Bethanechol is an oral, parasympathetic agonist, very similar to endogenous acetylcholine, in fact it mimics acetylcholine, but it is more resistant to inactivation by endogenous acetylcholinesterase, and therefore, it is much longer acting. “We have a pretty good idea from Stephen Davies’ work, and by inference, that many of our kids are hypochlorhydric (not enough HCl), and this must diminish the secretion of pancreatic digestive enzymes and peptide messengers, like Secretin, with receptors outside the gut. Bethanechol is a strong pancreatic stimulant. It has a ubiquitous, positive effect on gastric acid secretion. Happily, this increased parietal-cell activity isn’t usually associated with increased gastro-esophageal reflux. Relatively, there is a very long, clinical tradition using Bethanechol expressly for symptoms of G.E.-reflux.
In healthy adult males, Bethanechol increased gastric-residence time by 64%, but did not affect mouth-to-cecum time. (Pharmacotherapy 9[4] 226-231, 1989). Increased volume of stomach acid and increased time of exposure to it in the stomach would seem beneficial to digestion and absorption. In spite of its parasympathetic qualities, Bethanechol does not appear to cause problems with hypermotility (sic), and my very first Bethanechol patient had his first-ever, formed stool the following day. Improved digestion, and more ordered peristalsis may explain the firmed stool.
I have observed truly marked language and social gains within 40 minutes of the first dose of Bethanechol, as if a switch had been flipped. Bethanechol could have such an immediate effect either as a strong pancreatic stimulant physiologically upstream to Secretin, or through its own effect at numerous known CNS binding sites (Biochemical Pharmacology 38[5]: 837-50, 1989, Mar 1). My early impression, by the way, is that the children who have demonstrated a response to Secretin may fall within the group of likely Bethanechol-responders.
The official literature suggests contraindication in asthma, seizures, hyperthyroidism, and peptic ulcer, though one clinician reports a definite pattern of improvement with Bethanechol in numerous patients with seizure activity, and I have used it effectively in one child with quiescent-reactive, airway disease. At the low doses being used, no significant abdominal pain or other clinical suggestion of ulcer activation is being seen. I strongly advise observation of the first dose in the office for one hour with injectable Atropine handy in the unlikely case of respiratory difficulties.
I am very happy to add to this discussion some recent literature research from Teresa Binstock and Linda Carlton. Experimentally, Bethanechol stimulates secretion of numerous antimicrobial peptides (defensins) by the small intestine (Infect Immunol 64[12]:5161-5 Dec 1996). These defensins may have a wide spectrum, including antiviral. One child with damaged intestinal ganglia and pseudo-obstruction associated with active Epstein Barr was treated successfully with Bethanechol (Am J Gastroenterol 95[1]:280-4 Jan 2000). Dysbiosis control could be an important mechanism.
The thin, scored 10 mg Bethanechol tablets are easily halved or quartered for starting doses of 2.5-5.0 mg. For the tablet-averse, Bethanechol has been shown stable in water solution for at least thirty days (Ann. of Pharmacotherapy 31 Mar p 294-6 1997). There may be a preference for the generic Bethanechol over the proprietary (Urecholine™) in order to avoid the dyes. It is inexpensive.
Some adults have been on Bethanechol for many years for heartburn or urinary retention, but we must advise parents that safety in children over long periods has not been established. If a significant part of its mechanism is improved digestion and assimilation of nutrients, then perhaps the need for the Bethanechol will lessen over time.
I would emphasize that we don’t think that the Bethanechol is effective unless you prime for about two months prior with cod-liver oil. Kirkman Labs is the first supplier to tell me that their cod-liver oil is 100% natural, unspiked with any A-palmitate.
Protocol:
Pre-treat for a few days prior to cod-liver oil (and continue):
Use vitamin E 200-400 IU/day and vitamin C 250-1000 mg bid (twice daily).
