Cycleanine

Cycleanine at a Glance

Cycleanine is a bisbenzylisoquinoline (bisBIQ) alkaloid of the Menispermaceae — the moonseed family that also gives us tetrandrine, curine and the curare vines. Structurally it is the head-to-tail member of the family: where berbamine, tetrandrine and oxyacanthine are joined head-to-head, cycleanine’s two benzylisoquinoline halves are linked by two diaryl-ether bridges into a symmetrical macrocycle ^{12,26Reference 12Seow WK et al. · 1993Inhibitory effects of bisbenzylisoquinolines on synthesis of the inflammatory cytokines interleukin-1 and tumour necrosis factor-alphaView study →Reference 26Lai S et al. · 1993Lai S, Zhao TF, Wang XK, Shizuri Y, Yamamura S (1993). [Two novel bisbenzylisoquinoline alkaloids from Cyclea sutchuenensis Gagnep]. Yao Xue Xue Bao. https://pubmed.ncbi.nlm.nih.gov/8285068/View study →}. That difference in architecture is not cosmetic — it tracks real differences in activity, including a complete absence of the histamine-release inhibition that the head-to-head alkaloids show ^{27Reference 27Nakamura K et al. · 1992Histamine release inhibition activity of bisbenzylisoquinoline alkaloidsView study →}.

In the plants it matters most, it is not a trace constituent. It is roughly 85% of the identified bisBIQ alkaloids of Albertisia villosa root bark ^{7Reference 7Lohombo-Ekomba ML et al. · 2004Antibacterial, antifungal, antiplasmodial, and cytotoxic activities of Albertisia villosaView study →}, abundant enough in Triclisia subcordata root to be isolated at working scale ^{3Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →}, and a main stem and rhizome alkaloid of Cissampelos capensis ^{21Reference 21de Wet H et al. · 2011Alkaloidal variation in Cissampelos capensis (Menispermaceae)View study →}. In abuta (Cissampelos pareira) — the database herb that carries it — it is one alkaloid among many and has never been quantified ^{20Reference 20Bala M et al. · 2019Bioactive isoquinoline alkaloids from Cissampelos pareiraView study →}.

Its modern literature is narrow but real, and it comes from two places: West African and UK groups working on antiplasmodial and ovarian-cancer activity of the purified isolate ^{1,2,3Reference 1Uche FI et al. · 2016Cytotoxicity effects and apoptosis induction by bisbenzylisoquinoline alkaloids from Triclisia subcordataView study →Reference 2Uche FI et al. · 2018Synthesis of (aminoalkyl)cycleanine analogues: cytotoxicity, cellular uptake, and apoptosis induction in ovarian cancer cellsView study →Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →}, and older Japanese and Cuban pharmacology on cytokine suppression and calcium-channel antagonism ^{12,13,17Reference 12Seow WK et al. · 1993Inhibitory effects of bisbenzylisoquinolines on synthesis of the inflammatory cytokines interleukin-1 and tumour necrosis factor-alphaView study →Reference 13Kondo Y et al. · 1993Inhibitory effect of bisbenzylisoquinoline alkaloids on nitric oxide production in activated macrophagesView study →Reference 17Martínez JA et al. · 1998Calcium antagonist properties of the bisbenzylisoquinoline alkaloid cycleanineView study →}. There are no human trials of the molecule itself.

Not a Curare Alkaloid

Cycleanine occurs in the same family — and in at least one of the same plants — as the arrow-poison alkaloids, so the assumption is easy to make and wrong. d-Tubocurarine’s neuromuscular-blocking pharmacology has not been demonstrated for cycleanine, and the one head-to-head comparison in the literature separates them cleanly: in an alveolar-macrophage assay testing bisBIQ alkaloids side by side, cycleanine behaved like tetrandrine and berbamine while tubocurarine was effectively inert, with the authors noting that the class spans a wide range of potencies in which tubocurarine sits at the bottom ^{16Reference 16Ma JY et al. · 1992Inhibition of respiratory burst activity in alveolar macrophages by bisbenzylisoquinoline alkaloids: characterization of drug-cell interactionView study →}.

There is a genuine ganglion- and neuromuscular-blocking record in this compound’s family tree — but it belongs to a semi-synthetic quaternary derivative, not the natural free base. See the next section, and read the distinction as load-bearing: quaternising both nitrogens is exactly the chemical change that turns a lipophilic tertiary alkaloid into a curare-like cholinergic blocker.

Cycleanine Dimethobromide, The Quaternary Derivative

Between 1980 and 1985 a Chinese pharmacology group published a compact series on cycleanine dimethobromide (also written dimethyl cycleanine bromide), the bis-quaternary methylated salt of cycleanine, developed as an agent for deliberate (“controlled”) hypotension during surgery. The series covers its hypotensive effect ^{37Reference 37Sun Z et al. · 1980Sun Z, Yang XY, Dai ZL, Jin GZ, Zhang ZD (1980). [Hypotensive effect of dimethyl cycleanine bromide]. Zhongguo Yao Li Xue Bao. https://pubmed.ncbi.nlm.nih.gov/6175170/View study →}, its hypotensive mechanism ^{28Reference 28Jin GZ et al. · 1984Controlled hypotensive effect of cycleanine dimethobromideView study →}, its haemodynamics in anaesthetised dogs ^{31Reference 31Chen WZ et al. · 1980Chen WZ, Dong YL, Ding GS (1980). [Effects of dimethyl cycleanine bromide on cardiac hemodynamics of anesthetized dogs]. Zhongguo Yao Li Xue Bao. https://pubmed.ncbi.nlm.nih.gov/6461170/View study →}, its effect on the cardiac conduction system ^{32Reference 32Shen JF et al. · 1985Shen JF, Xi YQ, Cao ZE, Zhang GL, Fu CZ, Gao QL (1985). [Effects of cycleanine dimethobromide on heart conduction system]. Zhongguo Yao Li Xue Bao. https://pubmed.ncbi.nlm.nih.gov/2945367/View study →}, the disposition of a ¹⁴C-labelled analogue in rats ^{33Reference 33Zhang ZD et al. · 1983AnimalZhang ZD, Jin GZ, Sun Z, Chen XY, Zhang X (1983). [Disposition of 14C-cycleanine dimethoiodide in rats]. Zhongguo Yao Li Xue Bao. https://pubmed.ncbi.nlm.nih.gov/6230867/View study →} — and, directly on the point above, its blocking effects on autonomic ganglia and the neuromuscular junction ^{29Reference 29Lu YQ et al. · 1981Lu YQ, Xu DZ, Mao YK, Wei X, Yang ZC (1981). [Blocking effects of cycleanine dimethobromide on nerve ganglia and neuromuscular junctions]. Zhongguo Yao Li Xue Bao. https://pubmed.ncbi.nlm.nih.gov/6462019/View study →}. A 1982 Japanese anaesthesia report describes clinical use for controlled hypotension in people ^{30Reference 30Jin XY et al. · 1982Jin XY, Sun DJ, Sheng JN, Chu ZB (1982). [Clinical use of cycleanine for controlled hypotension during anesthesia]. Masui. https://pubmed.ncbi.nlm.nih.gov/7154227/View study →}, and a 1984 Chinese Medical Journal paper reports the controlled-hypotensive effect in English ^{28Reference 28Jin GZ et al. · 1984Controlled hypotensive effect of cycleanine dimethobromideView study →}.

