I don’t know a great deal about the issues in this post. Experts by Experience and The Marketing of Anticholinergic Maleficence along with Psychotropic Drug Follies will give some feel for the background that makes it difficult to be certain about anything linked to the cholinergic drugs. The Past Present and Future article will need to be downloaded to take to your doctor for reasons outlined below.
The post does not make treatment recommendations. It covers a topic lots of readers are asking about aimed at enabling you to make your own judgement calls. It might help to consult others – not a doctor. Best people would be someone on or previously on an anticholinergic or cholinomimetic drug.
During the 1980s and later, I and most doctors working in mental health gave out lots of anticholinergic drugs, usually by Brand Name. Knowing in this case means knowing by experience of seeing what the drugs did to people who took them and listening to what they said – as much if not more than knowing from academic articles.
The brands were well known without a drug rep handing out branded pens or stickies. This likely reflects the comfort most doctors and patients had with them. Being as comfortable as this with older, cheaper drugs typically leads to company vilification – usually through the medium of ‘responsible clinicians’, whose concerns get amplified in a way that never happens with concerns expressed on RxISK. From the late 80s onwards there was an increasing divergence between academic and patient level views about these drugs.
The main anticholinegic drugs in use in the UK and Ireland were:
- Benztropine, marketed as Cogentin,
- Biperiden, marketed as Akineton
- Procyclidine marketed as Kemadrin
- Orphenadrine, marketed as Disipal, Norflex
- Trihexyphenidyl, marketed as Artane, Trihexane, Tritane
This short list contrasts with the 350 or so drug names you will find on Anticholinergic Burden IACB) Lists. ACB lists include drugs with a claimed anticholinergic action. Your ACB score is got by adding the anticholinergic scores of all drugs you are on. If its high you will have dementia in the morning.
- Less than half the listed drugs have any effects on any cholinergic receptor.
- The effects of many are minimal compared to proper cholinergic antagonists.
- Many proper cholinergic antagonists do not cross the Blood Brain Barrier –
See this astonishing article – Lavrador et al..
The other 300+ drugs on these lists do cause dementia and other problems but its their serotonergic, dopaminergic and gabaergic actions which do this – especially when combined. Both pro and anti cholinergic system drugs are cognitive enhancing when used properly.
Withdrawal and the Cholinergic System
By 1961, imipramine and amitriptyline, the earliest antidepressants, had been reported to produce withdrawal reactions. Clinicians were warned that if these reactions cleared up on reinstating the antidepressant doctors and patients might be misled into thinking these drugs were more effective than they are.
These withdrawal reactions quickly got attributed to cholinergic rebound. The received wisdom was that cholinergic rebound like beta-blocker rebound would only last 48-72 hours, producing nausea, dizziness, disturbed sleep and nightmares. Strangely benztropine and procyclidine never seemed to cause withdrawal effects.
We now know that even for these older drugs withdrawal stems from their serotonergic effects and lasts much longer than 48-72 hours.
Antidepressant withdrawal is more complex than rebound. Rebound follows the expected dynamics of drugs separating from the receptors they are bound to – antidepressant withdrawal doesn’t. Rebound can be eased by tapering but can often be managed cold turkey and does not become protracted.
Tapering antidepressants and using Tapering Strips to help people off antidepressants has been a great step forward. It encourages many people to think about stopping a treatment that was only designed to be short term but often lasts decades. Dee Mangin introduced the term Legacy Drugs or Legacy Prescribing to describe what happens.
Tapering as currently practiced has keyed into what we know about the dynamics of drugs separating from receptors. The implication that we understand the science of what we are doing reassures and motivates people.
But I don’t understand the science of tapering any more than the science of anticholinergic drugs. The images of antidepressants mapped onto hyperbolic curves used to promote Tapering are in part an artefact. The curves stem from the fact these drugs were brought on the market way way above doses that fully block serotonin transporters. It is no surprise then that titrating down from 60 mg of fluoxetine, paroxetine or citalopram to 20 mg should show little receptor binding changes. The surprise is that some people can find this terribly difficult and have even greater problems when they try to increase the dose back to previously comfortable levels. Something has become unstable.
