Anagyrine

Anagyrine at a Glance

Anagyrine is a quinolizidine alkaloid — a bicyclic, nicotine-adjacent plant nitrogen compound — produced by many lupines (Lupinus spp.) and present as a minor constituent of blue cohosh (Caulophyllum thalictroides) rhizome. It is not a medicine and has no established therapeutic use. Its significance is almost entirely toxicological: it is the compound most closely associated with “crooked calf disease,” the congenital limb-and-jaw deformity seen in calves born to cows that grazed anagyrine-bearing lupine during a susceptible window of pregnancy ^{1,3,4Reference 1Keeler RF · 1976Lupin alkaloids from teratogenic and nonteratogenic lupinsView study →Reference 3Lee ST et al. · 2007Lupine induced “crooked calf disease” in Washington and Oregon: identification of the alkaloid profiles in Lupinus sulfureus, Lupinus leucophyllus, and Lupinus sericeusView study →Reference 4Keeler RF · 1989Piperidine alkaloid composition and relation to crooked calf disease-inducing potential of Lupinus formosusView study →}.

The core mechanism is now reasonably well understood. Anagyrine and its co-occurring alkaloid relatives act on fetal nicotinic acetylcholine receptors (nAChR), first stimulating then desensitising them, which suppresses fetal movement. A fetus that cannot move freely during the weeks its joints and palate are forming develops fixed skeletal contractures (arthrogryposis) and, in the worst cases, cleft palate — a mechanical, movement-dependent birth defect rather than a direct chemical malformation ^{5,6,7,8Reference 5Panter KE et al. · 1990Multiple congenital contractures (MCC) and cleft palate induced in goats by ingestion of piperidine alkaloid-containing plants: reduction in fetal movement as the probable causeView study →Reference 6Green BT et al. · 2010Actions of piperidine alkaloid teratogens at fetal nicotinic acetylcholine receptorsView study →Reference 7Panter KE et al. · 1999Lupines, poison-hemlock and Nicotiana spp: toxicity and teratogenicity in livestockView study →Reference 8Green BT et al. · 2017Anagyrine desensitization of peripheral nicotinic acetylcholine receptorsView study →}.

For a herbal-medicine audience the practical point is this: blue cohosh’s long and troubling reputation as a uterine stimulant, abortifacient and reproductive toxin — including documented harm from prenatal use — rests substantially on its nicotinic quinolizidine alkaloids, of which anagyrine (alongside N-methylcytisine) is the flagship teratogen ^{2,9,10Reference 2Rader JI · 2013Primary constituents of blue cohosh: quantification in dietary supplements and potential for toxicityView study →Reference 9Kennelly EJ et al. · 1999In vitroDetecting potential teratogenic alkaloids from blue cohosh rhizomes using an in vitro rat embryo cultureView study →Reference 10Rao RB · 2002Nicotinic toxicity from tincture of blue cohosh (Caulophyllum thalictroides) used as an abortifacientView study →}. Anagyrine is present in some, but not all, commercial blue cohosh products, at roughly 2–390 ppm ^{2Reference 2Rader JI · 2013Primary constituents of blue cohosh: quantification in dietary supplements and potential for toxicityView study →}.

Crooked Calf Disease: The Teratogen Signature

The single fact that defines anagyrine is its role in “crooked calf disease” (lupine-induced congenital arthrogryposis). This is the point of the page, so it deserves to be stated carefully and precisely.

What it is. When pregnant cattle graze certain lupines during a specific gestational window — roughly days 40 to 100 — a fraction of the resulting calves are born with multiple congenital contractures: twisted, fixed limbs (arthrogryposis), spinal curvature (scoliosis/torticollis), and sometimes cleft palate ^{1,4,5Reference 1Keeler RF · 1976Lupin alkaloids from teratogenic and nonteratogenic lupinsView study →Reference 4Keeler RF · 1989Piperidine alkaloid composition and relation to crooked calf disease-inducing potential of Lupinus formosusView study →Reference 5Panter KE et al. · 1990Multiple congenital contractures (MCC) and cleft palate induced in goats by ingestion of piperidine alkaloid-containing plants: reduction in fetal movement as the probable causeView study →}. The syndrome has caused real economic loss in the western United States for decades and is the reason lupine teratogenicity is among the best-characterised in veterinary toxicology.