Two honest caveats. First, almost all of these are titles without indexed abstracts — the ganglion/neuromuscular paper ^{29Reference 29Lu YQ et al. · 1981Lu YQ, Xu DZ, Mao YK, Wei X, Yang ZC (1981). [Blocking effects of cycleanine dimethobromide on nerve ganglia and neuromuscular junctions]. Zhongguo Yao Li Xue Bao. https://pubmed.ncbi.nlm.nih.gov/6462019/View study →}, the conduction-system paper ^{32Reference 32Shen JF et al. · 1985Shen JF, Xi YQ, Cao ZE, Zhang GL, Fu CZ, Gao QL (1985). [Effects of cycleanine dimethobromide on heart conduction system]. Zhongguo Yao Li Xue Bao. https://pubmed.ncbi.nlm.nih.gov/2945367/View study →} and the radiolabel disposition study ^{33Reference 33Zhang ZD et al. · 1983AnimalZhang ZD, Jin GZ, Sun Z, Chen XY, Zhang X (1983). [Disposition of 14C-cycleanine dimethoiodide in rats]. Zhongguo Yao Li Xue Bao. https://pubmed.ncbi.nlm.nih.gov/6230867/View study →} are indexed in Chinese with no abstract, so what can be stated is what the titles state, not the numbers behind them. Second, and more importantly, this is a different molecule from the cycleanine on the rest. Quaternary ammonium compounds are poorly absorbed orally, distribute differently and act at nicotinic receptors in a way tertiary bases generally do not. Nothing in the antiplasmodial, anticancer or anti-inflammatory sections below was measured on the dimethobromide, and nothing in this section should be read onto the free base.

What It's Used For

The evidence base splits into a well-defined modern strand (antiplasmodial, ovarian-cancer cytotoxicity) and an older, more scattered one (cytokine suppression, calcium antagonism, multidrug-resistance reversal). Almost all of it is on the purified isolate, which is this molecule’s main methodological strength — and all of it stops short of humans.

The strongest strand is antiplasmodial, and it reaches in vivo.Oral cycleanine at 50 mg/kg/day suppressed Plasmodium berghei parasitaemia by 86.5% in mice, close to chloroquine at 5 mg/kg, with prophylactic and curative activity too ^{3Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →}. In vitro potency against P. falciparum ranges from 0.07 µM to 17.7 µM depending on strain and assay — a spread the source paper itself flags as methodological ^{3,5,6Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →Reference 5Angerhofer CK et al. · 1999Antiplasmodial and cytotoxic activity of natural bisbenzylisoquinoline alkaloidsView study →Reference 6Fadaeinasab M et al. · 2015Anti-malarial activity of isoquinoline alkaloids from the stem bark of Actinodaphne macrophyllaView study →}.

The ovarian-cancer work is real but its selectivity is thin.Cycleanine kills four ovarian cancer lines at 7–14 µM through caspase-3/7 activation and PARP cleavage — but the IC₅₀ on normal human ovarian surface epithelium is 35 µM, a selectivity index of only about 2–5 ^{1,3Reference 1Uche FI et al. · 2016Cytotoxicity effects and apoptosis induction by bisbenzylisoquinoline alkaloids from Triclisia subcordataView study →Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →}. A cytotoxicity screen at that ratio is a starting point, not a cancer claim.

The honest headline:no human has ever been given isolated cycleanine in a published study. It is genuinely cardioactive (a sub-nanomolar vascular calcium antagonist ^{17Reference 17Martínez JA et al. · 1998Calcium antagonist properties of the bisbenzylisoquinoline alkaloid cycleanineView study →}) and genuinely immunosuppressive (TNF-α IC₅₀ 4.6 µM ^{12Reference 12Seow WK et al. · 1993Inhibitory effects of bisbenzylisoquinolines on synthesis of the inflammatory cytokines interleukin-1 and tumour necrosis factor-alphaView study →}) — and its neuromuscular reputation belongs to a quaternary derivative, not to it.

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. There is no human evidence for the isolate anywhere here, so every score is capped by that.

The best-developed application, and the only one where cycleanine has been given to a whole animal by mouth for the target indication. Isolate, throughout. In a 53-alkaloid bisBIQ panel, (−)-cycleanine was among the most selective antiplasmodial alkaloids, with more than 100-fold greater toxicity toward P. falciparum than toward cultured mammalian cells ^{5Reference 5Angerhofer CK et al. · 1999Antiplasmodial and cytotoxic activity of natural bisbenzylisoquinoline alkaloidsView study →}.

The underlying figures — IC₅₀ 0.07 µM against the chloroquine-sensitive D6 clone and 0.25 µM against chloroquine-resistant W2, against a KB-cell CC₅₀ above 33.7 µM (SI > 133) — were carried forward into the modern work ^{3Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →}.

Cycleanine isolated from Actinodaphne macrophylla stem bark gave IC₅₀ 0.08 µM against P. falciparum 3D7 ^{6Reference 6Fadaeinasab M et al. · 2015Anti-malarial activity of isoquinoline alkaloids from the stem bark of Actinodaphne macrophyllaView study →}.

A Keele/Nigeria group then measured 17.7 µM against the chloroquine-resistant Dd2 strain — two orders of magnitude weaker — and attributed the discrepancy to different assay methods and parasite clones rather than to the compound ^{3Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →}.

In vivo, oral cycleanine in P. berghei-infected mice suppressed parasitaemia 44.7% at 25 mg/kg and 86.5% at 50 mg/kg (chloroquine 5 mg/kg: 94.0%), raised mean survival time from 12.5 to 28.2 days, and gave 59.0% prophylactic suppression against pyrimethamine’s 76.2% ^{3Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →}.

At the plant level, cycleanine’s abundance in Albertisia villosa root bark is credited with the antiplasmodial activity of that traditional Congolese antimalarial drug ^{7Reference 7Lohombo-Ekomba ML et al. · 2004Antibacterial, antifungal, antiplasmodial, and cytotoxic activities of Albertisia villosaView study →}.

