pharmacology, 379(2), 115–125. https://pubmed.ncbi.nlm.nih.gov/18825370/View study →}; the anti-inflammatory work used reticuline isolated from Litsea cubeba or purchased ^{16Reference 16Yang X et al. · 2018Anti-inflammatory effects of boldine and reticuline isolated from Litsea cubeba through JAK2/STAT3 and NF-κB signaling pathways — animal studyView study →}; the antifungal screen used four alkaloids purified from Annona salzmanii bark ^{20Reference 20Paulo MQ et al. · 1992In vitroAntimicrobial activity of benzylisoquinoline alkaloids from Annona salzmanii D.C. — in vitroView study →}.

The plant-level evidence points the other way and is genuinely useful. California poppy’s sedative and anxiolytic reputation is a whole-herb effect, and the one study that measured GABAA modulation across its isolated alkaloids assigned that activity to reticuline while ruling out N-methyllaurotetanine ^{1Reference 1Fedurco M et al. · 2015In vitroModulatory effects of Eschscholzia californica alkaloids on recombinant GABAA receptors — in vitro electrophysiologyView study →} — which is why allocryptopine, chelerythrine and scoulerine all explicitly decline credit for the herb’s calming effect and point here instead. But the arithmetic imposes discipline: at 1.095 mg/g of dried aerial parts ^{1Reference 1Fedurco M et al. · 2015In vitroModulatory effects of Eschscholzia californica alkaloids on recombinant GABAA receptors — in vitro electrophysiologyView study →}, a 2 g dose of the herb delivers roughly 2 mg of (S)-reticuline — against a receptor EC50 of ~6 µM and rodent behavioural doses of 50–100 mg/kg ^{13Reference 13Morais LC et al. · 1998AnimalCentral depressant effects of reticuline extracted from Ocotea duckei in rats and mice — animal studyView study →}. Whether an ordinary tea or tincture reaches a GABAergically relevant brain concentration has never been shown.

For graviola the caveat is sharper still. Reticuline is the plant’s main alkaloid ^{2Reference 2Leboeuf M et al. · 1981Leboeuf M, Legueut C, Cavé A, Desconclois JF, Forgacs P, Jacquemin H. (1981). [Alkaloids of Annonaceae XXIX — alkaloids of Annona muricata]. Planta Medica, 42(1), 37–44. https://pubmed.ncbi.nlm.nih.gov/17401878/View study →}, but graviola’s pharmacology — good and bad — is dominated by the acetogenins, chiefly annonacin ^{33Reference 33Moghadamtousi SZ et al. · 2015ReviewAnnona muricata (Annonaceae) — a review of its traditional uses, isolated acetogenins and biological activitiesView study →}. The one finding that genuinely belongs to reticuline in that context is not a benefit: it is complex-I inhibition and neuroblastoma-cell toxicity ^{23Reference 23Kotake Y et al. · 2004Detection and determination of reticuline and N-methylcoclaurine in the Annonaceae family using liquid chromatography–tandem mass spectrometry — includes SH-SY5Y cytotoxicity and complex-I inhibitionView study →}.

Its Role in Plants

Reticuline’s role in the plant is to be spent. It is the last common intermediate of an enormous metabolic fan, and the enzymes that consume it — BBE toward sanguinarine and berberine, REPI toward morphine, CYP80G2 toward the aporphines, the O-methyltransferases toward papaverine — are what individuate a species’ alkaloid profile ^{3,4Reference 3Hagel JM · 2013ReviewBenzylisoquinoline alkaloid metabolism — a century of discovery and a brave new world — reviewView study →Reference 4Bird DA · 2001Berberine bridge enzyme, a key branch-point enzyme in benzylisoquinoline alkaloid biosynthesis, contains a vacuolar sorting determinant — plant biochemistryView study →}. Because it is consumed rather than stored, reticuline is usually a minor alkaloid even in plants that make large amounts of its descendants. Two experiments demonstrate this directly and inversely: knocking down the berberine bridge enzyme in cultured California-poppy cells collapsed sanguinarine production and made reticuline accumulate to 310 µg/g fresh weight, with the cells even secreting it into the medium ^{12Reference 12Fujii N et al. · 2007Knockdown of berberine bridge enzyme by RNAi accumulates (S)-reticuline and activates a silent pathway in cultured California poppy cells — plant cell cultureView study →}; and silencing codeinone reductase in opium poppy made a plant that stockpiles reticuline instead of morphine ^{10Reference 10Allen RS et al. · 2004RNAi-mediated replacement of morphine with the nonnarcotic alkaloid reticuline in opium poppy — plant biotechnologyView study →}.