Why anagyrine. Keeler’s foundational lupin-alkaloid work in the 1970s established that the teratogenic potential of a given lupine population tracked its anagyrine content — teratogenic lupines carried anagyrine, non-teratogenic selections largely did not — and that anagyrine concentration varied by species, plant part and stage of growth ^{1Reference 1Keeler RF · 1976Lupin alkaloids from teratogenic and nonteratogenic lupinsView study →}. This is why anagyrine became the marker alkaloid used to gauge whether a lupine stand is dangerous to grazing cattle ^{3,11Reference 3Lee ST et al. · 2007Lupine induced “crooked calf disease” in Washington and Oregon: identification of the alkaloid profiles in Lupinus sulfureus, Lupinus leucophyllus, and Lupinus sericeusView study →Reference 11Green BT et al. · 2013Plant alkaloids that cause developmental defects through the disruption of cholinergic neurotransmissionView study →}.

How it causes the defect. The deformity is not a direct poisoning of developing bone. It is a consequence of reduced fetal movement: the alkaloids depress the fetus’s own neuromuscular activity through nicotinic receptors, and a fetus held still during the contracture-susceptible weeks develops permanently fixed joints, while an immobile tongue and jaw can mechanically obstruct closure of the palatal shelves, producing cleft palate ^{5,6Reference 5Panter KE et al. · 1990Multiple congenital contractures (MCC) and cleft palate induced in goats by ingestion of piperidine alkaloid-containing plants: reduction in fetal movement as the probable causeView study →Reference 6Green BT et al. · 2010Actions of piperidine alkaloid teratogens at fetal nicotinic acetylcholine receptorsView study →}. Experimentally, this movement-suppression mechanism has been reproduced with piperidine- and quinolizidine-alkaloid-containing plants in cattle, goats and sheep ^{5,7Reference 5Panter KE et al. · 1990Multiple congenital contractures (MCC) and cleft palate induced in goats by ingestion of piperidine alkaloid-containing plants: reduction in fetal movement as the probable causeView study →Reference 7Panter KE et al. · 1999Lupines, poison-hemlock and Nicotiana spp: toxicity and teratogenicity in livestockView study →}.

An important nuance — handled in its own section below (Anagyrine, the Piperidine Alkaloids, and the “Marker vs. Actor” Question) — is that modern receptor work has complicated the simple “anagyrine is the teratogen” story: several piperidine alkaloids that co-occur with anagyrine are potent fetal-movement suppressors in their own right, and anagyrine may act partly as a reliable biomarker of teratogenic lupine as well as a direct actor ^{6,8Reference 6Green BT et al. · 2010Actions of piperidine alkaloid teratogens at fetal nicotinic acetylcholine receptorsView study →Reference 8Green BT et al. · 2017Anagyrine desensitization of peripheral nicotinic acetylcholine receptorsView study →}.

The Human Question

Direct human evidence is thin, and it must be stated without either alarmism or false reassurance.

There is one much-cited case report: an infant with skeletal dysplasia, a vascular anomaly and red-cell aplasia whose defects were attributed to maternal consumption of goat’s milk from goats that had grazed anagyrine-containing lupine — a proposed “crooked baby” analogue of crooked calf disease, since anagyrine can pass into milk ^{12Reference 12Ortega JA · 1987Anagyrine-induced red cell aplasia, vascular anomaly, and skeletal dysplasiaView study →}. This is a single, uncontrolled case report: it is hypothesis-generating, it cannot establish causation, and it has not been reproduced. It is genuinely notable — it is essentially the only human datapoint linking anagyrine specifically to a birth defect — but it should be read as a plausibility signal, not proof ^{12Reference 12Ortega JA · 1987Anagyrine-induced red cell aplasia, vascular anomaly, and skeletal dysplasiaView study →}.

The more relevant human exposure is blue cohosh in pregnancy. Blue cohosh has been used traditionally to stimulate labour and, historically, as an abortifacient; there are documented cases of serious neonatal harm (including cardiac injury and perinatal complications) after prenatal use, and a case of maternal nicotinic toxicity from blue cohosh tincture taken as an abortifacient ^{9,10Reference 9Kennelly EJ et al. · 1999In vitroDetecting potential teratogenic alkaloids from blue cohosh rhizomes using an in vitro rat embryo cultureView study →Reference 10Rao RB · 2002Nicotinic toxicity from tincture of blue cohosh (Caulophyllum thalictroides) used as an abortifacientView study →}. In-vitro rat-embryo-culture screening flagged the herb’s alkaloids — including anagyrine — as potential teratogens ^{9Reference 9Kennelly EJ et al. · 1999In vitroDetecting potential teratogenic alkaloids from blue cohosh rhizomes using an in vitro rat embryo cultureView study →}. No study isolates anagyrine as the sole cause of human harm from blue cohosh; the honest reading is that anagyrine is one of several nicotinic quinolizidine alkaloids (with N-methylcytisine the dominant one by abundance) that together underlie the herb’s reproductive toxicity ^{2,9Reference 2Rader JI · 2013Primary constituents of blue cohosh: quantification in dietary supplements and potential for toxicityView study →Reference 9Kennelly EJ et al. · 1999In vitroDetecting potential teratogenic alkaloids from blue cohosh rhizomes using an in vitro rat embryo cultureView study →}.