Use Cod (Salmon) Liver Oil according to vitamin A content:
Less than 2 years of age--850 IU vitamin A
2-5 years--2500 IU vitamin A
5-10 years--3750 IU vitamin A
Older--5000 IU vitamin A
Minimize A-Palmitate (It blocks a Retinol G-Protein Signaling Protein). Try to keep total supplementation with preformed vitamin A (Carotene sources do not count towards this maximum) not greater than double the amount provided with the CLO over the long term to stay well below potential toxic doses of vitamin A.
Begin Bethanechol after child has been on CLO for 2 months, continuing the CLO:
Less than 5 years of age--start with 2.5 mg of Bethanechol PO (by mouth)
5-8 years--start 5.0-7.5 mg
Older--start 10 mg
Adjust dosages upward to observe effect (arbitrary current maximum is 12.5 mg). A second dose in the afternoon is often desirable.
Pupillary size (gets smaller) may help guide dosing (anyone else seeing a tendency to relatively dilated pupils in our kids, by the way?)—Dr. Woody McGinnis, MD.
Dr. Amy Holmes, after supplementing 3500 units of vitamin A from cod-liver oil for three months found Mike’s (age 5) vitamin A level was still only 19 (“normal” being listed as 25-90). She is now giving significantly more vitamin A from cod-liver oil. My personal opinion is that Dr. Megson and Dr. McGinnis are recommending far too little cod-liver oil. Vitamin A in amounts up to 20,000 units (about 4 teaspoons) has been used with no evidence of toxicity in adults. This amount is needed for its EPA input as well. Dr. Robert Atkins, MD, recommends up to 50,000 IU (adults) at the beginning of any infection, reducing to 10,000 IU once symptoms have subsided. Three teaspoons of cod-liver oil approximates 6 oz of oily fish. The marker to reduce the amount is the clearing of the “Chicken-skin” bumps on shoulders, elbows, thighs, and calves. As Dr. McGinnis indicates, pupil size will decrease (normalize) as vitamin A stores are replaced and activated with Bethanechol. One can increase acetylcholine production, and better utilize the vitamin A, by supplementing one or more of these: lecithin granules, phosphatidylcholine, acetyl-L-carnitine, DMAE, TMG, or Coenzyme A as well as by using Bethanechol. This increase of acetylcholine will restore muscle tone to the intestines preventing impaction that often accompanies a lack of muscle tone exemplified by dilated eyes. It is reported that not all autistic children do well on choline, but this group should.
It should be noted that mainly Italian researchers have evaluated Acetyl-L-carnitine, but many other European and American doctors are not convinced of its benefits. Side effects can include nausea, stomach upset, dizziness, and headache. The side effects become less troublesome when using a lower dose of the preparation, but long-term effects are not clear. I experienced the stomach upset on 500 mg daily. It was the burning we often call “overacid stomach”. This could be a problem with children who cannot communicate. It stopped as soon as I discontinued.
Now, if one is going to resort to drugs to control reflux or to encourage speech, wouldn’t it be much better to use Bethanechol that supports digestion rather than Pepcid™, or other H2 blockers, that stops digestion of meats and proteins, and interferes with utilization of many vital nutrients? Additionally, the herb ginger is reported to tighten the sphincter muscles, and thus prevent reflux. It also controls heartburn after eating. It should be used with awareness that it enhances Phase I liver function, and could deplete several body elements and reduce the effectiveness of certain drugs. For this reason, peppermint tea or lozenge may be better for occasional heartburn. Additionally, ginger (and other herbs that enhance Phase I liver enzyme activity) and H2 blockers can diminish the effectiveness of many other drugs. In some cases, they can render them completely ineffective.