Gap: the two-orders-of-magnitude in-vitro spread is unresolved, and against Dd2 the selectivity index over normal human ovarian epithelium collapses to 2.0 ^{3Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →} — so the “selective antiplasmodial” reading depends heavily on which pair of numbers you use. No human antimalarial data of any kind, and the semi-synthetic analogues are up to 25-fold more potent than the parent, which is where the authors point development ^{3Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →}.

Cycleanine’s second-largest literature, and again isolate work — from the same Keele group, using cycleanine purified from Triclisia subcordata root. The crude alkaloid fraction was the most active extract on Ovcar-8 and A2780 (IC₅₀ < 2.4 µg/mL); purified cycleanine gave IC₅₀ 7–14 µM across Ovcar-8, A2780, Ovcar-4 and Igrov-1, against 35 ± 1 µM on normal human ovarian surface epithelial cells ^{1Reference 1Uche FI et al. · 2016Cytotoxicity effects and apoptosis induction by bisbenzylisoquinoline alkaloids from Triclisia subcordataView study →}.

Death was apoptotic: caspase-3/7 activation, cleavage of poly(ADP-ribose) polymerase, an increased subG1 fraction and a higher percentage of apoptotic cells by flow cytometry ^{1Reference 1Uche FI et al. · 2016Cytotoxicity effects and apoptosis induction by bisbenzylisoquinoline alkaloids from Triclisia subcordataView study →}.

Two (aminoalkyl)cycleanine analogues, made in two steps from the natural product, were more potent than cycleanine in three ovarian lines, with cellular uptake confirmed by click chemistry on an alkynyl analogue ^{2Reference 2Uche FI et al. · 2018Synthesis of (aminoalkyl)cycleanine analogues: cytotoxicity, cellular uptake, and apoptosis induction in ovarian cancer cellsView study →}.

A later docking and molecular-dynamics study proposed that cycleanine forms a stable complex with PARP1, i.e. that it may be a PARP1 inhibitor rather than only a caspase activator ^{4Reference 4Nwaefulu ON et al. · 2022The impact of cycleanine in cancer research: a computational studyView study →} — computational only, no enzyme assay. Separately, in Cissampelos pareira, cycleanine was active against KB cells, though hayatinine was the more active isolate there ^{20Reference 20Bala M et al. · 2019Bioactive isoquinoline alkaloids from Cissampelos pareiraView study →}.

Gap: the selectivity index over normal ovarian epithelium is roughly 2–5, which is a screening-hit ratio, not a therapeutic window; there is no xenograft or any other in-vivo tumour model for cycleanine; and the PARP1 mechanism is docking, never tested against the enzyme ^{1,4Reference 1Uche FI et al. · 2016Cytotoxicity effects and apoptosis induction by bisbenzylisoquinoline alkaloids from Triclisia subcordataView study →Reference 4Nwaefulu ON et al. · 2022The impact of cycleanine in cancer research: a computational studyView study →}.

The oldest coherent strand, mostly Japanese, and the one with the cleanest human-cell numbers. Against human monocytes/macrophages, cycleanine inhibited synthesis of TNF-α with an IC₅₀ of 4.6 µM and IL-1β with an IC₅₀ of 25.0 µM — competitive with the head-to-head alkaloids on TNF-α, notably weaker on IL-1β ^{12Reference 12Seow WK et al. · 1993Inhibitory effects of bisbenzylisoquinolines on synthesis of the inflammatory cytokines interleukin-1 and tumour necrosis factor-alphaView study →}.

It suppressed nitric oxide production by LPS-stimulated murine peritoneal macrophages at 5 µg/mL, slightly more effectively than tetrandrine, with suppression persisting at least 48 hours ^{13Reference 13Kondo Y et al. · 1993Inhibitory effect of bisbenzylisoquinoline alkaloids on nitric oxide production in activated macrophagesView study →}, and it inhibited the alveolar-macrophage respiratory burst at roughly berbamine’s potency ^{16Reference 16Ma JY et al. · 1992Inhibition of respiratory burst activity in alveolar macrophages by bisbenzylisoquinoline alkaloids: characterization of drug-cell interactionView study →}.

In vivo, cycleanine at 10 mg/kg/day for three days before endotoxin challenge strongly suppressed serum ALT and AST and reduced the TNF peak in BCG-primed, LPS-challenged mice ^{14Reference 14Kondo Y et al. · 1993AnimalSuppression of lipopolysaccharide-induced fulminant hepatitis and tumor necrosis factor production by bisbenzylisoquinoline alkaloids in bacillus Calmette-Guerin-treated miceView study →}, and seven daily doses significantly improved survival in the same lethal model ^{15Reference 15Kondo Y et al. · 1990AnimalInhibitory effect of bisbenzylisoquinoline alkaloids on the quick death of mice treated with BCG/LPSView study →}.

A clear negative: unlike the head-to-head bisBIQs, cycleanine had no histamine-release-inhibiting effect at all, which the authors attributed to its head-to-tail structure ^{27Reference 27Nakamura K et al. · 1992Histamine release inhibition activity of bisbenzylisoquinoline alkaloidsView study →}.

Gap: every result is a cell assay or a rodent endotoxin model — no arthritis, colitis, or any disease-relevant in-vivo inflammation model, and no human data. The same activity is the safety signal: a molecule that suppresses TNF-α at 4.6 µM in human monocytes is an immunosuppressant, not just an anti-inflammatory ^{12,14Reference 12Seow WK et al. · 1993Inhibitory effects of bisbenzylisoquinolines on synthesis of the inflammatory cytokines interleukin-1 and tumour necrosis factor-alphaView study →Reference 14Kondo Y et al. · 1993AnimalSuppression of lipopolysaccharide-induced fulminant hepatitis and tumor necrosis factor production by bisbenzylisoquinoline alkaloids in bacillus Calmette-Guerin-treated miceView study →}.

The pharmacology that most defines the chemotype, and the one place cycleanine is unusually potent. Cycleanine extracted from Stephania glabra bulbs inhibited KCl-induced contraction of rabbit aortic rings with an IC₅₀ of 0.8 nM — roughly nine-fold more potent than nifedipine in the same preparation — while having only minor effects on noradrenaline-induced contraction; it depressed rat ventricular contraction far more weakly (IC₅₀ 3 µM vs nifedipine’s 0.03 µM), shortened action-potential duration, and blocked L-type calcium current in single ventricular myocytes in a voltage- and frequency-dependent way. The authors’ conclusion: a potent, vascular-selective calcium antagonist ^{17Reference 17Martínez JA et al. · 1998Calcium antagonist properties of the bisbenzylisoquinoline alkaloid cycleanineView study →}.