What It's Used For

Anagyrine has no therapeutic pharmacology to report — the “evidence by application” below is really evidence by documented biological effect, ranked by how well each is supported. The load-bearing caveat of the whole page is that the strongest evidence is livestock and receptor work, not human data, and that anagyrine rarely acts alone.

Evidence by IndicationStrength of support · Beta

Support is an experimental score — weighted by study type (human > animal > in vitro) and volume. A beta, not a validated metric. These rows are documented toxicological effects, not therapeutic uses — a higher bar means the harm/effect is better evidenced, never that the effect is desirable.

01Teratogenicity: Crooked Calf DiseasePromising62%Decades of field + experimental cattle/goat data; anagyrine as teratogenicity marker ^{1,3,4,5Reference 1Keeler RF · 1976Lupin alkaloids from teratogenic and nonteratogenic lupinsView study →Reference 3Lee ST et al. · 2007Lupine induced “crooked calf disease” in Washington and Oregon: identification of the alkaloid profiles in Lupinus sulfureus, Lupinus leucophyllus, and Lupinus sericeusView study →Reference 4Keeler RF · 1989Piperidine alkaloid composition and relation to crooked calf disease-inducing potential of Lupinus formosusView study →Reference 5Panter KE et al. · 1990Multiple congenital contractures (MCC) and cleft palate induced in goats by ingestion of piperidine alkaloid-containing plants: reduction in fetal movement as the probable causeView study →}

02Fetal Nicotinic Receptor BlockadePromising48%Receptor electrophysiology + in-vivo fetal-movement studies (mechanism) ^{6,8Reference 6Green BT et al. · 2010Actions of piperidine alkaloid teratogens at fetal nicotinic acetylcholine receptorsView study →Reference 8Green BT et al. · 2017Anagyrine desensitization of peripheral nicotinic acetylcholine receptorsView study →}

03CYP450 Enzyme InhibitionShaky30%In-vitro CYP-inhibition assay of blue cohosh alkaloids ^{13Reference 13Madgula VL et al. · 2009In vitroAlkaloids and saponins as cytochrome P450 inhibitors from blue cohosh (Caulophyllum thalictroides) in an in vitro assayView study →}

04Acute Nicotinic ToxicityShaky26%Nicotinic pharmacology of the class + blue cohosh tincture case ^{8,10Reference 8Green BT et al. · 2017Anagyrine desensitization of peripheral nicotinic acetylcholine receptorsView study →Reference 10Rao RB · 2002Nicotinic toxicity from tincture of blue cohosh (Caulophyllum thalictroides) used as an abortifacientView study →}

Mechanisms

The throughline is nicotinic: a receptor that normally drives fetal muscle contraction is silenced by desensitisation, and it is the resulting stillness of the fetus — not a direct chemical attack on cartilage or bone — that deforms the calf ^{5,6Reference 5Panter KE et al. · 1990Multiple congenital contractures (MCC) and cleft palate induced in goats by ingestion of piperidine alkaloid-containing plants: reduction in fetal movement as the probable causeView study →Reference 6Green BT et al. · 2010Actions of piperidine alkaloid teratogens at fetal nicotinic acetylcholine receptorsView study →}.