Phase I activity is often desynchronized from Phase II activity resulting in high-level production of highly-reactive, oxidized metabolites which outstrips the neutralizing capacity of the Phase II system. These patients exhibit strong reactivity to a wide-range of environmental chemicals and medications and require heavy antioxidant and Phase II support whilst avoiding interventions that upregulate Phase I activity. Children with PST problems should avoid ginger, milk thistle, and other herbs that selectively stimulate the Phase I enzymes unless testing shows this to be desirable. This induction of enzymes involved in detoxification may be caused by substances that selectively upregulate a Phase I enzyme without co-induction of the corresponding Phase II enzyme. This leads to a higher level of the reactive (harmful), intermediate compounds that can cause damage to DNA, RNA, and proteins. Examples include the polycyclic hydrocarbons from cigarette smoke, aryl amines from charbroiled meats, and prolonged intake of the antiepileptic medication, phenobarbital.
Dr. McGinnis offers these further observations about Bethanechol based on continuing experience:
This is looking oh-so muscarinic (producing direct stimulation of smooth muscles, though in this usage he means the opposite—WSL)—big pupils (we are measuring them now—its easy with the graded circles, which can be drawn by hand in mm diameters, and held right alongside the eye), poor vision, bowel dysmotility with constipation and large-bore stools (diarrhea can stem from dysmotility, too, and of course even if they have a muscarinic block, the overgrowths and malabsorption may manifest as diarrhea), decreased sweating, and pallor. All this is consistent with low, muscarinic tone. There will be subgroups, but many of these autistic kids are looking clinically like muscarinic wipeout. Our assumption is that the CLO is building receptors, or otherwise favoring transmission so the Bethanechol can work.
These kids really turn around like nothing I’ve ever seen or heard before, especially as a single intervention. They are fun, connected, social, “with-it” kids, with many waking-up age appropriate. First changes are sometimes immediate, sometimes a little later. Bowels improve. Appetite improves. There is cumulative improvement in gaze, speech, sociability, and language. We expect urinary organic acids and intestinal permeability will improve if the Cod-liver Oil and Bethanechol are restoring the gut as expected.
More than ever, I’m realizing that the visual problem these kids have is in many ways worse than total blindness. It is more confusing, harder to integrate with the other senses. Dilated pupils and poor ciliary function from the muscarinic failure means fuzzy vision. Absent or poor rod function (we have all those long-ignored ERGs) means poor shading. The poor shading and edge definition cripple depth perception. We have a flat canvas with poor focus, and changing, fuzzy masses of color. A swing moving back and forth toward you would be a growing and shrinking colored mass. He sees body and head shapes by color, but no facial features. Spooky. It’s no wonder these kids start running around hugging everybody after the Bethanechol.
One might worry about damaging receptors by over-stimulation with long-term use of a messenger like Bethanechol, but I found two children who was improving on this cholinergic for several months, and then they started acting over-stimulated, hyperactive, and driven. With lower doses, this stopped right away, and behavior continues to improve. I find this comforting, and hope it is a real trend, that the taper will continue. There is no suggestion of tolerance so far.
No serious adverse reactions yet, even in quiescent reactive airway. We have a report of a seventy-pound child having really excessive lacrimation with a 25 mg initial dose of oral Bethanechol, prompting immediate dose lowering. There was no suggestion of excessive bronchial secretion, or of a need for atropine in this case, but one should be ready.
Chronic low-level insecticide exposure is known to decimate muscarinic receptor populations in animals. Some of the insecticides hang around for an awfully long time. Mercury is awfully rough on muscarinic receptors, too.
Typical signs of excess Bethanechol commonly include sweating, salivation, flushing, lowered blood pressure, nausea, abdominal cramps/diarrhea, and even bronchospasm, and would indicate a reduced dosage. Excessive saliva production is also a symptom of poisoning from particular chemicals, such as anticholinesterases (insect poison, mercury, aluminum, fluoride, sage, Aricept™, Huperzine A™), and a shortage of salt.