Separately, cycleanine is the most potent Na⁺,K⁺-ATPase inhibitor among the Stephania cepharantha bisBIQ alkaloids (IC₅₀ 6.2 × 10⁻⁴ M), inhibiting non-competitively with respect to ATP by a mechanism distinct from ouabain’s, with only slight effects on Mg²⁺-, H⁺- and Ca²⁺-ATPases ^{18Reference 18Satoh K et al. · 2003Inhibition of Na(+),K(+)-ATPase by the extract of Stephania cephararantha HAYATA and bisbenzylisoquinoline alkaloid cycleanine, a major constituentView study →}.

The human-facing end of this story is the quaternary derivative discussed above, used to produce controlled hypotension during anaesthesia ^{28,30Reference 28Jin GZ et al. · 1984Controlled hypotensive effect of cycleanine dimethobromideView study →Reference 30Jin XY et al. · 1982Jin XY, Sun DJ, Sheng JN, Chu ZB (1982). [Clinical use of cycleanine for controlled hypotension during anesthesia]. Masui. https://pubmed.ncbi.nlm.nih.gov/7154227/View study →}.

Gap: isolated-tissue and single-cell electrophysiology, in rabbit and rat, from one 1998 paper — no blood-pressure measurement in a conscious animal for the free base, and the Na⁺,K⁺-ATPase IC₅₀ of ~620 µM is far above any concentration the other activities occur at, so its physiological relevance is unestablished ^{17,18Reference 17Martínez JA et al. · 1998Calcium antagonist properties of the bisbenzylisoquinoline alkaloid cycleanineView study →Reference 18Satoh K et al. · 2003Inhibition of Na(+),K(+)-ATPase by the extract of Stephania cephararantha HAYATA and bisbenzylisoquinoline alkaloid cycleanine, a major constituentView study →}.

Mechanisms

Target / pathway	Effect	Relevant to
L-type voltage-gated Ca²⁺ current (vascular ≫ cardiac)	voltage- and frequency-dependent block; KCl-contraction IC₅₀ 0.8 nM in rabbit aorta	vasodilation; the class-defining action
Na⁺,K⁺-ATPase	non-competitive inhibition (IC₅₀ ~6.2 × 10⁻⁴ M), mechanism distinct from ouabain	cellular ion handling (relevance unclear at that concentration)
Caspase-3/7 → PARP cleavage, subG1 accumulation	apoptosis in ovarian cancer lines	anticancer
PARP1 (in silico only)	stable docked complex; predicted inhibitor	anticancer — computationalnever assayed
TNF-α and IL-1β synthesis (human monocytes)	inhibition, IC₅₀ 4.6 µM and 25.0 µM	anti-inflammatory / immunosuppression
Inducible NO production (LPS-stimulated macrophages)	suppression at 5 µg/mL, persisting ≥48 h	anti-inflammatory
Alveolar-macrophage respiratory burst	inhibition (≈ berbamine; ≫ tubocurarine)	anti-inflammatory
Trypanothione reductase	mixed-type inhibition (characterised for the class)	antitrypanosomal
Drug efflux — intracellular doxorubicin accumulation	reversal of acquired MDR, more active than verapamil	chemosensitisation; interaction risk
Hsp90α (middle domain)	weak binder, Kd 159 µM — the weakest of four biscoclaurines tested	probably not a real mechanism
Histamine release	no effect	not an antiallergic — the head-to-tail structure appears to cost this activity
Dopamine receptors / apomorphine-induced rotation	weakest of the tetrahydroisoquinolines tested	essentially a negative result
Autonomic ganglia + neuromuscular junction	blockade — reported for cycleanine dimethobromide, the quaternary derivative, not the free base	controlled hypotension in anaesthesia

The bottom four rows are on the page deliberately. Cycleanine’s negatives — no histamine-release inhibition ^{27Reference 27Nakamura K et al. · 1992Histamine release inhibition activity of bisbenzylisoquinoline alkaloidsView study →}, the weakest antidopaminergic potency of the tetrahydroisoquinolines tested against apomorphine-induced rotation ^{40Reference 40Watanabe H et al. · 1985Antidopaminergic effects of bisbenzyl and benzyl tetrahydroisoquinoline alkaloidsView study →}, the weakest Hsp90α binding of four biscoclaurine alkaloids compared head to head (Kd 159 µM against cepharanthine’s 5.3 µM) ^{38Reference 38Haginaka J et al. · 2013Interaction of cepharanthine with immobilized heat shock protein 90α (Hsp90α) and screening of Hsp90α inhibitorsView study →}, and a neuromuscular record that belongs to a different molecule ^{29Reference 29Lu YQ et al. · 1981Lu YQ, Xu DZ, Mao YK, Wei X, Yang ZC (1981). [Blocking effects of cycleanine dimethobromide on nerve ganglia and neuromuscular junctions]. Zhongguo Yao Li Xue Bao. https://pubmed.ncbi.nlm.nih.gov/6462019/View study →} — are as informative as its positives, and they are where class-level assumptions about bisBIQ alkaloids go wrong.

Pharmacokinetics

There is no human pharmacokinetic data, no oral bioavailability figure, no half-life and no volume of distribution for cycleanine in any species. What exists is a metabolite map: after intragastric administration to rats, HPLC-electrospray-tandem MS detected twelve novel metabolites, with hydroxylation, dehydrogenation and demethylation as the operating pathways ^{3Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →}. That the compound is orally active in mice across suppressive, prophylactic and curative malaria models ^{3Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →} and in T. cruzi-infected mice at 2 mg/kg ^{10Reference 10Fournet A et al. · 1997AnimalThe effect of bisbenzylisoquinoline alkaloids on Trypanosoma cruzi infections in miceView study →} establishes that meaningful oral exposure is achievable, but no number attaches to it. As a large dimeric bisBIQ it inherits the class profile of poor aqueous solubility and low, variable oral bioavailability documented across the family ^{35Reference 35Zhang H et al. · 2021Thirteen bisbenzylisoquinoline alkaloids in five Chinese medicinal plants: botany, traditional uses, phytochemistry, pharmacokinetic and toxicity studiesView study →}, and the medicinal-chemistry work on cycleanine has been explicitly aimed at that limitation — the dimethylamino analogue was designed partly to raise water solubility ^{3Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →}. Separately, the disposition of ¹⁴C-labelled cycleanine dimethoiodide in rats was studied in 1983 ^{33Reference 33Zhang ZD et al. · 1983AnimalZhang ZD, Jin GZ, Sun Z, Chen XY, Zhang X (1983). [Disposition of 14C-cycleanine dimethoiodide in rats]. Zhongguo Yao Li Xue Bao. https://pubmed.ncbi.nlm.nih.gov/6230867/View study →}, but that is the quaternary derivative and its handling should not be assumed to reflect the free base.

