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Why going twice a day may have the best health effect of anything you ever do
Constipation is a common problem, one affecting up to 52% of adults.
There are dozens of remedies marketed for this condition, together comprising nearly as many mechanisms of action.
Some of the more common remedies include osmotic agents (MgSO4), prostaglandin analogues (lubiprostone), opiate antagonists (alvimopan), serotonin agonists (tegaserod), and PPARγ activators (emodin).
Yet constipation treatments in general share two common denominators.
They act to either increase intestinal water content in some way — e.g., osmotic agents, PPARγ activators, prostaglandin analogues…
And/or they provoke the release of the neurotransmitter acetylcholine.
The cell membrane receptors that are most central to G.I. motility are known to modulate acetylcholine, thereby contracting or relaxing muscles.
Activation of κ‑ and μ‑opiate receptors is known to inhibit the release of acetylcholine (Shahbazian, 2002), an effect prevented by anti‑opiates such as alvimopan.
The same can be said about inhibitory α1‑adrenoceptors, yet treatments targeting those can be dangerous.
One the other side of the coin are the motility promoting receptors, such as 5‑HT4, which provoke the release of acetylcholine and induce muscle activity (Kilbinger, 1992).
Cisapride, mosapride, renzapride, and tegaserod all activate 5‑HT4 and are marketed as prokinetic treatments.
Yet the activity of these receptors (α1, μ2, 5‑HT4) ultimately depend upon M1, M3, and M5. These are the downstream muscarinic acetylcholine receptors ultimately responsible for executing contraction.
For this reason one of the most direct ways to increase G.I. motility is by using cholinesterase inhibitors, substances which increase acetylcholine by inhibiting the enzyme that breaks it down.
“Acetylcholinesterase inhibitors stimulate gastrointestinal motility and are potential treatments of conditions associated with inadequate GI motility.” ―Jarvie, 2008
Yet cholinesterase inhibitors often have effects elsewhere throughout the body.
Although these treatments are beneficial for cognition, their widespread activity can limit how much is safe.
Most are absorbed quickly while others, such as donepezil, are retained within the intestinal tract long enough for promotility action.
Spectaline and cassine are two natural cholinesterase inhibitors similar to donepezil both in structure and function.
Conversely, the inhibitors incapable of crossing the blood-brain barrier can safely be used in doses high enough to affect motility.
These substances include neostigmine and pyridostigmine, the two cholinergics most commonly given for constipation.
There are numerous case reports of success using donepezil (Lepkowski, 2017), neostigmine (Rubiales, 2006), and pyridostigmine (Sadjadpour, 1983) for increasing motility.
There’re also a few double‑blind clinical trials employing these treatments, as well as many experimental studies demonstrating their effects.
There’s even indication that spectaline and cassine, two natural cholinesterase inhibitors, are partly responsible for the effects of Senna leaves — a very popular laxative.
This study highlights the role of acetylcholine in the small intestine by using neostigmine, a brain‑impermeable cholinesterase inhibitor.
They placed eight pressure sensors along the intestinal tract of each of the 28 subjects, all of whom had gastrointestinal dysmotility, and then injected them with 1mg neostigmine.
The result was an increase in both amplitude and frequency of intestinal pressure waves throughout all locations examined.
Such is the effect of acetylcholine, the ubiquitous neurotransmitter. This goes to show that, unlike many receptor types, M1 and M3 are expressed throughout the entire digestive tract.
Although other neurotransmitters can affect transit through the agency of acetylcholine, each type is expressed in discrete locations, and thus have a more specific effect.
For instance: opiate receptors are only expressed on intestinal circular muscle cells (Bitar, 1985), not longitudinal ones.
“By contrast, neostigmine increased both the amplitude and frequency of pressure waves in the small intestine.” ―Parthasarathy, 2015
These same results have been reported previously using a similar method (Kreis, 2001), and in both cases the motility index had increased significantly.
The motility index is calculated by multiplying the waves’ frequencies by their amplitudes, a logical way to quantify total muscle activity.
A similar substance, pyridostigmine, has also been studied for this application, showing a 33% increase in colonic transit (Bharucha, 2013).
Pyridostigmine has also been found more effective than bisacodyl (Soufi-Ashar, 2015), a popular over‑the‑counter laxative.
Of the brain‑permeable cholinesterase inhibitors, donepezil has been found most effective.
This is probably on account of its relatively low bioavailability, with at least 15% being eliminated by the digestive tract (Tiseo, 1998).