Pharmacokinetics

Robust pharmacokinetic data for isolated anagyrine are limited, and essentially all of it is livestock-oriented. Key points that are documented: anagyrine is maternally ingested (whole plant) and reaches the fetus, since the teratogenic effect is transplacental; it can also be excreted into milk, the basis of the proposed goat-milk human exposure ^{12Reference 12Ortega JA · 1987Anagyrine-induced red cell aplasia, vascular anomaly, and skeletal dysplasiaView study →}. Its serum concentration in grazing cattle depends on the dam’s body condition — thin animals and those in different physiological states show different serum levels of anagyrine (and the co-teratogen ammodendrine), which helps explain why not every exposed pregnancy yields an affected calf ^{15,16Reference 15Lee ST et al. · 2008The effect of body condition on serum concentrations of two teratogenic alkaloids (anagyrine and ammodendrine) from lupines (Lupinus species) that cause crooked calf diseaseView study →Reference 16Lopez-Ortiz S et al. · 2004The effect of body condition on disposition of alkaloids from silvery lupine (Lupinus argenteus Pursh) in sheepView study →}. Anagyrine has been detected in unusual matrices as an exposure record, including earwax, reflecting cumulative grazing exposure ^{17Reference 17Stonecipher CA et al. · 2024The use of earwax to determine livestock exposure to teratogenic lupineView study →}. Human ADME parameters — absorption fraction, half-life, oral bioavailability of the isolate — are not established ^{15,16Reference 15Lee ST et al. · 2008The effect of body condition on serum concentrations of two teratogenic alkaloids (anagyrine and ammodendrine) from lupines (Lupinus species) that cause crooked calf diseaseView study →Reference 16Lopez-Ortiz S et al. · 2004The effect of body condition on disposition of alkaloids from silvery lupine (Lupinus argenteus Pursh) in sheepView study →}.

Clinical Trials

There are no clinical trials of anagyrine and there will not be — it is a teratogen, not a candidate therapeutic. The human record consists of a single case report ^{12Reference 12Ortega JA · 1987Anagyrine-induced red cell aplasia, vascular anomaly, and skeletal dysplasiaView study →} and the pregnancy-harm literature of the parent herb ^{9,10Reference 9Kennelly EJ et al. · 1999In vitroDetecting potential teratogenic alkaloids from blue cohosh rhizomes using an in vitro rat embryo cultureView study →Reference 10Rao RB · 2002Nicotinic toxicity from tincture of blue cohosh (Caulophyllum thalictroides) used as an abortifacientView study →}. The substantive experimental literature is veterinary and mechanistic.

Last checked: July 2026.

Anagyrine, the Piperidine Alkaloids, and the “Marker vs. Actor” Question

The most important scientific subtlety about anagyrine — and one worth getting exactly right — is whether it is itself the direct teratogen or a reliable chemical marker for teratogenic lupine populations.

The classic view (Keeler) was straightforward: teratogenic lupines contain anagyrine, non-teratogenic ones do not, and anagyrine concentration predicts the risk of crooked calf disease ^{1Reference 1Keeler RF · 1976Lupin alkaloids from teratogenic and nonteratogenic lupinsView study →}. On that basis anagyrine has been used for decades as the alkaloid to measure when assessing whether a lupine stand is safe to graze ^{3,11Reference 3Lee ST et al. · 2007Lupine induced “crooked calf disease” in Washington and Oregon: identification of the alkaloid profiles in Lupinus sulfureus, Lupinus leucophyllus, and Lupinus sericeusView study →Reference 11Green BT et al. · 2013Plant alkaloids that cause developmental defects through the disruption of cholinergic neurotransmissionView study →}.

Later mechanistic work complicated this. The most potent fetal-movement suppressors identified are often piperidine alkaloids — such as ammodendrine and related compounds — that frequently co-occur with anagyrine in the same lupines ^{7,15Reference 7Panter KE et al. · 1999Lupines, poison-hemlock and Nicotiana spp: toxicity and teratogenicity in livestockView study →Reference 15Lee ST et al. · 2008The effect of body condition on serum concentrations of two teratogenic alkaloids (anagyrine and ammodendrine) from lupines (Lupinus species) that cause crooked calf diseaseView study →}. In these plants anagyrine and the active piperidine alkaloids travel together, so a high anagyrine reading reliably flags a dangerous plant even if part of the teratogenic punch is delivered by its companions. At the same time, receptor studies show anagyrine does act on nicotinic receptors and desensitises them, so it is not merely an inert tracer ^{6,8Reference 6Green BT et al. · 2010Actions of piperidine alkaloid teratogens at fetal nicotinic acetylcholine receptorsView study →Reference 8Green BT et al. · 2017Anagyrine desensitization of peripheral nicotinic acetylcholine receptorsView study →}.

The careful synthesis: anagyrine is both a genuine nicotinic-active alkaloid and the field’s most useful biomarker of teratogenic lupine, and the crooked-calf syndrome is best understood as the effect of a nicotinic-alkaloid mixture acting on the fetal receptor, not of one molecule in isolation ^{6,8Reference 6Green BT et al. · 2010Actions of piperidine alkaloid teratogens at fetal nicotinic acetylcholine receptorsView study →Reference 8Green BT et al. · 2017Anagyrine desensitization of peripheral nicotinic acetylcholine receptorsView study →}. This is precisely why the safety message for blue cohosh cannot be reduced to a single compound.