Clinical Trials

None for isolated cycleanine. No completed, planned or terminated trial of the free base exists in any indication. The only human exposure documented anywhere in this molecule’s literature is legacy anaesthesia practice with the quaternary derivative — cycleanine dimethobromide used to induce controlled hypotension during surgery in 1980s China and Japan ^{28,30Reference 28Jin GZ et al. · 1984Controlled hypotensive effect of cycleanine dimethobromideView study →Reference 30Jin XY et al. · 1982Jin XY, Sun DJ, Sheng JN, Chu ZB (1982). [Clinical use of cycleanine for controlled hypotension during anesthesia]. Masui. https://pubmed.ncbi.nlm.nih.gov/7154227/View study →} — which is 1980s clinical/regulatory practice, not trial-grade evidence, and not this molecule.

Completed	Planned	Terminated	Preclinical
None for the isolate (quaternary-derivative anaesthesia use only, non-RCT) ^{28,30Reference 28Jin GZ et al. · 1984Controlled hypotensive effect of cycleanine dimethobromideView study →Reference 30Jin XY et al. · 1982Jin XY, Sun DJ, Sheng JN, Chu ZB (1982). [Clinical use of cycleanine for controlled hypotension during anesthesia]. Masui. https://pubmed.ncbi.nlm.nih.gov/7154227/View study →}	—	—	Antiplasmodial(in vitro + three murine models), ovarian-cancer cytotoxicity, antitrypanosomal (in vitro + murine), cytokine/NO suppression, cardiovascular ^{1,2,3,9,10,12,13,14,17Reference 1Uche FI et al. · 2016Cytotoxicity effects and apoptosis induction by bisbenzylisoquinoline alkaloids from Triclisia subcordataView study →Reference 2Uche FI et al. · 2018Synthesis of (aminoalkyl)cycleanine analogues: cytotoxicity, cellular uptake, and apoptosis induction in ovarian cancer cellsView study →Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →Reference 9Fournet A et al. · 1998Trypanocidal bisbenzylisoquinoline alkaloids are inhibitors of trypanothione reductaseView study →Reference 10Fournet A et al. · 1997AnimalThe effect of bisbenzylisoquinoline alkaloids on Trypanosoma cruzi infections in miceView study →Reference 12Seow WK et al. · 1993Inhibitory effects of bisbenzylisoquinolines on synthesis of the inflammatory cytokines interleukin-1 and tumour necrosis factor-alphaView study →Reference 13Kondo Y et al. · 1993Inhibitory effect of bisbenzylisoquinoline alkaloids on nitric oxide production in activated macrophagesView study →Reference 14Kondo Y et al. · 1993AnimalSuppression of lipopolysaccharide-induced fulminant hepatitis and tumor necrosis factor production by bisbenzylisoquinoline alkaloids in bacillus Calmette-Guerin-treated miceView study →Reference 17Martínez JA et al. · 1998Calcium antagonist properties of the bisbenzylisoquinoline alkaloid cycleanineView study →}

Last checked: July 2026.

Isolate vs. Plant Studies

This molecule sits unusually well on the isolate side of the ledger. Nearly every pharmacological result here was generated with purified cycleanine: the 53-alkaloid antiplasmodial panel ^{5Reference 5Angerhofer CK et al. · 1999Antiplasmodial and cytotoxic activity of natural bisbenzylisoquinoline alkaloidsView study →}, the murine malaria and metabolism work ^{3Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →}, all four ovarian cancer lines and the analogue chemistry ^{1,2Reference 1Uche FI et al. · 2016Cytotoxicity effects and apoptosis induction by bisbenzylisoquinoline alkaloids from Triclisia subcordataView study →Reference 2Uche FI et al. · 2018Synthesis of (aminoalkyl)cycleanine analogues: cytotoxicity, cellular uptake, and apoptosis induction in ovarian cancer cellsView study →}, the human-monocyte cytokine IC₅₀s ^{12Reference 12Seow WK et al. · 1993Inhibitory effects of bisbenzylisoquinolines on synthesis of the inflammatory cytokines interleukin-1 and tumour necrosis factor-alphaView study →}, the rabbit-aorta and cardiomyocyte electrophysiology ^{17Reference 17Martínez JA et al. · 1998Calcium antagonist properties of the bisbenzylisoquinoline alkaloid cycleanineView study →}, the Na⁺,K⁺-ATPase kinetics ^{18Reference 18Satoh K et al. · 2003Inhibition of Na(+),K(+)-ATPase by the extract of Stephania cephararantha HAYATA and bisbenzylisoquinoline alkaloid cycleanine, a major constituentView study →} and the MDR reversal ^{19Reference 19Tian H · 1997Modulation of multidrug resistance by three bisbenzyl-isoquinolines in comparison with verapamilView study →}. That is a genuine strength — it means the numbers belong to the molecule, not to a mixture.

The whole-extract layer is smaller and mostly ethnopharmacological: the Triclisia subcordata crude alkaloid fraction (more potent on ovarian lines than the purified compound, IC₅₀ < 2.4 µg/mL) ^{1Reference 1Uche FI et al. · 2016Cytotoxicity effects and apoptosis induction by bisbenzylisoquinoline alkaloids from Triclisia subcordataView study →}, the Albertisia villosa root-bark alkaloid extract ^{7Reference 7Lohombo-Ekomba ML et al. · 2004Antibacterial, antifungal, antiplasmodial, and cytotoxic activities of Albertisia villosaView study →}, and the Epinetrum villosum methanol fraction ^{8Reference 8Otshudi AL et al. · 2005Biologically active bisbenzylisoquinoline alkaloids from the root bark of Epinetrum villosumView study →}. In two of those three the authors explicitly attribute the extract’s activity to cycleanine’s abundance — an inference, not a demonstration, and in E. villosum a different alkaloid turned out to carry the antimicrobial activity ^{8Reference 8Otshudi AL et al. · 2005Biologically active bisbenzylisoquinoline alkaloids from the root bark of Epinetrum villosumView study →}.

The transferability caveat runs the other way for this site’s own herb. In abuta (Cissampelos pareira), cycleanine is a minor constituent: the 2019 phytochemical survey isolated it as compound 6 of seven and built a quantitative UPLC method for five other alkaloids — magnoflorine, magnocurarine, cissamine, curine and hayatinine — leaving cycleanine unquantified ^{20Reference 20Bala M et al. · 2019Bioactive isoquinoline alkaloids from Cissampelos pareiraView study →}. Abuta’s own antimalarial evidence is extract-level and docking-level, not cycleanine-level. Nothing here should be read as evidence about the herb, and nothing about the herb transfers to this molecule.