Donepezil has also been found to synergize with prucalopride, a 5‑HT4 agonist.
Sub‑threshold doses of donepezil, having no effect on their own, had potentiated effects of prucalopride threefold (Broad, 2013).
That finding suggests, intuitively, that treatments which act to release acetylcholine are more potent when cholinesterase is prevented from degrading it.
“Acetylcholinesterase inhibitors, e.g., neostigmine, are known to increase upper and lower gastrointestinal motility and are used to treat acute colonic pseudoobstruction.” ―Parthasarathy, 2015
Although galantamine and huperzine are practically absorbed entirely, and hence have little-to-no effect on motility, there are two natural cholinesterase inhibitors more suitable for constipation.
Spectaline and cassine are two potent cholinesterase inhibitors found in the leaves of Senna species, plants historically used as laxatives.
And most importantly…
Spectaline and cassine also have molecular properties suggestive of incomplete absorption, perhaps even biliary excretion:
They are both long, fatty, terminate in a piperidine ring, and hence expected to be partially retained within the G.I. tract.
Spectaline and cassine combine to comprise 6.21% of Senna alata leaves (Onyegeme-Okerenta, 2017), a concentration approximately fourfold greater than the anthraquinones found in the same species (Panichayupakaranant, 2009).
“Cassia alata Linn. is a medical plant. Its leaves have been claimed to be effective as a laxative. […] The plant has been found to contain anthraquinones, presumed to be the active ingredient causing the laxative effect.” ―Thamlikitkul, 1990
Despite the relatively low anthraquinone content of Senna alata, as compared to S. angustifolia and S. acutifolia (Metzger, 1996), it has been found effective in constipation (Thamlikitkul, 1990)
Cassine and spectaline are both highly active cholinesterase inhibitors, with their hydrochloride versions having potencies comparable to physostigmine (Pivatto, 2005):
It may seem besides the point because Senna works regardless — be it from its piperidine alkaloids or anthraquinone glycosides…
Yet their presence implies that whole Senna leaves should be more effective than OTC products containing only sennosides.
And there’s at least one study that strongly implies that the piperidine alkaloids of Senna leaves contribute to the laxative effect:
This study had examined the laxative effect of Senna macranthera extracts using five different solvents: hexane, methanol, butanol, chloroform, and ethyl acetate.
They had used high‑performance liquid chromatography to determine the emodin concentration in each fraction, and each one was given to rats for motility studies.
Extracts of Senna macranthera predictably increased motility, yet surprisingly this wasn’t correlated with their emodin concentrations.
“Certainly, emodine contributed to the observed laxative and intestinal motility activities, but this compound was not the only one responsible for those activities as it was found in a greater amount in the inactive extracts.” ―Guarize, 2012
In fact, it was the most active fraction — the hexane fraction — that contained the least emodin.
The difference was substantial, being about twenty times less than the butanol fraction.
And coincidentally, out of six solvents used, other researchers found the Senna alata hexane fraction to contain the greatest anti‑cholinesterase activity (Upadhyay, 2011).
You might expect that hexane would be the best solvent for cassine and spectaline, with water and ethanol being better for sennosides.
So even though the anthraquinones in Senna actually do work for constipation — most likely through activating PPARγ thereby upregulating aquaporin‑3 ion channels (Zheng, 2014) — you could be selling yourself short by not buying the whole leaf.
Senna leaves contain upwards of ~6% cassine and spectaline.
Instead of paying for fillers in OTC products containing only sennosides, buying whole Senna leaf or crude extracts thereof would also supply two natural cholinesterase inhibitors.
“A laxative effect was observed for the methanolic and hexane extracts comparative to the standard ‘treatment’ bisacodyl; however, only the hexane extract increased the intestinal motility in the studied period.” ―Guarize, 2012
—-Important Message for Men With Bowel Issues—-
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Pivatto, Marcos. "Evaluation of anticholinesterase activity of homologous alkaloids (−)-cassine and (−)-spectaline isolated from Senna spectabilis and semisynthetic derivatives (−)-3-O-acetyl-cassine and (−)-3-O-acetyl spectaline." Sociedade Brasileira de Química (circa 2005) https://inis.iaea.org/collection/NCLCollectionStore/_Public/45/031/45031605.pdf
Guarize, Lyvia. "Anti-inflammatory, laxative and intestinal motility effects of Senna macranthera leaves." Natural product research (2012) https://pdfs.semanticscholar.org/13a3/f54a71accbafa6f9f4d0776f0dd4351aebe2.pdf