Isolate vs. Plant Studies

Almost all anagyrine evidence is whole-plant (lupine) exposure, not isolated-compound dosing. The teratogenicity is established by cattle and goats grazing lupine and by chemical correlation of anagyrine content with outbreaks ^{1,3,4Reference 1Keeler RF · 1976Lupin alkaloids from teratogenic and nonteratogenic lupinsView study →Reference 3Lee ST et al. · 2007Lupine induced “crooked calf disease” in Washington and Oregon: identification of the alkaloid profiles in Lupinus sulfureus, Lupinus leucophyllus, and Lupinus sericeusView study →Reference 4Keeler RF · 1989Piperidine alkaloid composition and relation to crooked calf disease-inducing potential of Lupinus formosusView study →}; the mechanism work uses alkaloid-containing plant material and, at the receptor level, isolated alkaloids to dissect the nicotinic action ^{5,6,8Reference 5Panter KE et al. · 1990Multiple congenital contractures (MCC) and cleft palate induced in goats by ingestion of piperidine alkaloid-containing plants: reduction in fetal movement as the probable causeView study →Reference 6Green BT et al. · 2010Actions of piperidine alkaloid teratogens at fetal nicotinic acetylcholine receptorsView study →Reference 8Green BT et al. · 2017Anagyrine desensitization of peripheral nicotinic acetylcholine receptorsView study →}. This matters two ways. First, it means the “teratogenic dose” is a grazing exposure, modulated by plant alkaloid content, season, and the dam’s physiology ^{15,16Reference 15Lee ST et al. · 2008The effect of body condition on serum concentrations of two teratogenic alkaloids (anagyrine and ammodendrine) from lupines (Lupinus species) that cause crooked calf diseaseView study →Reference 16Lopez-Ortiz S et al. · 2004The effect of body condition on disposition of alkaloids from silvery lupine (Lupinus argenteus Pursh) in sheepView study →} — not a clean isolate dose-response. Second, for blue cohosh, anagyrine is one alkaloid within a mixture dominated by N-methylcytisine and including baptifoline, so herb-level reproductive harm cannot be pinned on anagyrine alone ^{2,9Reference 2Rader JI · 2013Primary constituents of blue cohosh: quantification in dietary supplements and potential for toxicityView study →Reference 9Kennelly EJ et al. · 1999In vitroDetecting potential teratogenic alkaloids from blue cohosh rhizomes using an in vitro rat embryo cultureView study →}. The single human case report is likewise a whole-exposure observation (contaminated milk), not an isolate study ^{12Reference 12Ortega JA · 1987Anagyrine-induced red cell aplasia, vascular anomaly, and skeletal dysplasiaView study →}.

Its Role in Plants

In lupines and related legumes, quinolizidine alkaloids such as anagyrine are chemical defence compounds — bitter, nicotinic-active nitrogen metabolites that deter insect and vertebrate herbivores. They are synthesised from the amino acid lysine via cadaverine and a series of quinolizidine-forming steps, and they accumulate in a species-, tissue- and season-dependent pattern: anagyrine content shifts markedly with plant part and stage of growth, which is exactly why grazing risk is seasonal ^{1Reference 1Keeler RF · 1976Lupin alkaloids from teratogenic and nonteratogenic lupinsView study →}. The same bitterness that makes high-alkaloid (“bitter”) lupines toxic is what plant breeders selected against to create low-alkaloid (“sweet”) lupine varieties for food and feed ^{18Reference 18Keeler RF · 1980The total alkaloid and anagyrine contents of some bitter and sweet selections of lupin species used as foodView study →}. Anagyrine’s ecological job — repelling herbivores — is incidental to its accidental veterinary importance: cattle will graze lupine anyway, especially when other forage is scarce.

Prevalence in Nature

Anagyrine is characteristic of the legume family (Fabaceae), above all the genus Lupinus — many bitter lupine species carry it, and it is the alkaloid used to rate their teratogenic risk ^{1,3Reference 1Keeler RF · 1976Lupin alkaloids from teratogenic and nonteratogenic lupinsView study →Reference 3Lee ST et al. · 2007Lupine induced “crooked calf disease” in Washington and Oregon: identification of the alkaloid profiles in Lupinus sulfureus, Lupinus leucophyllus, and Lupinus sericeusView study →}. It is also reported from other quinolizidine-rich legumes such as Anagyris, Thermopsis and Baptisia. Its concentration in lupine is highly variable — by species, plant part (new growth, seed and pods often richest), and phenological stage — so a single species can be dangerous in one season and much less so in another ^{1Reference 1Keeler RF · 1976Lupin alkaloids from teratogenic and nonteratogenic lupinsView study →}.