The downstream products are largely chemical-defence compounds. Sanguinarine, for instance, accumulates in the vacuole of opium-poppy cells specifically in response to fungal elicitors ^{4Reference 4Bird DA · 2001Berberine bridge enzyme, a key branch-point enzyme in benzylisoquinoline alkaloid biosynthesis, contains a vacuolar sorting determinant — plant biochemistryView study →} — and reticuline itself carries some antifungal activity in the Annona alkaloid fraction ^{20Reference 20Paulo MQ et al. · 1992In vitroAntimicrobial activity of benzylisoquinoline alkaloids from Annona salzmanii D.C. — in vitroView study →}, consistent with a defensive role for the whole branch.

One striking piece of biology sits outside plants entirely: a darkling beetle expresses an aldo-keto reductase (AKR1B1) that converts (S)- to (R)-reticuline in vitro, apparently as part of the insect’s alkaloid-detoxification machinery — the first reticuline isomerase found in an animal ^{31Reference 31Zhang L et al. · 2026Reticuline isomerase AKR1B1 with aldo-keto reductase activity and detoxification function from the insect Blaps rhynchopetera — enzymologyView study →}.

Prevalence in Nature

Reticuline occurs across the alkaloid-forming orders — Papaveraceae, Annonaceae, Lauraceae, Menispermaceae, Magnoliaceae, Ranunculaceae and Berberidaceae — essentially wherever benzylisoquinoline metabolism runs at all, because it is the obligatory intermediate ^{3Reference 3Hagel JM · 2013ReviewBenzylisoquinoline alkaloid metabolism — a century of discovery and a brave new world — reviewView study →}. What varies is whether a species lets any of it accumulate.

• Graviola (Annona muricata). Reticuline is the main alkaloid of the leaves, root bark and stem bark, alongside coclaurine, coreximine, atherosperminine, stepharine and the minor tetrahydrobenzylisoquinolines anomurine and anomuricine ^{2Reference 2Leboeuf M et al. · 1981Leboeuf M, Legueut C, Cavé A, Desconclois JF, Forgacs P, Jacquemin H. (1981). [Alkaloids of Annonaceae XXIX — alkaloids of Annona muricata]. Planta Medica, 42(1), 37–44. https://pubmed.ncbi.nlm.nih.gov/17401878/View study →}. LC-MS/MS surveys detected reticuline in every part of the plant examined except pulp and seed, and did not detect it in sweetsop fruit — a distribution that matters because the compound was being profiled as a candidate neurotoxin ^{23Reference 23Kotake Y et al. · 2004Detection and determination of reticuline and N-methylcoclaurine in the Annonaceae family using liquid chromatography–tandem mass spectrometry — includes SH-SY5Y cytotoxicity and complex-I inhibitionView study →}.
• California poppy (Eschscholzia californica). Quantified at 1.095 ± 0.16 mg/g of dried aerial parts by LC-diode-array — a genuinely minor alkaloid there, roughly a tenth of californidine (12.5 mg/g) and an eighth of eschscholtzine (8.7 mg/g) ^{1Reference 1Fedurco M et al. · 2015In vitroModulatory effects of Eschscholzia californica alkaloids on recombinant GABAA receptors — in vitro electrophysiologyView study →}.
• Opium poppy (Papaver somniferum). Present in opium as a minor alkaloid and as the metabolic parent of codamine, laudanosine and laudanine ^{26Reference 26Al-Amri AM et al. · 2004The GC-MS detection and characterization of reticuline as a marker of opium use — forensic studyView study →}; it accumulates to high levels only in engineered or mutant lines ^{5,10Reference 5Winzer T et al. · 2015Morphinan biosynthesis in opium poppy requires a P450-oxidoreductase fusion protein (STORR) — plant geneticsView study →Reference 10Allen RS et al. · 2004RNAi-mediated replacement of morphine with the nonnarcotic alkaloid reticuline in opium poppy — plant biotechnologyView study →}.
• Elsewhere. Ocotea duckei (Lauraceae) stem bark, where (S)-reticuline is the major benzylisoquinoline and the source of most of the cardiovascular pharmacology ^{15Reference 15Medeiros MAA et al. · 2009Medeiros MAA, Nunes XP, Barbosa-Filho JM, Lemos VS, Pinho JF, Roman-Campos D, de Medeiros IA, Araújo DAM, Cruz JS. (2009). (S)-reticuline induces vasorelaxation through the blockade of L-type Ca²⁺ channels — patch-clamp and isolated-tissue study. Naunyn-Schmiedeberg’s Archives of Pharmacology, 379(2), 115–125. https://pubmed.ncbi.nlm.nih.gov/18825370/View study →}; Litsea cubeba ^{16Reference 16Yang X et al. · 2018Anti-inflammatory effects of boldine and reticuline isolated from Litsea cubeba through JAK2/STAT3 and NF-κB signaling pathways — animal studyView study →}; the flower buds of Magnolia salicifolia (the Sino-Japanese drug shin-i), where it occurs with coclaurine and higenamine ^{27Reference 27Kimura I et al. · 1989Inotropic effects of (±)-higenamine and its chemically related components, (+)-R-coclaurine and (+)-S-reticuline, contained in the traditional medicines “bushi” and “shin-i” in isolated guinea-pig papillary muscle — isolated-tissue studyView study →}; Stephania species ^{22Reference 22Mo J et al. · 2026In vitroVirtual and CMC-based screening identified reticuline, an intermediate of BIA biosynthesis, as a potential agonist of D5R — in vitroView study →}; and Sinomenium acutum and other Menispermaceae ^{32Reference 32Yang Y et al. · 2022Full-length transcriptome and metabolite analysis reveal reticuline epimerase-independent pathways for benzylisoquinoline alkaloid biosynthesis in Sinomenium acutum — plant genomicsView study →}.

