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p-Coumaric acid - towards a 'safe and effective anxiolytic functional food'?

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p-Coumaric acid activates the GABA-A receptor in vitro and is orally anxiolytic in vivo.

The increasing prevalence and social burden of subclinical anxiety in the western world represents a significant psychosocial and financial cost. Consumers are favouring a more natural and nonpharmacological approach for alleviating the effects of everyday stress and anxiety. The gamma-aminobutyric acid (GABA) receptor is the primary mediator of central inhibitory neurotransmission, and GABA-receptor agonists are well known to convey anxiolytic effects. Using an in vitro screening approach to identify naturally occurring phytochemical GABA agonists, we discovered the plant secondary metabolite p-coumaric acid to have significant GABAergic activity, an effect that could be blocked by co-administration of the specific GABA-receptor antagonist, picrotoxin. Oral administration of p-coumaric acid to rodents induced a significant anxiolytic effect in vivo as measured using the elevated plus paradigm, in line with the effects of oral diazepam. Given that p-coumaric acid is reasonably well absorbed following oral consumption in man and is relatively nontoxic, it may be suitable for the formulation of a safe and effective anxiolytic functional food.

Pubchem

I'm trying to get the full article from the authors but if anyone has access, that would be great.

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Nice find.

PM me your email address if you're still after the paper.

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To summarise:

Of the compounds tested, p-coumaric acid gave the most significant GABAergic response [EC50 of 6.9 +/- 0.3 uM]

Oral p-coumaric acid at doses of 3, 30 and 90mg/kg conveyed a significant anxiolytic effect (inducing a level of anxiolysis in line with that conveyed by an oral dose of 3mg/kg diazepam) while doses of 10mg/kg did not, suggesting a U-shaped dose-response curve. These effective oral doses translate to human dose equivalents of ~ 0.49, 4.86 and 14.6mg/kg.

Unlike most dietary phenolic compounds, orally consumed p-coumaric acid has reasonable bioavailability both in animals and man (Natella et al., 2007), reaching plasma levels of up to 5 mg/mL, with a Tmax between 60 and 180 min (Konishi et al., 2004; Yeh and Yen, 2006). Its bioavailability to plasma is likely mediated by passive diffusion through the stomach wall as well as its affinity to the monocarboxylic acid transporter (Konishi et al., 2004).
p-Coumaric acid has a published oral median lethal dose (LD50) of 2850 mg/kg in mice, and acute oral doses of up to 2000 mg/kg have been used in rats without any toxicity being reported (Barros et al., 2008). Furthermore, a published patent has suggested that oral p-coumaric acid in man may inhibit the enzymes acyl-CoA, cholesterol-o-transferase and 3-hydroxy-3methylglutaryl coenzyme-A and thus be of benefit in reducing plasma cholesterol levels. The inventors went on to administer 10mg/kg/day p-coumaric acid to hyperlipidaemic human patients (n = 2), which induced a modest reduction in serum cholesterol without adverse side effects being reported (Bok et al., 2000).
In summary, orally ingested p-coumaric acid appears to be a safe and beneficial compound with reasonable bioavailability, and has the potential to convey antioxidant, antihyperlipidaemic and anticarcinogenic potential. Here, we show for the first time that p-coumaric acid has significant in vivo anxiolytic activity in rats when consumed orally at acute doses of between 3 and 90 mg/kg, in line with the effects of oral diazepam. Given that we discovered this activity using a GABA-A assay without a benzodiazepine site, it is less likely to be either habituating or amnesiac, as benzodiazepine agonists are well known to be. These data suggest that p-coumaric acid has potential for inclusion in an orally active nutritional supplement or functional food to reduce the symptoms of mild to moderate stress and anxiety. The evidence presented here suggests that a placebo-controlled, double-blinded and randomized human intervention trial for the anxiolytic activity of an acute oral administration of p-coumaric acid is warranted.
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All trials were with the water soluble sodium salt of p-coumaric acid (doses given for the free acid).

At the estimated human equivalent oral doses (0.5, 4.9 and 14.6mg/kg) of active rodent doses used in the study, it's subtle (if at all active) with no apparent side-effects. Doses up to 50mg/kg per day have been tolerated - the only side-effects being slight nausea and diarrhea with the higher doses. Even the high doses were generally without any detectable level of clinically-relevant anxiolysis. Sustained dosing over the period of a week (25mg/kg per day) was unremarkable. There was a slight hint of possible anxiolytic effects with this dose at times but these effects were unreliably present.

Unfortunately, I'd personally say it isn't an overly promising lead for the treatment of anxiety. One benefit it may have is that it doesn't seem to have problems with sedation or cognitive impairment and maybe others might respond to it better. The doses tested could all be in the 'inactive' part of the 'U' shape dose-response curve but I find that unlikely.

At all doses, I'd say abuse potential is non-existent.

My recommendation would be to stick with the seemingly more effective compounds such as magnolol/honokiol [1] or oral lavender oil [2].

If anyone has a use for p-coumaric acid, do let me know.

Edited by Alchemica

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Bummer it didn't work

But thank you so much for posting a concise writeup of your negative results here.

Writeups of negative results are as deadset important as positive results and will doubtless help others in the future

I wish every single publication had to have a written account of stuff that didn't work, science would be much faster

Every now and again you find a publication where you can read between the lines and almost follow the thought processes of the researchers, I've read a couple that were like torrid film scripts

Edited by Darklight
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The offer for people with mild anxiety to try p-coumaric acid is still there on the condition you stick to sensible doses [estimated human equivalent oral doses (0.5, 4.9 and 14.6mg/kg)]. I've come to the conclusion my GABA system is too out of whack to be a good test subject. PM me and I can send some free samples.

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I've tried 100mg on several occasions now. Which is slightly more than 1mg/kg and have had noticeable anxiolytic effects. Subtle but detectable above placebo.

I haven't had any negative side effects.

Thanks alchemica!

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Had any more experiences with this @stonewolf? Got a fair bit of it I'd like to go to a good home for free if anyone wants to try it?

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I will eat anything although I should be last on the list.

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Nah it's cool, plenty to go around - PM me your address and I'll send you some. I just want to get an idea if it's useful or not as a mild anxiolytic. I think my issues make testing things too complicated unfortunately.

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Hi Alchemica.Just wondering if the experiment was still going?

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Just an update on this. If anyone's had results, let me know.

It has been shown to reduce oxidative stress, inhibit genotoxicity and exert neuroprotection. p-coumaric acid exhibits antidepressant-like effects, enhances long-term potentiation and recovers scopolamine-induced learning and memory impairments [https://www.ncbi.nlm.nih.gov/pubmed/28830814] and may inhibit hippocampal neurodegeneration via potent antioxidant, anti-inflammatory and anti-apoptotic properties. It has been recommended as a hopeful adjuvant agent against brain neurodegeneration, including in diabetics [https://www.ncbi.nlm.nih.gov/pubmed/28573601]

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