Outside the lupines, its notable occurrence for this database is blue cohosh (Caulophyllum thalictroides), where it is a minor, product-dependent rhizome alkaloid measured at roughly 2–390 ppm dry weight and present in some but not all commercial supplements — unlike N-methylcytisine, which is found in essentially every analysed blue cohosh product ^{2Reference 2Rader JI · 2013Primary constituents of blue cohosh: quantification in dietary supplements and potential for toxicityView study →}. In “sweet” (low-alkaloid) food lupines bred for the human and animal food chain, anagyrine is deliberately minimised, though the adequacy of debittering is a recognised food-safety concern ^{18Reference 18Keeler RF · 1980The total alkaloid and anagyrine contents of some bitter and sweet selections of lupin species used as foodView study →}.

Discovery & Synthesis

Anagyrine was isolated from lupines and related legumes in the early twentieth century as part of the broad chemical survey of quinolizidine (“lupin”) alkaloids; the name derives from the genus Anagyris, a Mediterranean legume in which such alkaloids occur. Its lasting scientific identity, however, was fixed not by its isolation but by Richard Keeler’s lupin-alkaloid programme in the 1970s, which linked anagyrine content to the teratogenicity of lupines and made it the marker molecule of crooked calf disease ^{1Reference 1Keeler RF · 1976Lupin alkaloids from teratogenic and nonteratogenic lupinsView study →}. Structurally it is a bis-quinolizidine (α-pyridone-type) alkaloid, related to the sparteine/lupanine family and to cytisine-type nicotinic quinolizidines.

Anagyrine is obtained for research by extraction from plant material rather than by synthesis; there is no commercial manufacture, because it is a toxin of study interest, not a product. Its total synthesis is not well documented in the accessible literature, and no established industrial route exists.

Patents: not yet researched.

Toxicity & Safety

Anagyrine carries a strong toxicity flag because it is a bona-fide developmental toxin (teratogen), not because of high acute lethality. Its danger is specific and conditional: it threatens a pregnancy exposed during a defined window, far more than it threatens a non-pregnant adult at ordinary exposure.

Safety at a Glance

☠️ Toxic

• Teratogen in pregnancy — the defining risk. Established cause (as the marker alkaloid) of lupine “crooked calf disease”: skeletal contractures and cleft palate when susceptible cattle graze anagyrine-containing lupine during roughly gestational days 40–100 ^{1,4,5Reference 1Keeler RF · 1976Lupin alkaloids from teratogenic and nonteratogenic lupinsView study →Reference 4Keeler RF · 1989Piperidine alkaloid composition and relation to crooked calf disease-inducing potential of Lupinus formosusView study →Reference 5Panter KE et al. · 1990Multiple congenital contractures (MCC) and cleft palate induced in goats by ingestion of piperidine alkaloid-containing plants: reduction in fetal movement as the probable causeView study →}.
• Blue cohosh in pregnancy is the real-world exposure. Present in some blue cohosh products (~2–390 ppm); the herb has documented prenatal harm and an abortifacient history, driven by its nicotinic quinolizidine alkaloids as a group ^{2,9,10Reference 2Rader JI · 2013Primary constituents of blue cohosh: quantification in dietary supplements and potential for toxicityView study →Reference 9Kennelly EJ et al. · 1999In vitroDetecting potential teratogenic alkaloids from blue cohosh rhizomes using an in vitro rat embryo cultureView study →Reference 10Rao RB · 2002Nicotinic toxicity from tincture of blue cohosh (Caulophyllum thalictroides) used as an abortifacientView study →}.
• Human evidence is a single case report. An infant’s skeletal dysplasia was attributed to anagyrine passing into goat’s milk — notable but unreplicated and not proof of causation ^{12Reference 12Ortega JA · 1987Anagyrine-induced red cell aplasia, vascular anomaly, and skeletal dysplasiaView study →}.
• Nicotinic and CYP-inhibitory. Belongs to the class producing the nicotinic toxidrome at poisoning-level exposure and inhibits cytochrome-P450 enzymes in vitro (drug-interaction flag) ^{8,10,13Reference 8Green BT et al. · 2017Anagyrine desensitization of peripheral nicotinic acetylcholine receptorsView study →Reference 10Rao RB · 2002Nicotinic toxicity from tincture of blue cohosh (Caulophyllum thalictroides) used as an abortifacientView study →Reference 13Madgula VL et al. · 2009In vitroAlkaloids and saponins as cytochrome P450 inhibitors from blue cohosh (Caulophyllum thalictroides) in an in vitro assayView study →}.
• Not a hazard at trace dietary levels in properly debittered “sweet” lupine food. Risk is tied to bitter, high-alkaloid material and to concentrated herbal products, not to well-processed lupine foods ^{18Reference 18Keeler RF · 1980The total alkaloid and anagyrine contents of some bitter and sweet selections of lupin species used as foodView study →}.