Because reticuline is a transit metabolite, published concentration figures are sparse — only the California-poppy value above is quantified with a number here. The rest of the occurrence record is qualitative.

Discovery & Synthesis

Reticuline takes its name from Annona reticulata — custard apple, or bullock’s heart — the species from which it was first obtained; the Chinese name for the molecule, niúxīnguǒ jiǎn, is a literal translation of the same botanical origin ^{30Reference 30Wu Z et al. · 2026ReviewWu Z, Wang P, Chiu TY. (2026). [Recent advances in the application value and biosynthesis of chiral reticuline] — review. Sheng Wu Gong Cheng Xue Bao (Chinese Journal of Biotechnology), 42(3), 1042–1061. https://pubmed.ncbi.nlm.nih.gov/41873066/View study →}. Its early history is chemical rather than pharmacological: through the twentieth century, isotope-feeding and enzymology progressively established it as the hub of benzylisoquinoline metabolism, a story reviewed as “a century of discovery” ^{3Reference 3Hagel JM · 2013ReviewBenzylisoquinoline alkaloid metabolism — a century of discovery and a brave new world — reviewView study →}. The precise first-isolation report and date were not pinned down here.

There is no classical total synthesis in commercial use, and no bulk market for the isolated alkaloid: reticuline circulates as an analytical reference standard and a research chemical. Its modern preparation is instead a showcase of biocatalysis and metabolic engineering:

• Microbial de novo synthesis. A seven-enzyme route from L-tyrosine gave (S)-reticuline from glucose in Saccharomyces cerevisiae, enabled by an enzyme-coupled L-DOPA biosensor used to find and improve a functional tyrosine hydroxylase ^{9Reference 9DeLoache WC et al. · 2015An enzyme-coupled biosensor enables (S)-reticuline production in yeast from glucose — metabolic engineeringView study →}. Reticuline is the standard staging post for microbial BIA production generally ^{8,30Reference 8Galanie S et al. · 2015Complete biosynthesis of opioids in yeast — metabolic engineeringView study →Reference 30Wu Z et al. · 2026ReviewWu Z, Wang P, Chiu TY. (2026). [Recent advances in the application value and biosynthesis of chiral reticuline] — review. Sheng Wu Gong Cheng Xue Bao (Chinese Journal of Biotechnology), 42(3), 1042–1061. https://pubmed.ncbi.nlm.nih.gov/41873066/View study →}.
• Chemo-enzymatic synthesis of the (R)-enantiomer. The prochiral intermediate 1,2-dehydroreticuline is built by conventional organic synthesis, then reduced stereoselectively by 1,2-dehydroreticuline reductase to give (R)-reticuline at >99% ee and 92% isolated yield — after which membrane-bound salutaridine synthase closes it to (+)-salutaridine ^{29Reference 29Cigan E et al. · 2023Concise synthesis of (R)-reticuline and (+)-salutaridine by combining early-stage organic synthesis and late-stage biocatalysis — chemo-enzymatic synthesisView study →}.
• Plant metabolic engineering. RNAi silencing of codeinone reductase produced an opium-poppy line accumulating reticuline in place of morphine, thebaine, codeine and oripavine ^{10Reference 10Allen RS et al. · 2004RNAi-mediated replacement of morphine with the nonnarcotic alkaloid reticuline in opium poppy — plant biotechnologyView study →}; BBE knockdown does the equivalent in California-poppy cell culture ^{12Reference 12Fujii N et al. · 2007Knockdown of berberine bridge enzyme by RNAi accumulates (S)-reticuline and activates a silent pathway in cultured California poppy cells — plant cell cultureView study →}.