There are other problems. Even tapering extraordinarily carefully and scientifically, some people can have terrible difficulties or find it impossible, while others can stop from huge doses relatively quickly – see Withdrawal Mysteries.
Then there is protracted withdrawal which seems to cover two different states. One is a terrible withdrawal taking a very long time as in Justin above. The other is a sense that yes I am off this drug, not suffering acutely, but a lot of things are not back to normal – with this latter state taking several years to respond – see The Colour of Life.
For me this suggests two interacting elements. One is likely to be a semi-classic withdrawal syndrome involving the drug separating from a binding site.
The other is antidepressant neurotoxicity. There is evidence serotonergic drugs choke or fry small peripheral nerve endings. This may underpin their ‘marginal’ benefits for pain. They degrade the fibres or sensory receptors mediating pain. Stopping the drug lifts the chokehold leading to a re-emergence of the symptoms of peripheral neuropathy that seem to map well onto the features of protracted withdrawal.
There are few articles on antidepressants and brain cell loss but there is evidence they cause osmotic demyelination – which is brain damaging. The radiological evidence that antipsychotics lead to brain cell loss is more compelling. Antipsychotics commonly, and SSRIs less commonly, trigger tardive dyskinesia – a state of significant neurological dysfunction if not damage.
If a neurotoxic effect is at least an element of what is happening, then part of the answer for some to getting off antidepressants and antipsychotics and perhaps anticonvulsants and benzodiazepines may lie in nerve regeneration. But until recently this seemed impossible.
The standard view on MS was that an inflammatory process attacks the myelin sheath protecting nerves. Treatments aimed at suppressing this inflammation included high cost monoclonal antibodies that also have a high cost in terms of lethal side effects.
When myelin breaks down, it is usually repaired by oligodendrocyte cells. But in MS these cells are missing in action.
Scripps screened old drugs to see could any stimulate oligodendrocytes and found benztropine did. Tested in animal models, benztropine reversed the defects found in MS. They said no other anticholinergic does this – so it was nothing to do with benztropine’s anticholinergic action.
It seemed the benefit could be found in very low doses which suggested some novel action beneath the headline cholinergic effects. This can happen – Josef Knoll’s famous studies on important catecholamine effects lying beneath the effects everyone thought were all there was is an astonishing story – See The Psychopharmacology of Life and Death.
Equally interesting was the fact Merck removed Cogentin from almost all markets – even China. They and others may have spotted a fortune to be made by finding out what the underlying effect was or a fortune to be lost if Monoclonal Antibody sales dropped.
Cogentin remained available in the US. A RxISK Nobel Prize post asked benztropine takers – but got no responses- whether:
- anyone with MS using benztropine figured it helps
- anyone on benztropine figured it makes a difference to something.
- anyone outside the US whose benztropine was stopped found they had developed new complaints since it was replaced by another anticholinergic.
- anyone could tell us the inside story on benztropine’s removal
- anyone knows how to get benztropine to people living outside the US
The Scripps effect was on big rather than small nerve fibres. Since then Paul Fernyhough in Manitoba and colleagues in San Diego, linked to WinSanTor have shown in animal models that another anticholinergic drug, Pirenzepine, regenerates small fibres in animals. WinSanTor have pushed forward with clinical trials and a press release, but not yet a publication, claiming pirenzepine produces benefits in diabetic neuropathy.
So it’s not just benztropine and not just big fibres but it is the anticholinergic action, acting perhaps to stimulate mitochondria back into action or to liberate VEGF which gets blood vessels to sprout with the nerves following the blood supply.
Another point to note is muscarinic – cholinergic drugs appear to modulate receptors rather than choke them like some of the SSRIs choke (bind with high affinity) to serotonin transporter sites.
There may be steps in between M-3 and nerve regeneration. Benztropine for instance has effects on ACE-2 receptors which SSRIs can knock out.