Full Safety & Interactions Detail

Teratogenicity (the central concern). Anagyrine is the alkaloid by which lupine teratogenicity is measured; whole-plant exposure during the susceptible gestational window causes congenital contractures and cleft palate in calves through fetal-movement suppression at nicotinic receptors ^{1,4,5,6Reference 1Keeler RF · 1976Lupin alkaloids from teratogenic and nonteratogenic lupinsView study →Reference 4Keeler RF · 1989Piperidine alkaloid composition and relation to crooked calf disease-inducing potential of Lupinus formosusView study →Reference 5Panter KE et al. · 1990Multiple congenital contractures (MCC) and cleft palate induced in goats by ingestion of piperidine alkaloid-containing plants: reduction in fetal movement as the probable causeView study →Reference 6Green BT et al. · 2010Actions of piperidine alkaloid teratogens at fetal nicotinic acetylcholine receptorsView study →}. Whether the effect is delivered by anagyrine itself or by co-occurring piperidine alkaloids it reliably accompanies, the practical rule is the same: anagyrine-containing plant material is a reproductive hazard, and any exposure during pregnancy should be avoided ^{6,8Reference 6Green BT et al. · 2010Actions of piperidine alkaloid teratogens at fetal nicotinic acetylcholine receptorsView study →Reference 8Green BT et al. · 2017Anagyrine desensitization of peripheral nicotinic acetylcholine receptorsView study →}.

Blue cohosh in pregnancy. The herb’s traditional use to induce labour and its historical use as an abortifacient sit on top of documented cases of serious perinatal harm, and in-vitro embryo screening flags its alkaloids — including anagyrine — as potential teratogens ^{9Reference 9Kennelly EJ et al. · 1999In vitroDetecting potential teratogenic alkaloids from blue cohosh rhizomes using an in vitro rat embryo cultureView study →}. A case of maternal nicotinic toxicity followed blue cohosh tincture taken as an abortifacient ^{10Reference 10Rao RB · 2002Nicotinic toxicity from tincture of blue cohosh (Caulophyllum thalictroides) used as an abortifacientView study →}. Anagyrine is one of several nicotinic quinolizidines responsible (N-methylcytisine being the most abundant), so the caution attaches to the whole herb in pregnancy, not to a single molecule ^{2,9Reference 2Rader JI · 2013Primary constituents of blue cohosh: quantification in dietary supplements and potential for toxicityView study →Reference 9Kennelly EJ et al. · 1999In vitroDetecting potential teratogenic alkaloids from blue cohosh rhizomes using an in vitro rat embryo cultureView study →}.

The human goat-milk case. A single report attributes an infant’s skeletal dysplasia, vascular anomaly and red-cell aplasia to maternal ingestion of goat’s milk from lupine-grazing goats — a proposed transfer of anagyrine into milk ^{12Reference 12Ortega JA · 1987Anagyrine-induced red cell aplasia, vascular anomaly, and skeletal dysplasiaView study →}. It is the strongest specific human signal for anagyrine and simultaneously the weakest kind of evidence (n = 1, uncontrolled, unreplicated); it warrants caution, not certainty.

Drug interactions. Blue cohosh alkaloids including anagyrine inhibit cytochrome-P450 enzymes in vitro (isoforms reported for the herb include CYP2C19, CYP3A4, CYP2D6 and CYP1A2), a theoretical interaction risk for co-administered CYP-metabolised drugs; no human interaction study exists for the isolate ^{13Reference 13Madgula VL et al. · 2009In vitroAlkaloids and saponins as cytochrome P450 inhibitors from blue cohosh (Caulophyllum thalictroides) in an in vitro assayView study →}.