Patents: not yet researched.

Toxicity & Safety

Reticuline carries a moderate flag. It is not a narcotic — the engineered poppy that accumulates it was explicitly described as producing “the nonnarcotic alkaloid reticuline” ^{10Reference 10Allen RS et al. · 2004RNAi-mediated replacement of morphine with the nonnarcotic alkaloid reticuline in opium poppy — plant biotechnologyView study →}, and it has no reported opioid-receptor activity of its own. But it is not inert either, and the case for caution rests on three specific, cited findings rather than on class suspicion.

Mitochondrial complex-I inhibition and neuronal cytotoxicity. In the study that profiled Annonaceae alkaloids as candidate neurotoxins behind the Guadeloupean cluster of atypical parkinsonism, reticuline, N-methylcoclaurine and norreticuline were all toxic to SH-SY5Y neuroblastoma cells and inhibited mitochondrial respiratory complex I; the authors proposed that dietary uptake and brain accumulation of these benzylisoquinolines could contribute to the disease ^{23Reference 23Kotake Y et al. · 2004Detection and determination of reticuline and N-methylcoclaurine in the Annonaceae family using liquid chromatography–tandem mass spectrometry — includes SH-SY5Y cytotoxicity and complex-I inhibitionView study →}. This is the same mechanistic class as the Annona acetogenin annonacin, which carries the better-developed neurotoxicity case ^{33Reference 33Moghadamtousi SZ et al. · 2015ReviewAnnona muricata (Annonaceae) — a review of its traditional uses, isolated acetogenins and biological activitiesView study →} — but it means reticuline cannot be waved through as the benign fraction of graviola.

Cardiovascular depression at injected doses. Intravenous reticuline at 5–20 mg/kg produced intense hypotension in normotensive rats ^{14Reference 14Dias KL et al. · 2004AnimalCardiovascular effects induced by reticuline in normotensive rats — animal studyView study →}, and the mechanism includes L-type Ca²⁺-channel blockade ^{15Reference 15Medeiros MAA et al. · 2009Medeiros MAA, Nunes XP, Barbosa-Filho JM, Lemos VS, Pinho JF, Roman-Campos D, de Medeiros IA, Araújo DAM, Cruz JS. (2009). (S)-reticuline induces vasorelaxation through the blockade of L-type Ca²⁺ channels — patch-clamp and isolated-tissue study. Naunyn-Schmiedeberg’s Archives of Pharmacology, 379(2), 115–125. https://pubmed.ncbi.nlm.nih.gov/18825370/View study →} plus a negative inotropic effect on cardiac muscle ^{27Reference 27Kimura I et al. · 1989Inotropic effects of (±)-higenamine and its chemically related components, (+)-R-coclaurine and (+)-S-reticuline, contained in the traditional medicines “bushi” and “shin-i” in isolated guinea-pig papillary muscle — isolated-tissue studyView study →}. Anyone reading the vasorelaxant data as a therapeutic lead should read it equally as a hypotension and cardiac-depression hazard at dose.

Additive CNS depression. Reticuline is a GABAA positive allosteric modulator ^{1Reference 1Fedurco M et al. · 2015In vitroModulatory effects of Eschscholzia californica alkaloids on recombinant GABAA receptors — in vitro electrophysiologyView study →} and produces a full sedative syndrome in rodents at 50–100 mg/kg, including prolongation of pentobarbital sleeping time ^{13Reference 13Morais LC et al. · 1998AnimalCentral depressant effects of reticuline extracted from Ocotea duckei in rats and mice — animal studyView study →} — a classic marker of additive risk with sedatives, alcohol and anaesthetics.