Most popular insecticides kill insects by inhibiting
the cholinesterase enzyme in the insect nervous system. Unfortunately,
humans rely on the same neurotransmitter and will experience the same
breakdown of the nervous system. An alternative insecticide blocks the
insect neurotransmitter octopamine. Mammals, birds, and fish do not have
octopamine in their nervous systems. This alternative insecticide is derived
from plant and tree essential oils. It is manufactured by Ecosmart
Technologies (
In those who show the dilated eyes, and other signs of loss of smooth muscle tone, avoid these foods, herbs, and drugs that relax smooth muscles: Most increase nitric oxide (NO)—the gas that relaxes the smooth muscles in blood vessels contributing to better blood flow. The results are essentially the same as for calcium and beta channel blockers (prescription drugs) that should be avoided also. A supplement of manganese will likely help to degrade arginine, preventing excessive levels, and zinc inhibits nitric-oxide formation. Be aware that stress increases nitric oxide production, and that excess NO inhibits the mitochondrial function, especially in Complexes I to III, and it depletes intracellular glutathione. The detriment can be reversed by high intensity light or by replenishment of intracellular reduced glutathione.
Oleuropein
(Olive Leaf Extract)
.................................
Garlic
(allicin).............................................................
Niacin
Arginine
(amino acid), and high arginine......................
Ginkgo Biloba, increases blood flow
foods. Increases growth hormone and NO.
to brain, increasing oxygen and increasing nutrients to the brain.
Increases nitric oxide synthase & increases NO. It has other negative
effects on Phase I liver detox pathways that contraindicate its use.
Choline......................................................................
Inositol
Ginger........................................................................
Yohimbine
increases NO
Nitroglycerine,
increases NO....................................
Fluvastatin (cholesterol lowering drug),
Nitrates
increase NO.
Noni Juice increases NO.
Viagra™
increases NO (should not be........................
Chocolate
used with these other nitric oxide donors.)
................... Forskolin
Sumatripan
(antimigraine drug)...................................
Ginseng,
increases NO by blocking Cyclic GMP (Chen 1995). Hypoglycemic persons should
not use it.
Aspirin/salicylate/Cox Inhibitors
enhances
............ Schizandra,
increases NO.
NO synthase (NOS-1) increases NO.
Additionally, organic solvents and pesticides, whose exposure is reported to precede and presumably induce multiple-chemical sensitivities, are also reported to induce excessive, nitric-oxide synthesis. Such chemicals are also reported to induce increased synthesis of inflammatory cytokines (growth hormones) that, in turn, increases the inducible nitric oxide synthase (leading to increased synthesis of nitric oxide). All excitotoxin damage (primarily glutamate and MSG) generates high levels of nitric oxide that has been shown to inhibit sulfation of GAGS. A recent study of Fibromyalgia implicates elevated nitric oxide, and also elevated NMDA stimulation, which stimulation (primarily by glutamate) is known to increase nitric oxide synthesis. Infection and other stresses that often precede CFS may produce CFS. The theory predicts that each of these can lead into this mechanism by inducing excessive nitric oxide. Infection is not the only stress that may be involved in this way; both physical trauma and severe psychological trauma can produce excessive nitric oxide synthesis. In addition, tissue hypoxia may induce this cycle by increasing levels of superoxide (present in Down’s) (the other precursor of peroxynitrite).
In animal models of MCS, there is convincing evidence for an essential role for both excessive NMDA activity (where such activity is known to induce excessive nitric oxide) and for excessive nitric oxide synthesis itself. If one blocks the excessive, nitric-oxide synthesis in these animal models, the characteristic biological response is also blocked.
An increased production of nitric oxide and of various inflammatory peptides—such as substance P (a neurotransmitter that transmits pain and modulates inflammation), CGRP (calcitonin-gene related peptide), and VIP (Vasoactive Intestinal Peptide); and Secretin (a 27 amino acid peptide, one of a family of neuropeptides that include VIP and glucagon)—is observed in magnesium deficient rats, so I suggest that a high intake of vitamin B6 and magnesium (5-10 mg/kg/day) and an equal amount of calcium can benefit these low-muscle-tone kids, including, of course, the ones with weak peristalsis. (A distinct, new family of G-protein-coupled receptors includes VIP, PACAP, glucagon, parathyroid hormone, and calcitonin.) VIP seems to play a modulating role (with a bias toward inhibition) in the inflammatory process in these diseases, as does Substance P and CGRP.