Another piece in the jigsaw was a 2017 report of a cholinergic dysautonomia in a 14 year old girl. This gave her an atonic bladder and bowel. She responded over a 5 month period to bethanecol – a cholinergic agonist for M-3 receptors. See Dysautonomia improving with Bethanecol. The authors figured that it was the agonist effect that helped but the time course of full recovery is consistent with nerve regeneration.
Muscarinic-3 (M-3) receptors are where the nerve regeneration action is these days. Muscarinic Acetylcholine Receptors
This poses a problem. Bethanecol is an agonist at M-3 receptors and benztropine and pirenzepine are antagonists – surely doing the opposite thing? In the bladder, the anticholinergic oxybutynin damps down bladder activity while bethanecol stimulates it – but both cases nerve regeneration may help.
The different actions may be resolvable. In the autonomic system, cholinergic fibres can be pre-ganglionic and post-ganglionic and each of these drugs may give opposite effects if acting pre or post-ganglionically. In addition in different cases – autonomic or peripheral neuropathies – they can appear to do the same thing – regenerate nerves.
The Treatment End
Benztropine and other anticholinergic drugs have been used for akathisia. They can help but are not particularly useful – red wine and beta blockers and P-5-P at least for some people are better. Bethanecol can be useful for sexual function but its not Viagra (although Viagra is not as good as the marketing hype suggests).
We are not looking for headline benefits like these – although the comments after the Visual Snow post raise the prospect of an immediate visual effect when eyes are dilated with an anticholinergic drug. Nerve regeneration is a slow process taking 3-6 months in all likelihood.
If the toxicity story is right, the nerves needing repair have been poisoned by high doses of drugs. They do not need toxic doses of a cholinergic or anticholinergic drug. At present, the research suggests the lower the dose the better. If a drug needs to be taken for months, you do not want it causing problems.
The first step is to aim at the lowest available dose and perhaps only one pill per day – think of it as more like a vitamin. This is a case of Less is More – along the lines of Knoll’s demonstrations in the psychopharmacology of life and death.
In all likelihood all anticholinergics will work but maybe not for all people. Pirenzepine is not absorbed into the body – it is used as a paste on skin or for gut problems.
For people outside the US and Canada who want benztropine, the next issue is how to get it. I don’t know whether internet shopping is safe. Some readers likely do – please advise in a comment.
After that, whether in the US or elsewhere in the world, especially Europe or the UK, the next problem is persuading your doctor to give you an anticholinergic off-label.
Technically this is easy – doctors are free to prescribe off-label. The label of a drug is supposed to control the claims companies can make about their medicines. Labels are irrelevant when it comes to what doctors can prescribe. Many doctors, however, are bamboozled by this and will insist they cannot prescribe off label. See Healy and Nutt – Prescriptions, Licenses and Evidence. You can try bringing them this post and the H and N article. But it may be no good and you may need a friend to get it for you.
Even if your doctor is relaxed about labels, they might not want to prescribe an anticholinergic drug for you or a cholinomimetic (for Alzheimer’s) drug or something ancient they have never prescribed before like bethanecol.
This is especially the case for anticholinergics, which have been vilified possibly more than any other drug group in history. The most you can probably do is leave the articles and posts with them and let them think about it. We are talking about something in a very low dose that is probably less harmful than low dose aspirin, a drug that you would commit to stopping immediately if there is any hint it is not suiting you.
Who Does this apply to
Anticholinergics are not an antidote to SSRI withdrawal effects. It seems most appropriate to try them if you have been able to get off an SSRI but have residual symptoms, especially if they are severe to the point of thinking you may need to go back on an SSRI.
Going back on a previously successful SSRI often doesn’t work. This is one more indication that something else is going on in these protracted states not typical of withdrawal.
If the problem symptoms seem more gut or cardiac (POTs) rather than altered sensations around the body especially in hands or feet, bethanecol may be worth considering rather than an anticholinergic. Gut and cardiac symptoms point to an autonomic neuropathy rather than a peripheral neuropathy. The case of the 14 year old girl noted above suggests bethanecol may work better for an autonomic neuropathy.
What to do for complex protracted withdrawals with both autonomic and peripheral neuropathy features? Who knows! Perhaps treat the more severe set of problems first.