A fourth, minor note: reticuline inhibits uterine smooth-muscle contraction by lowering cytosolic calcium in isolated tissue ^{28Reference 28Martin ML et al. · 1988Uterine inhibitory effect of reticuline — isolated-tissue studyView study →}. That is a pharmacological finding on isolated uterus, not a reproductive-toxicity assessment; no developmental or reproductive toxicology exists for this molecule.

Safety at a Glance

⚠️ Moderate toxicitySedative interactionsCardiac caution

• Not a narcotic and not an opioid. Reticuline is a precursor of morphine, not an opiate; engineered poppies accumulating it are described as non-narcotic ^{10Reference 10Allen RS et al. · 2004RNAi-mediated replacement of morphine with the nonnarcotic alkaloid reticuline in opium poppy — plant biotechnologyView study →}.
• Inhibits mitochondrial complex I and is cytotoxic to neuroblastoma cells — profiled as a candidate contributor to Annonaceae-linked atypical parkinsonism ^{23Reference 23Kotake Y et al. · 2004Detection and determination of reticuline and N-methylcoclaurine in the Annonaceae family using liquid chromatography–tandem mass spectrometry — includes SH-SY5Y cytotoxicity and complex-I inhibitionView study →}.
• Intense hypotension and negative inotropy at injected doses in rats, via L-type Ca²⁺-channel blockade and NO/muscarinic mechanisms ^{14,15,27Reference 14Dias KL et al. · 2004AnimalCardiovascular effects induced by reticuline in normotensive rats — animal studyView study →Reference 15Medeiros MAA et al. · 2009Medeiros MAA, Nunes XP, Barbosa-Filho JM, Lemos VS, Pinho JF, Roman-Campos D, de Medeiros IA, Araújo DAM, Cruz JS. (2009). (S)-reticuline induces vasorelaxation through the blockade of L-type Ca²⁺ channels — patch-clamp and isolated-tissue study. Naunyn-Schmiedeberg’s Archives of Pharmacology, 379(2), 115–125. https://pubmed.ncbi.nlm.nih.gov/18825370/View study →Reference 27Kimura I et al. · 1989Inotropic effects of (±)-higenamine and its chemically related components, (+)-R-coclaurine and (+)-S-reticuline, contained in the traditional medicines “bushi” and “shin-i” in isolated guinea-pig papillary muscle — isolated-tissue studyView study →}.
• Additive sedation. A GABAA positive allosteric modulator that prolongs barbiturate sleep in rodents — plausible additive effect with alcohol, benzodiazepines and other CNS depressants ^{1,13Reference 1Fedurco M et al. · 2015In vitroModulatory effects of Eschscholzia californica alkaloids on recombinant GABAA receptors — in vitro electrophysiologyView study →Reference 13Morais LC et al. · 1998AnimalCentral depressant effects of reticuline extracted from Ocotea duckei in rats and mice — animal studyView study →}.
• No human safety data at all. No genotoxicity, carcinogenicity, repeat-dose, reproductive or drug-interaction (CYP/P-gp) assessment exists for isolated reticuline. Treat silence as unknown, not safe.

Drug-interaction and pregnancy/lactation decisions belong on the California poppy and graviola monographs, where intake is actually decided and where the better-characterised alkaloids (California poppy’s CYP-inhibiting eschscholtzine and protopine; graviola’s acetogenins) drive the verdict.

Dosage

There is no established or studied human dose for reticuline. It has never been administered to people as a medicine. Every figure below is an animal dose or a laboratory concentration, listed so the numbers in the sections above can be compared honestly.

Human exposure is indirect. Dried California-poppy aerial parts carry about 1.095 mg of (S)-reticuline per gram, so a 2 g preparation supplies roughly 2 mg ^{1Reference 1Fedurco M et al. · 2015In vitroModulatory effects of Eschscholzia californica alkaloids on recombinant GABAA receptors — in vitro electrophysiologyView study →}; graviola preparations carry reticuline as their main alkaloid but without a published quantitative figure ^{2Reference 2Leboeuf M et al. · 1981Leboeuf M, Legueut C, Cavé A, Desconclois JF, Forgacs P, Jacquemin H. (1981). [Alkaloids of Annonaceae XXIX — alkaloids of Annona muricata]. Planta Medica, 42(1), 37–44. https://pubmed.ncbi.nlm.nih.gov/17401878/View study →}. These are doses studied in research and are not a personal recommendation.