Dopamine, a neurotransmitter, and the amino acid tyramine (formed from tyrosine metabolism that produces dopamine) are phenolic compounds that are strongly vasodilative, and they lower the pressure (in the gut) at which peristalsis begins. It seems then that a supplement of tyrosine would help with these kids with poor peristalsis. Furthermore, since serotonin induces a stronger peristalsis, a cautious use of 5-HTP should benefit the low, smooth-muscle-tone condition.
One can increase acetylcholine production and enhance the tone of skeletal muscles by supplementing one or more of these: Bethanechol, melatonin, acetyl-L-carnitine (or L-carnitine), CDP Choline, MSM, SAMe, DMAE, TMG, manganese, Coenzyme A, lecithin granules (choline), or phosphatidylcholine. The effectiveness of these will be enhanced by a supplement of pantothenic acid (vitamin B5). It is reported that not all autistic children do well on choline, but this group should. Loss of gut mucosal integrity (common in ASD) would decrease by 85% gut absorption of CoA (the critical enzyme when choline is converted to acetylcholine), shunting choline into homocysteine production that SAMe, folic acid, vitamin B6, and B12 metabolize back into usable aminos. TMG helps make SAM. I think that in building acetylcholine, one should supplement the TMG, folic acid, vitamin B6 and B12, and possibly SAMe, to protect against a build up of homocysteine. There is probably a need to detoxify mercury, PCBs, and Candida for all depress acetylcholine production. There may be a real need for serotonin. Serotonin stimulates the peristalsis of the bowel. So, I suggest the supplementing of vitamin B6 and magnesium to conserve serotonin, and, unless the child is strongly PST, of TMG, SAMe, and/or 5-HTP to create more serotonin. See cautions in using 5-HTP elsewhere in this paper. The laxative of choice for low peristalsis is cascara sagrada, said to actually improve muscle tone of the bowel. Cabbage juice is also an effective laxative for these children with low peristalsis.
Acetylcholinesterase is an enzyme in the blood and tissues that hydrolyses spent acetylcholine in the fashion that MAO-B catabolizes serotonin/dopamine. An excess of Acetylcholinesterase inhibitors such as Aricept™, Huperzine™, Meshinon™, Galantamine, insecticides, mercury, aluminum, fluoride, sage, and a shortage of salt can produce aggression and violence by keeping acetylcholine on the receptors, revved up and firing. This will make the child truly unable to sit or stand still! Everything is getting the signal to go-go. These do not increase acetylcholine stores, as sometimes suggested, but simply keep acetylcholine in the synapse longer. In small amounts, use of these inhibitors can sometimes make do with less acetylcholine or be beneficial when receptors are diminished or insensitive. In larger amounts, it can kill by paralysis of vital organs. Low cholinesterase levels (an enzyme present largely in the brain) induce a vitamin B1 deficiency that lowers dopamine levels, and thus Epinephrine and Norepinephrine levels. Where possible, it is better to produce more acetylcholine, as indicated above, rather than mess with these enzymes.
As stated, dopamine and the amino acid tyramine are strongly vasodilative, and they lower the pressure (in the gut) at which peristalsis begins. A reduction of norepinephrine (NE) and/or dopamine, or too much acetylcholine activity causes diarrhea, irritable bowel syndrome, cramps, nervous stomach, increased saliva, raised insulin levels, and airways and cerebral blood vessels constrict. A lack of dopamine is a problem in some patients with chronic anxiety.
It has been shown that a deficiency of vitamin A, the amino acid cysteine, the minerals zinc, iodine, iron, and selenium, tyrosine, and of the antioxidant glutathione (which requires cysteine), and an excess of copper will adversely slow the thyroid function creating low muscle tone. White sugar also paralyzes the intestinal peristalsis, and leads to immune system failure. Copper slows the thyroid while zinc increases thyroid action.