Prevalence in Nature

Cycleanine is a Menispermaceae alkaloid, and within that family it is often the dominant bisbenzylisoquinoline rather than a trace one.

Its richest documented sources are African. In Albertisia villosa root bark it makes up about 85% of the identified bisBIQ alkaloids, alongside cocsoline and N-desmethylcycleanine ^{7Reference 7Lohombo-Ekomba ML et al. · 2004Antibacterial, antifungal, antiplasmodial, and cytotoxic activities of Albertisia villosaView study →}. In Epinetrum villosum root bark it accompanies cycleanine N-oxide, isochondodendrine and cocsoline ^{8Reference 8Otshudi AL et al. · 2005Biologically active bisbenzylisoquinoline alkaloids from the root bark of Epinetrum villosumView study →}, and it was isolated from Epinetrum cordifolium and E. mangenotii with norcycleanine and isochondrodendrine in the 1966 work that put it on the African map ^{23Reference 23Debray M et al. · 1966Debray M, Plat M, Le Men J (1966). [Alkaloids of African Menispermaceae, Epinetrum cordifolium and Epinetrum mangenotii: isolation of cycleanine, norcycleanine and isochondrodendrine]. Annales Pharmaceutiques Françaises. https://pubmed.ncbi.nlm.nih.gov/5955797/View study →}. Synclisia scabrida stems yielded cycleanine, norcycleanine, cocsuline and cocsoline, plus the first report of cycleanine N-oxide ^{22Reference 22Ohiri FC et al. · 1983Cycleanine N-oxide, a new alkaloid from Synclisia scabridaView study →}. Triclisia subcordata root is abundant enough to have supplied every gram of the modern Keele isolation programme ^{1,3Reference 1Uche FI et al. · 2016Cytotoxicity effects and apoptosis induction by bisbenzylisoquinoline alkaloids from Triclisia subcordataView study →Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →}.

In southern Africa, Cissampelos capensis carries cycleanine as one of the main alkaloids of both stems (with bulbocapnine, cissacapine and insularine) and rhizome (with 12-O-methylcurine and cissacapine), while the leaves are dominated by aporphines and a morphinane instead — a clean example of how plant-part-specific these alkaloid profiles are ^{21Reference 21de Wet H et al. · 2011Alkaloidal variation in Cissampelos capensis (Menispermaceae)View study →}. In Asia it appears in Stephania cepharantha tuberous root, where it is one of the two major benzylisoquinoline alkaloids alongside cepharanthine and accumulates markedly more in roots than in leaves ^{18,36Reference 18Satoh K et al. · 2003Inhibition of Na(+),K(+)-ATPase by the extract of Stephania cephararantha HAYATA and bisbenzylisoquinoline alkaloid cycleanine, a major constituentView study →Reference 36Feng Y et al. · 2026Transcriptome analysis of Stephania cepharantha and characterization of two CYP80B genes involved in the benzylisoquinoline alkaloid biosynthesisView study →}; in Stephania glabra bulbs ^{17,25Reference 17Martínez JA et al. · 1998Calcium antagonist properties of the bisbenzylisoquinoline alkaloid cycleanineView study →Reference 25Semwal DK · 2015Efficacy and safety of Stephania glabra: an alkaloid-rich traditional medicinal plantView study →}; in Stephania rotunda, whose review lists cycleanine among the alkaloids with evaluated toxicity ^{24Reference 24Desgrouas C et al. · 2014Ethnobotany, phytochemistry and pharmacology of Stephania rotunda LourView study →}; and in Cyclea sutchuenensis roots, alongside its epimer isocycleanine ^{26Reference 26Lai S et al. · 1993Lai S, Zhao TF, Wang XK, Shizuri Y, Yamamura S (1993). [Two novel bisbenzylisoquinoline alkaloids from Cyclea sutchuenensis Gagnep]. Yao Xue Xue Bao. https://pubmed.ncbi.nlm.nih.gov/8285068/View study →}. In the Amazon it occurs in the bark of Chondodendron tomentosum — the classic curare vine — with chondrocurine and 12-O-methylcurine ^{11Reference 11González-Coloma A et al. · 2012Antileishmanial, antitrypanosomal, and cytotoxic screening of ethnopharmacologically selected Peruvian plantsView study →}. And in abuta (Cissampelos pareira) it is one of seven isoquinoline alkaloids isolated from the plant ^{20Reference 20Bala M et al. · 2019Bioactive isoquinoline alkaloids from Cissampelos pareiraView study →}.

The one confirmed source outside the Menispermaceae is Actinodaphne macrophylla (Lauraceae) stem bark, where it was isolated among seven antiplasmodial isoquinoline alkaloids ^{6Reference 6Fadaeinasab M et al. · 2015Anti-malarial activity of isoquinoline alkaloids from the stem bark of Actinodaphne macrophyllaView study →}.

Abundance is nowhere quantified as a percentage of dry plant weight — the 85% figure is a proportion of the alkaloid fraction, not of the tissue ^{7Reference 7Lohombo-Ekomba ML et al. · 2004Antibacterial, antifungal, antiplasmodial, and cytotoxic activities of Albertisia villosaView study →}, and no validated quantitative method for cycleanine in any plant has been published. On the biosynthetic side, Stephania cepharantha transcriptomics has begun mapping the pathway that feeds cycleanine and cepharanthine, with two CYP80B 3’-hydroxylases (acting on N-methylcoclaurine and coclaurine) functionally characterised in yeast ^{36Reference 36Feng Y et al. · 2026Transcriptome analysis of Stephania cepharantha and characterization of two CYP80B genes involved in the benzylisoquinoline alkaloid biosynthesisView study →}.

Discovery & Synthesis

First isolation is not well documented in the indexed literature. The name derives from the Menispermaceae genus Cyclea, and the compound was already a known alkaloid by the time the first PubMed-indexed reports appear — the 1966 isolation from the African vines Epinetrum cordifolium and E. mangenotii, alongside norcycleanine and isochondrodendrine ^{23Reference 23Debray M et al. · 1966Debray M, Plat M, Le Men J (1966). [Alkaloids of African Menispermaceae, Epinetrum cordifolium and Epinetrum mangenotii: isolation of cycleanine, norcycleanine and isochondrodendrine]. Annales Pharmaceutiques Françaises. https://pubmed.ncbi.nlm.nih.gov/5955797/View study →}. Its structural relationship to its neighbours was settled early: isochondodendrine is a demethylated analogue of cycleanine ^{3Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →}, and cycleanine’s two benzylisoquinoline halves are joined head-to-tail by two diaryl-ether bridges, in contrast to the head-to-head architecture of berbamine, tetrandrine and oxyacanthine ^{12,26Reference 12Seow WK et al. · 1993Inhibitory effects of bisbenzylisoquinolines on synthesis of the inflammatory cytokines interleukin-1 and tumour necrosis factor-alphaView study →Reference 26Lai S et al. · 1993Lai S, Zhao TF, Wang XK, Shizuri Y, Yamamura S (1993). [Two novel bisbenzylisoquinoline alkaloids from Cyclea sutchuenensis Gagnep]. Yao Xue Xue Bao. https://pubmed.ncbi.nlm.nih.gov/8285068/View study →}.