References

1. Fedurco M, Gregorová J, Šebrlová K, Kantorová J, Peš O, Baur R, Sigel E, Táborská E. (2015). Modulatory effects of Eschscholzia californica alkaloids on recombinant GABAA receptors — in vitro electrophysiology. Biochemistry Research International, 2015, 617620. https://pubmed.ncbi.nlm.nih.gov/26509084/
2. Leboeuf M, Legueut C, Cavé A, Desconclois JF, Forgacs P, Jacquemin H. (1981). [Alkaloids of Annonaceae XXIX — alkaloids of Annona muricata]. Planta Medica, 42(1), 37–44. https://pubmed.ncbi.nlm.nih.gov/17401878/
3. Hagel JM, Facchini PJ. (2013). Benzylisoquinoline alkaloid metabolism — a century of discovery and a brave new world — review. Plant and Cell Physiology, 54(5), 647–672. https://pubmed.ncbi.nlm.nih.gov/23385146/
4. Bird DA, Facchini PJ. (2001). Berberine bridge enzyme, a key branch-point enzyme in benzylisoquinoline alkaloid biosynthesis, contains a vacuolar sorting determinant — plant biochemistry. Planta, 213(6), 888–897. https://pubmed.ncbi.nlm.nih.gov/11722125/
5. Winzer T, Kern M, King AJ, Larson TR, Teodor RI, Donninger SL, Li Y, Dowle AA, Cartwright J, Bates R, Ashford D, Thomas J, Walker C, Bowser TA, Graham IA. (2015). Morphinan biosynthesis in opium poppy requires a P450-oxidoreductase fusion protein (STORR) — plant genetics. Science, 349(6245), 309–312. https://pubmed.ncbi.nlm.nih.gov/26113639/
6. Farrow SC, Hagel JM, Beaudoin GAW, Burns DC, Facchini PJ. (2015). Stereochemical inversion of (S)-reticuline by a cytochrome P450 fusion in opium poppy — identification of reticuline epimerase (REPI). Nature Chemical Biology, 11(9), 728–732. https://pubmed.ncbi.nlm.nih.gov/26147354/
7. Gesell A, Rolf M, Ziegler J, Díaz Chávez ML, Huang FC, Kutchan TM. (2009). CYP719B1 is salutaridine synthase, the C–C phenol-coupling enzyme of morphine biosynthesis in opium poppy — enzymology. The Journal of Biological Chemistry, 284(36), 24432–24442. https://pubmed.ncbi.nlm.nih.gov/19567876/
8. Galanie S, Thodey K, Trenchard IJ, Filsinger Interrante M, Smolke CD. (2015). Complete biosynthesis of opioids in yeast — metabolic engineering. Science, 349(6252), 1095–1100. https://pubmed.ncbi.nlm.nih.gov/26272907/
9. DeLoache WC, Russ ZN, Narcross L, Gonzales AM, Martin VJJ, Dueber JE. (2015). An enzyme-coupled biosensor enables (S)-reticuline production in yeast from glucose — metabolic engineering. Nature Chemical Biology, 11(7), 465–471. https://pubmed.ncbi.nlm.nih.gov/25984720/
10. Allen RS, Millgate AG, Chitty JA, Thisleton J, Miller JA, Fist AJ, Gerlach WL, Larkin PJ. (2004). RNAi-mediated replacement of morphine with the nonnarcotic alkaloid reticuline in opium poppy — plant biotechnology. Nature Biotechnology, 22(12), 1559–1566. https://pubmed.ncbi.nlm.nih.gov/15543134/
11. Han X, Lamshöft M, Grobe N, Ren X, Fist AJ, Kutchan TM, Spiteller M, Zenk MH. (2010). The biosynthesis of papaverine proceeds via (S)-reticuline — stable-isotope precursor feeding. Phytochemistry, 71(11–12), 1305–1312. https://pubmed.ncbi.nlm.nih.gov/20494383/
12. Fujii N, Inui T, Iwasa K, Morishige T, Sato F. (2007). Knockdown of berberine bridge enzyme by RNAi accumulates (S)-reticuline and activates a silent pathway in cultured California poppy cells — plant cell culture. Transgenic Research, 16(3), 363–375. https://pubmed.ncbi.nlm.nih.gov/17103244/