A further group of people are those who have tapered down to a certain point and feel unable to taper further and contemplate going back up a dose. It is difficult to know how to advise them. Take a plunge and go cold turkey and then start an anticholinergic? Or stay on the same dose and start an anticholinergic and perhaps Taper later if it feels like it has become easier to do so?
I have had one lady in this state that benztropine added to her SSRI does not appear to have helped – but a lot of people in these states want rapid benefits or to ‘feel’ a benefit and saying you have to take this drug for weeks or months can sound like the advice many people got from their doctor about SSRIs in the first place that landed them with the problems they now have.
Enduring Sexual Dysfunction
A key group of people are those with PSSD, PFS and PRSD. I believe a decade back after the Nobel Prize post, I had a patient whose PSSD improved on benztropine, but I lost contact with him.
If there is going to be any benefit in any of these states it may take months to appear. It is also possible that bethanecol may be a better bet than an anticholinergic if PSSD and related conditions stem from an autonomic neuropathy rather than a peripheral neuropathy.
The 14 year old girl had an atonic bladder rather than an overactive one. If PSSD looks to you more like an atonic state rather than an overactive state, then bethanecol may be the way to go. On this line of thinking an anticholinergic drug may be more helpful for PGAD.
Having made these points there seems to be an interaction between cholinergic and ACE-systems that needs exploring further and Luisa Guerrini in Milan is the person to do this.
Bowel, Heart and Vision Problems
One of the most consulted and commented on RxISK posts was Bladder and Bowel Problems on Antidepressants Serotonin Reuptake inhibiting drugs cause Pelvic Floor Dyssynergia – a terrible problem that leads to suicide.
SSRIs also cause Gastroparesis – another debilitating condition, with to date no treatment. This looks like a good candidate for bethanecol.
Then there are the Vision Problems outlined in the Visual Snow post, some of which tantalisingly might even respond dramatically quickly to an anticholinergic drug – although it might need to be continued for some time to cement the response in place.
There are also cardiovascular problems like Postural Orthostatic Tachycardia Syndrome (POTs), triggered by SSRIs and Covid Vaccines it seems. Many people have had antibody tests done in conditions like these and antibodies to the M3 receptor turn up regularly.
Many of these Gut, Heart and Vision conditions just as with protracted withdrawal and PSSD often appear on stopping the drug and endure for ages afterwards pointing to a commonality.
The Nicotine System
Nicotine can be a wonderful cognitive enhancer and stress reliever – as good for some people as SSRIs for OCD or depression. Its not a treatment for PSSD. Sexually its more linked to erectile dysfunction although part of this may stem from smoking it.
There are a number of nicotinic antagonists like suxamethonium and rocuronium. Linked to this, a regular commenter on RxISK posts recently claimed ECT had cured his PSSD – and definitely cured his emotional numbing, anhedonia.
It is difficult to see how ECT would do this – it acts on motor rather than sensory systems. But to get ECT, you have to be put to sleep and also be given a muscle relaxant, either suxamethonium or rocuronium and these nicotine antagonists have profound depolarising effects across the body.
If anyone had relief from their PSSD, PFS, PGAD, gastroparesis or withdrawal states after an operation, let us know. You likely had suxamethonium or rocuronium when you were put to sleep.
The Vagus Nerve
The Vagus Nerve lies at the heart of all these issues. It is viewed in many quarters as the most important nerve in the body – key to making us sociable.
Anyone who wants to spin a good story about the matters dealt with in this post might being by acquainting themselves with Polyvagal Theory.
To Infinity and Beyond
After a recent lecture covering PSSD, a woman asked me if anyone had tried DMSO for nerve regeneration. I had never heard of Dimethyl Sulfoxide. Just shows how little I know so treat this with care – appearing it may at least stabilize nerve damage but of course as with all things available over the counter there is a lot of information out there telling us this is highly dangerous. It may well be for all I know.
Almost immediately after I heard first about DMSO, I heard about it again. It seems we may have discovered Life on a Faraway Planet . The evidence for this is the James Webb Telescope has found chemical evidence in the spectroscopy of this planet that looks highly like DMSO.