The first total synthesis was reported in 1967 by Tomita, Aoyagi, Sakatani and Fujita, as paper CCXL of their long “Studies on the alkaloids of menispermaceous plants” series: a cupric-oxide-catalysed Ullmann condensation of dl-8-bromoarmepavine, forming the macrocycle by double diaryl-ether coupling ^{39Reference 39Tomita M et al. · 1967Studies on the alkaloids of menispermaceous plantsView study →}. Later chemistry filled in the congeners — mCPBA oxidation gave two diastereomeric mono-N-oxides whose NMR spectra turned out to differ significantly from the natural product previously reported as “cycleanine N-oxide”, leaving that natural structure in question ^{34Reference 34Kashiwaba N et al. · 1998Synthesis of cycleanine mono-N-oxidesView study →}, and Cyclea sutchuenensis work established isocycleanine as cycleanine’s epimer ^{26Reference 26Lai S et al. · 1993Lai S, Zhao TF, Wang XK, Shizuri Y, Yamamura S (1993). [Two novel bisbenzylisoquinoline alkaloids from Cyclea sutchuenensis Gagnep]. Yao Xue Xue Bao. https://pubmed.ncbi.nlm.nih.gov/8285068/View study →}.

There is no commercial manufacture. Cycleanine is not sold as a supplement or a drug anywhere; research material is obtained by extraction from Menispermaceae root and root bark — chiefly Triclisia subcordata — and the semi-synthetic derivatives that have shown improved potency (the aminoalkyl anticancer analogues ^{2Reference 2Uche FI et al. · 2018Synthesis of (aminoalkyl)cycleanine analogues: cytotoxicity, cellular uptake, and apoptosis induction in ovarian cancer cellsView study →} and the C-5 dimethylamino/alkynylamino antiplasmodial analogues ^{3Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →}) are all made from isolated natural cycleanine rather than by total synthesis.

Patents: not yet researched.

Toxicity & Safety

Cycleanine carries a moderate flag. Its acute rodent toxicity is genuinely low, but three things keep it above a low grading: it is a potent calcium antagonist at sub-nanomolar concentrations in vascular tissue ^{17Reference 17Martínez JA et al. · 1998Calcium antagonist properties of the bisbenzylisoquinoline alkaloid cycleanineView study →}, its cytotoxicity is barely selective — normal human ovarian epithelium dies at only 2–5× the concentration that kills the cancer lines ^{1,3Reference 1Uche FI et al. · 2016Cytotoxicity effects and apoptosis induction by bisbenzylisoquinoline alkaloids from Triclisia subcordataView study →Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →} — and it is immunosuppressive at low micromolar concentrations in human cells ^{12Reference 12Seow WK et al. · 1993Inhibitory effects of bisbenzylisoquinolines on synthesis of the inflammatory cytokines interleukin-1 and tumour necrosis factor-alphaView study →}. It is not escalated further: no organ toxicity, mutagenicity or lethality signal appears anywhere in the record at reasonable exposures.

Safety at a Glance

Moderate toxicityCardiac cautionDrug interactions

Low acute toxicity in rodents. A median lethal dose of about 4.5 g/kg in mice, described by the investigators as a good safety profile ^{3Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →}.
Cytotoxicity is not selective. IC₅₀ 7–14 µM on ovarian cancer lines against 35 µM on normal ovarian epithelium — a selectivity index of roughly 2–5, and as low as 2.0 against the Dd2 malaria strain.
Immunosuppressive, not merely anti-inflammatory. It suppresses TNF-α (IC₅₀ 4.6 µM) and IL-1β in human monocytes and blunts macrophage nitric oxide and respiratory burst.
Genuinely cardioactive. A vascular-selective L-type calcium-channel blocker more potent than nifedipine in rabbit aorta; additive hypotension with calcium-channel blockers and antihypertensives is chemistry-based, though never measured clinically.
A plausible drug-efflux interaction. It reverses multidrug resistance more effectively than verapamil and raises intracellular doxorubicin — the same property that would raise levels of co-administered substrates.
No human safety data for the free base. No repeat-dose, genotoxicity or reproductive-toxicity package exists; the human record belongs to the quaternary derivative.

Full Safety & Interactions Detail

Acute toxicity. The only whole-animal toxicity figure is an acute median lethal dose of ~4.5 g/kg in mice, reported alongside the murine antimalarial work; the investigators read it as a good safety margin and noted that it would permit oral doses above 50 mg/kg/day ^{3Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →}. That is a single determination, in one species, over 24 hours, and it says nothing about repeat dosing.

Cardiovascular. This is the substantive caution. Cycleanine inhibits KCl-induced vascular contraction with an IC₅₀ of 0.8 nM — roughly nine-fold more potent than nifedipine in the same rabbit-aorta preparation — blocks L-type calcium current in ventricular myocytes in a voltage- and frequency-dependent manner, and shortens ventricular action-potential duration ^{17Reference 17Martínez JA et al. · 1998Calcium antagonist properties of the bisbenzylisoquinoline alkaloid cycleanineView study →}. It also inhibits Na⁺,K⁺-ATPase non-competitively, by a mechanism distinct from ouabain’s ^{18Reference 18Satoh K et al. · 2003Inhibition of Na(+),K(+)-ATPase by the extract of Stephania cephararantha HAYATA and bisbenzylisoquinoline alkaloid cycleanine, a major constituentView study →}, though at a much higher concentration (~620 µM) whose relevance is unclear. Theoretical additive hypotension and negative inotropy with calcium-channel blockers, other antihypertensives, and cardioactive drugs follow from the chemistry; none has been measured in people.