Acute toxicity. As a nicotinic alkaloid, anagyrine can contribute to the nicotinic toxidrome at poisoning-level exposure, though within blue cohosh the acute nicotinic effect is generally attributed more to N-methylcytisine ^{8,10Reference 8Green BT et al. · 2017Anagyrine desensitization of peripheral nicotinic acetylcholine receptorsView study →Reference 10Rao RB · 2002Nicotinic toxicity from tincture of blue cohosh (Caulophyllum thalictroides) used as an abortifacientView study →}.

Pregnancy and lactation decisions for blue cohosh belong on the herb monograph, where intake is decided; the finding stated here is that anagyrine is a documented developmental toxin and that anagyrine-containing material should be avoided in pregnancy.

Dosage

There is no therapeutic dose for anagyrine — it is a plant toxin with no medicinal use. The only meaningful “dose” figures are exposure and research figures, presented to describe risk:

These are exposure and research figures used to characterise a hazard. They are not a recommendation, and anagyrine has no safe intended dose.

References

1. Keeler RF, Cronin EH (1976). Lupin alkaloids from teratogenic and nonteratogenic lupins. IV. Concentration of total alkaloids, individual major alkaloids, and the teratogen anagyrine as a function of plant part and stage of growth and their relationship to crooked calf disease. Journal of Toxicology and Environmental Health. https://pubmed.ncbi.nlm.nih.gov/966319/
2. Rader JI, Pawar RS (2013). Primary constituents of blue cohosh: quantification in dietary supplements and potential for toxicity. Analytical and Bioanalytical Chemistry. https://pubmed.ncbi.nlm.nih.gov/23420136/
3. Lee ST, Cook D, Panter KE, et al. (2007). Lupine induced “crooked calf disease” in Washington and Oregon: identification of the alkaloid profiles in Lupinus sulfureus, Lupinus leucophyllus, and Lupinus sericeus. Journal of Agricultural and Food Chemistry. https://pubmed.ncbi.nlm.nih.gov/18038992/
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5. Panter KE, Bunch TD, Keeler RF, et al. (1990). Multiple congenital contractures (MCC) and cleft palate induced in goats by ingestion of piperidine alkaloid-containing plants: reduction in fetal movement as the probable cause. Journal of Toxicology. Clinical Toxicology. https://pubmed.ncbi.nlm.nih.gov/2381024/
6. Green BT, Lee ST, Panter KE, et al. (2010). Actions of piperidine alkaloid teratogens at fetal nicotinic acetylcholine receptors. Neurotoxicology and Teratology. https://pubmed.ncbi.nlm.nih.gov/20116429/
7. Panter KE, James LF, Gardner DR (1999). Lupines, poison-hemlock and Nicotiana spp: toxicity and teratogenicity in livestock. Journal of Natural Toxins. https://pubmed.ncbi.nlm.nih.gov/10091132/
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11. Green BT, Lee ST, Panter KE, Welch KD (2013). Plant alkaloids that cause developmental defects through the disruption of cholinergic neurotransmission. Birth Defects Research Part C: Embryo Today. https://pubmed.ncbi.nlm.nih.gov/24339035/
12. Ortega JA, Lazerson J (1987). Anagyrine-induced red cell aplasia, vascular anomaly, and skeletal dysplasia. The Journal of Pediatrics. https://pubmed.ncbi.nlm.nih.gov/3110390/
13. Madgula VL, Ali Z, Smillie T, et al. (2009). Alkaloids and saponins as cytochrome P450 inhibitors from blue cohosh (Caulophyllum thalictroides) in an in vitro assay. Planta Medica. https://pubmed.ncbi.nlm.nih.gov/19137500/
14. Green BT, Panter KE, Lee ST, et al. (2015). Differences between Angus and Holstein cattle in the Lupinus leucophyllus induced inhibition of fetal activity. Toxicon. https://pubmed.ncbi.nlm.nih.gov/26341422/
15. Lee ST, Panter KE, Gardner DR, et al. (2008). The effect of body condition on serum concentrations of two teratogenic alkaloids (anagyrine and ammodendrine) from lupines (Lupinus species) that cause crooked calf disease. Journal of Animal Science. https://pubmed.ncbi.nlm.nih.gov/18539842/
16. Lopez-Ortiz S, Panter KE, Pfister JA, Launchbaugh KL (2004). The effect of body condition on disposition of alkaloids from silvery lupine (Lupinus argenteus Pursh) in sheep. Journal of Animal Science. https://pubmed.ncbi.nlm.nih.gov/15446497/
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