13. Morais LC, Barbosa-Filho JM, Almeida RN. (1998). Central depressant effects of reticuline extracted from Ocotea duckei in rats and mice — animal study. Journal of Ethnopharmacology, 62(1), 57–61. https://pubmed.ncbi.nlm.nih.gov/9720612/
14. Dias KL, Da Silva Dias C, Barbosa-Filho JM, Almeida RN, De Azevedo Correia N, Medeiros IA. (2004). Cardiovascular effects induced by reticuline in normotensive rats — animal study. Planta Medica, 70(4), 328–333. https://pubmed.ncbi.nlm.nih.gov/15095148/
15. Medeiros MAA, Nunes XP, Barbosa-Filho JM, Lemos VS, Pinho JF, Roman-Campos D, de Medeiros IA, Araújo DAM, Cruz JS. (2009). (S)-reticuline induces vasorelaxation through the blockade of L-type Ca²⁺ channels — patch-clamp and isolated-tissue study. Naunyn-Schmiedeberg’s Archives of Pharmacology, 379(2), 115–125. https://pubmed.ncbi.nlm.nih.gov/18825370/
16. Yang X, Gao X, Cao Y, Guo Q, Li S, Zhu Z, Zhao Y, Tu P, Chai X. (2018). Anti-inflammatory effects of boldine and reticuline isolated from Litsea cubeba through JAK2/STAT3 and NF-κB signaling pathways — animal study. Planta Medica, 84(1), 20–25. https://pubmed.ncbi.nlm.nih.gov/28651290/
17. Lyu X, Liu J, Liu Z, Wu Y, Zhu P, Liu C. (2024). Anti-inflammatory effects of reticuline on the JAK2/STAT3/SOCS3 and p38 MAPK/NF-κB signaling pathway in a mouse model of obesity-associated asthma — animal study. The Clinical Respiratory Journal, 18(1), e13729. https://pubmed.ncbi.nlm.nih.gov/38286741/
18. Xu S, Zhu J, Wen J, Wang C, Chen X, Liao W, Lu Z, Wang Z, Gong P. (2025). Reticuline modulates astrocyte and microglial responses to enhance prognosis after traumatic brain injury — animal study. Neurotherapeutics, 22(6), e00709. https://pubmed.ncbi.nlm.nih.gov/40769849/
19. Tian J, Zhang J, Yang Y, Song Y, Yuan Z, Chang S. (2026). Reticuline alleviates rheumatoid arthritis by suppressing the JAK/STAT signaling pathway — in vitro and collagen-induced arthritis model. Clinical Rheumatology. https://pubmed.ncbi.nlm.nih.gov/42484797/
20. Paulo MQ, Barbosa-Filho JM, Lima EO, Maia RF, Barbosa RC, Kaplan MAC. (1992). Antimicrobial activity of benzylisoquinoline alkaloids from Annona salzmanii D.C. — in vitro. Journal of Ethnopharmacology, 36(1), 39–41. https://pubmed.ncbi.nlm.nih.gov/1501491/
21. Alghamdi HA, Alghamdi SS, Al-Zahrani MH, Trivilegio T, Bahattab S, AlRoshody R, Alhaidan Y, Alghamdi RA, Matou-Nasri S. (2025). Reticuline and coclaurine exhibit vitamin D receptor-dependent anticancer and pro-apoptotic activities in the colorectal cancer cell line HCT116 — in vitro. Current Issues in Molecular Biology, 47(10), 810. https://pubmed.ncbi.nlm.nih.gov/41150758/
22. Mo J, Sun Z, Xu G, Zhang G, Xie Z, Zhao J, Heng GP, Cong Z, Leng L, Chen S. (2026). Virtual and CMC-based screening identified reticuline, an intermediate of BIA biosynthesis, as a potential agonist of D5R — in vitro. Molecules, 31(8), 1285. https://pubmed.ncbi.nlm.nih.gov/42075963/
23. Kotake Y, Okuda K, Kamizono M, Matsumoto N, Tanahashi T, Hara H, Caparros-Lefebvre D, Ohta S. (2004). Detection and determination of reticuline and N-methylcoclaurine in the Annonaceae family using liquid chromatography–tandem mass spectrometry — includes SH-SY5Y cytotoxicity and complex-I inhibition. Journal of Chromatography B, 806(1), 75–78. https://pubmed.ncbi.nlm.nih.gov/15149614/
