Luo Bu Ma

476 healthy US adults seeking improvement in self-reported anxiety and stress were randomised to 50 mg/day of a standardised Apocynum venetum leaf extract (n = 234) or placebo (n = 242) for 6 weeks, with weekly PROMIS Anxiety 8A, perceived stress, sleep quality and cognition assessments. The active group improved significantly faster than placebo on perceived stress and sleep disturbance and was significantly more likely to reach a minimal clinically important difference in perceived stress; the effect on the anxiety measure itself was only marginally significant. Reported side effects did not differ between arms. This is the largest controlled human dataset for the herb, and it supports a sleep and stress effect rather than an antidepressant or cognitive one.

The standardised leaf extract reduced sleep latency dose-dependently and lengthened non-REM sleep without changing delta activity in mice, and chronic dosing sustained the effect without withdrawal signs. In vitro the extract had appreciable affinity for the benzodiazepine binding site of the GABA-A receptor, and in vivo flumazenil antagonised the hypnotic effect, confirming that the mechanism runs through the GABA-A benzodiazepine site. This is the mechanistic basis for treating co-administration with prescribed hypnotics as an additive interaction.

Leaf extract at 10 micrograms/mL suppressed angiotensin II-induced contraction of both endothelium-intact and endothelium-denuded rat aortic rings; L-NAME reversed the effect in intact rings, and the extract concentration-dependently reduced angiotensin II-stimulated superoxide production. Phenylephrine-induced contraction was inhibited only in endothelium-intact rings. The authors conclude the antihypertensive folk use rests on superoxide scavenging combined with nitric oxide release, which is a species-specific finding for Apocynum venetum leaf and not for Poacynum.

In the perfused rat mesenteric vascular bed with active tone and intact endothelium, leaf extract caused dose-dependent vasodilation that was abolished by chemical removal of the endothelium but not by L-NAME, was partially inhibited by high-K+ solution and tetraethylammonium, and was completely abolished by the combination. Atropine had no effect. The vasodilation is therefore endothelium-dependent and mediated by endothelium-derived hyperpolarising factor through K+ channel activation, with a nitric oxide component appearing only at higher concentrations.

Extracts of Apocynum venetum leaf, root, stem, old stem and a polyphenol-rich leaf extract all produced a weak positive inotropic and chronotropic response in isolated guinea-pig right atria at 1 mg/mL that was not blocked by propranolol. Cymarin was quantified by LC-MS/MS and ranked old stem >> stem > root > leaf >> leaf polyphenol extract. Because the cardiotonic effect did not follow cymarin content, the authors tested and found phosphodiesterase 3 inhibition by all extracts against enzyme purified from human platelets. This is the key study separating the cardenolide content of the woody parts from the pharmacology of the leaf.

Endothelium-dependent relaxation of rat aorta by leaf extract was reduced by the Src kinase inhibitor PP2 and by the PI3-kinase inhibitors wortmannin and LY294002, and abolished by L-NAME and by the guanylyl cyclase inhibitor ODQ. The extract raised total nitrite and nitrate in rat aorta and in human umbilical vein endothelial cells and phosphorylated Akt and eNOS concentration-dependently, and it inhibited superoxide from both NADPH oxidase and the xanthine oxidase system. The signalling pathway for the vasodilator effect is therefore Src/PI3K/Akt-dependent eNOS activation.