Immune suppression. TNF-α synthesis in human monocytes is inhibited with an IC₅₀ of 4.6 µM and IL-1β at 25.0 µM ^{12Reference 12Seow WK et al. · 1993Inhibitory effects of bisbenzylisoquinolines on synthesis of the inflammatory cytokines interleukin-1 and tumour necrosis factor-alphaView study →}; murine macrophage nitric oxide production is suppressed at 5 µg/mL for at least 48 hours ^{13Reference 13Kondo Y et al. · 1993Inhibitory effect of bisbenzylisoquinoline alkaloids on nitric oxide production in activated macrophagesView study →}; and the alveolar-macrophage respiratory burst is inhibited at berbamine-like potency ^{16Reference 16Ma JY et al. · 1992Inhibition of respiratory burst activity in alveolar macrophages by bisbenzylisoquinoline alkaloids: characterization of drug-cell interactionView study →}. The in-vivo protection against BCG/LPS fulminant hepatitis and lethality is the same effect read as a benefit ^{14,15Reference 14Kondo Y et al. · 1993AnimalSuppression of lipopolysaccharide-induced fulminant hepatitis and tumor necrosis factor production by bisbenzylisoquinoline alkaloids in bacillus Calmette-Guerin-treated miceView study →Reference 15Kondo Y et al. · 1990AnimalInhibitory effect of bisbenzylisoquinoline alkaloids on the quick death of mice treated with BCG/LPSView study →}. In any setting where innate immune competence matters, that direction of effect is a risk, not a feature.

Drug interactions. The named, evidence-based one is drug efflux: cycleanine reversed doxorubicin and vincristine resistance in MCF-7/Adr and KBv200 cells and increased intracellular doxorubicin accumulation, outperforming verapamil ^{19Reference 19Tian H · 1997Modulation of multidrug resistance by three bisbenzyl-isoquinolines in comparison with verapamilView study →}. No transporter was identified and no CYP inhibition data of any kind exist for this molecule — which is itself a gap, not a clean bill.

The quaternary derivative is a separate risk profile. Cycleanine dimethobromide blocks autonomic ganglia and the neuromuscular junction ^{29Reference 29Lu YQ et al. · 1981Lu YQ, Xu DZ, Mao YK, Wei X, Yang ZC (1981). [Blocking effects of cycleanine dimethobromide on nerve ganglia and neuromuscular junctions]. Zhongguo Yao Li Xue Bao. https://pubmed.ncbi.nlm.nih.gov/6462019/View study →}, affects the cardiac conduction system ^{32Reference 32Shen JF et al. · 1985Shen JF, Xi YQ, Cao ZE, Zhang GL, Fu CZ, Gao QL (1985). [Effects of cycleanine dimethobromide on heart conduction system]. Zhongguo Yao Li Xue Bao. https://pubmed.ncbi.nlm.nih.gov/2945367/View study →} and produces surgical-grade hypotension ^{28,31,37Reference 28Jin GZ et al. · 1984Controlled hypotensive effect of cycleanine dimethobromideView study →Reference 31Chen WZ et al. · 1980Chen WZ, Dong YL, Ding GS (1980). [Effects of dimethyl cycleanine bromide on cardiac hemodynamics of anesthetized dogs]. Zhongguo Yao Li Xue Bao. https://pubmed.ncbi.nlm.nih.gov/6461170/View study →Reference 37Sun Z et al. · 1980Sun Z, Yang XY, Dai ZL, Jin GZ, Zhang ZD (1980). [Hypotensive effect of dimethyl cycleanine bromide]. Zhongguo Yao Li Xue Bao. https://pubmed.ncbi.nlm.nih.gov/6175170/View study →}. Those are properties of a bis-quaternary ammonium salt developed as an anaesthesia adjunct, and they should not be read onto natural cycleanine — but they do mean that any quaternised preparation of this alkaloid is a fundamentally different and more acutely dangerous agent.

Reproductive and developmental note (prose only). No reproductive or developmental toxicity study of isolated cycleanine exists in any species. Pregnancy and lactation decisions belong to the herb or product page where intake is decided, not to a molecule page. Likewise, no genotoxicity, carcinogenicity or repeat-dose toxicology package has been published for the free base.

Dosage

There is no dose. Cycleanine is not sold as a supplement or prescribed as a drug in any market, and no human has been given the isolated free base in a published study. Every figure below is a dose or concentration used in research — recorded so the numbers here can be read in context, not as guidance.

Setting	Preparation	Dose / concentration studied
Murine malaria — suppressive, prophylactic and curative P. berghei models	oral cycleanine	25 and 50 mg/kg/day ^{3Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →}
Murine Chagas disease (T. cruzi, Y and CL strains)	oral cycleanine	2 mg/kg/day × 10 days ^{10Reference 10Fournet A et al. · 1997AnimalThe effect of bisbenzylisoquinoline alkaloids on Trypanosoma cruzi infections in miceView study →}
Murine BCG/LPS hepatitis and lethality	cycleanine (route not stated in the indexed abstract)	10 mg/kg/day × 3–7 days ^{14,15Reference 14Kondo Y et al. · 1993AnimalSuppression of lipopolysaccharide-induced fulminant hepatitis and tumor necrosis factor production by bisbenzylisoquinoline alkaloids in bacillus Calmette-Guerin-treated miceView study →Reference 15Kondo Y et al. · 1990AnimalInhibitory effect of bisbenzylisoquinoline alkaloids on the quick death of mice treated with BCG/LPSView study →}
Acute toxicity ceiling	cycleanine, mice	LD₅₀ ~4.5 g/kg ^{3Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →}
Ovarian cancer cell lines (in vitro)	isolate	IC₅₀ 7–14 µM; normal ovarian epithelium 35 µM ^{1Reference 1Uche FI et al. · 2016Cytotoxicity effects and apoptosis induction by bisbenzylisoquinoline alkaloids from Triclisia subcordataView study →}
P. falciparum (in vitro)	isolate	IC₅₀ 0.07–17.7 µM, strain- and assay-dependent ^{3,5,6Reference 3Uche FI et al. · 2021In vitroIn vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of semisynthetic analoguesView study →Reference 5Angerhofer CK et al. · 1999Antiplasmodial and cytotoxic activity of natural bisbenzylisoquinoline alkaloidsView study →Reference 6Fadaeinasab M et al. · 2015Anti-malarial activity of isoquinoline alkaloids from the stem bark of Actinodaphne macrophyllaView study →}
Human monocyte cytokine suppression (in vitro)	isolate	IC₅₀ 4.6 µM (TNF-α), 25.0 µM (IL-1β) ^{12Reference 12Seow WK et al. · 1993Inhibitory effects of bisbenzylisoquinolines on synthesis of the inflammatory cytokines interleukin-1 and tumour necrosis factor-alphaView study →}
Controlled hypotension during anaesthesia	cycleanine dimethobromide — a different, quaternary molecule	human use documented; dose not recoverable from the indexed record ^{28,30Reference 28Jin GZ et al. · 1984Controlled hypotensive effect of cycleanine dimethobromideView study →Reference 30Jin XY et al. · 1982Jin XY, Sun DJ, Sheng JN, Chu ZB (1982). [Clinical use of cycleanine for controlled hypotension during anesthesia]. Masui. https://pubmed.ncbi.nlm.nih.gov/7154227/View study →}

These are doses studied in research and are not a personal recommendation.

References

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