24. Poeaknapo C, Schmidt J, Brandsch M, Dräger B, Zenk MH. (2004). Endogenous formation of morphine in human cells — (S)-reticuline identified as an endogenous precursor. Proceedings of the National Academy of Sciences USA, 101(39), 14091–14096. https://pubmed.ncbi.nlm.nih.gov/15383669/
25. Zhu W, Ma Y, Cadet P, Yu D, Bilfinger TV, Bianchi E, Stefano GB. (2003). Presence of reticuline in rat brain — a pathway for morphine biosynthesis. Brain Research. Molecular Brain Research, 117(1), 83–90. https://pubmed.ncbi.nlm.nih.gov/14499484/
26. Al-Amri AM, Smith RM, El-Haj BM, Juma’a MH. (2004). The GC-MS detection and characterization of reticuline as a marker of opium use — forensic study. Forensic Science International, 142(1), 61–69. https://pubmed.ncbi.nlm.nih.gov/15272474/
27. Kimura I, Chui LH, Fujitani K, Kikuchi T, Kimura M. (1989). Inotropic effects of (±)-higenamine and its chemically related components, (+)-R-coclaurine and (+)-S-reticuline, contained in the traditional medicines “bushi” and “shin-i” in isolated guinea-pig papillary muscle — isolated-tissue study. Japanese Journal of Pharmacology, 50(1), 75–78. https://pubmed.ncbi.nlm.nih.gov/2724702/
28. Martin ML, Sagredo JA, Morais JM, Montero MJ, Sanchez MT, San Roman L. (1988). Uterine inhibitory effect of reticuline — isolated-tissue study. Journal of Pharmacy and Pharmacology, 40(11), 801–802. https://pubmed.ncbi.nlm.nih.gov/2907562/
29. Cigan E, Pletz J, Berger SA, Hierzberger B, Grilec-Zlamal M, Steiner A, Oroz-Guinea I, Kroutil W. (2023). Concise synthesis of (R)-reticuline and (+)-salutaridine by combining early-stage organic synthesis and late-stage biocatalysis — chemo-enzymatic synthesis. Chemical Science, 14(36), 9863–9871. https://pubmed.ncbi.nlm.nih.gov/37736642/
30. Wu Z, Wang P, Chiu TY. (2026). [Recent advances in the application value and biosynthesis of chiral reticuline] — review. Sheng Wu Gong Cheng Xue Bao (Chinese Journal of Biotechnology), 42(3), 1042–1061. https://pubmed.ncbi.nlm.nih.gov/41873066/
31. Zhang L, Zhou S, Yang X, Mwangi J, Cao K, Zhang C, Meng P, Wang Z, Zhao M, Shi L, Lu Q. (2026). Reticuline isomerase AKR1B1 with aldo-keto reductase activity and detoxification function from the insect Blaps rhynchopetera — enzymology. International Journal of Biological Macromolecules, 352, 151224. https://pubmed.ncbi.nlm.nih.gov/41791543/
32. Yang Y, Sun Y, Wang Z, Yin M, Sun R, Xue L, Huang X, Wang C, Yan X. (2022). Full-length transcriptome and metabolite analysis reveal reticuline epimerase-independent pathways for benzylisoquinoline alkaloid biosynthesis in Sinomenium acutum — plant genomics. Frontiers in Plant Science, 13, 1086335. https://pubmed.ncbi.nlm.nih.gov/36605968/
33. Moghadamtousi SZ, Fadaeinasab M, Nikzad S, Mohan G, Ali HM, Kadir HA. (2015). Annona muricata (Annonaceae) — a review of its traditional uses, isolated acetogenins and biological activities. International Journal of Molecular Sciences, 16(7), 15625–15658. https://pubmed.ncbi.nlm.nih.gov/26184167/
34. Gafner S, Dietz BM, McPhail KL, Scott IM, Glinski JA, Russell FE, McCollom MM, Budzinski JW, Foster BC, Bergeron C, Rhyu MR, Bolton JL. (2006). Alkaloids from Eschscholzia californica and their capacity to inhibit binding of [3H]8-hydroxy-2-(di-N-propylamino)tetralin to 5-HT1A receptors in vitro. Journal of Natural Products, 69(3), 432–435. https://pubmed.ncbi.nlm.nih.gov/16562853/

View all 34 references▾