“Anticholinergics” refers to a family of substances and drugs that either block or reduce the activity of the neurotransmitter acetylcholine. In part one of our SelfHacked series on anticholinergics, we discussed the historical background of these compounds, how they work, and some of the medical applications that have been proposed for them. In this post, we’ll review what the current science has to say about the potential side-effects, drug interactions, and other possible risks associated with the use of these drugs. Read on to learn more!
Disclaimer: This article is not a recommendation or endorsement for any of the drugs or other substances mentioned throughout this post. Many of these medications have only been FDA-approved for the treatment of certain specific medical conditions, and most can only be taken by prescription and with oversight from a licensed medical professional. We have written this post for informational purposes only, and our goal is solely to inform people about the science behind these drugs’ possible side-effects and other potential risks. None of the information in this post should ever be used to replace conventional medical care or treatment — and always make sure to discuss any new medications or other health-related treatment changes with your doctor first!
Anticholinergics: A Brief Review
“Anticholinergics” refers to a family of drugs and other compounds that block the activity of the neurotransmitter acetylcholine. In general, these compounds work by binding to many of the same receptors throughout the body and brain that acetylcholine naturally activates, thereby preventing (“blocking”) its normal effects [1, 2].
Some “natural” anticholinergics are found in variety of plants and herbs, whereas others are “synthetic,” meaning that they were scientifically designed to target certain symptoms of various health disorders [3, 4].
Anticholinergics are widely used by medical practitioners to treat a variety of health conditions, including asthma, bronchitis, irritable bowel syndrome (IBS), Parkinson’s disease, among many others [5, 6, 7, 8, 9, 10, 11].
However, the use of anticholinergics also comes with certain risks — especially if taken in excess, or without the active supervision of a qualified medical professional.
In part one of our SelfHacked series on anticholinergics, we reviewed some of the general mechanisms behind these acetylcholine-targeting drugs, as well as discussed some of their current and potential medical applications. We highly recommend starting with that post, especially if you are new to workings of the acetylcholine system!
In this post, we’ll review some of the various potential side-effects, drug interactions, and other possible risks associated with the use of anticholinergic compounds. Read on to learn more!
Side-Effects and Toxicity
Like any drug, anticholinergics have the potential to cause a variety of unwanted and adverse side-effects, even when used as directed and prescribed by a medical professional. Therefore, it is important to be aware of these.
As always, the best way to avoid potential negative side-effects is to discuss your treatment options with your doctor! Only a fully-qualified medical professional has the necessary expertise and training to help you navigate the possible therapeutic benefits and risks associated with a particular course of treatment. Therefore, the information contained in this post should never be used as a replacement for conventional medical care.
Additionally, if you think you may be experiencing any of the side-effects discussed below, it is extremely important to seek out medical care as soon as possible.
Because the anticholinergics primarily target the acetylcholine system — and because the acetylcholine system is very complex and has a wide variety of different functions — the range of potential side-effects is quite broad, and often depends on the nuances of how a particular anticholinergic compound interacts with different specific components of the acetylcholine system (such as different receptor types).
For example, the side-effects of muscarinic anticholinergics are broad and can include dry mouth, difficulty urinating, redness, blurry vision, dizziness, and cognitive impairment (memory loss and information processing) [12].
The following mnemonics are sometimes used to summarize some of the more typical side-effects associated with anticholinergics in general [13, 14]:
- Blind as a bat (dilated pupils / impaired vision)
- Red as a beet (skin redness / flushing)
- Hot as a hare (hyperthermia)
- Dry as a bone (dry skin or mouth)
- Mad as a hatter (hallucinations / agitation)
- Bloated as a toad (urine retention / constipation)
- The heart runs alone (tachycardia)
Side-Effects in Children and Adolescents
In one clinical study, 912 patients between the ages of 3-12 were observed for adverse reactions following single- and double-dosages of eye drops containing the anticholinergic drug cyclopentolate. Adverse reactions such as drowsiness were common, although other side-effects such as dizziness and irritability were reported to occur at a lower rate compared to other treatments [15].
Several cases of anticholinergic toxicity in infants have been documented, with irritation, quickened heart rate, and acute inflammation being some of the more common reported adverse side-effects [3].
Side-Effects in Psychiatric Treatment
In one study of 104 patients with schizophrenia, the administration of antipsychotics with anticholinergic-based effects was reported to lead to impaired cognitive performance, information processing, and memory, as compared to antipsychotic medications without anticholinergic effects or mechanisms [16].
Another study in 24 stabilized schizophrenic patients reported that blood levels of anticholinergic drugs were correlated with reduced performance in memory-based cognitive tests [17].
The measure of total anticholinergic agents in a person’s system is sometimes referred to as anticholinergic burden. According to one case-controlled review study, increased anticholinergic burden may be correlated with increased long-term risk of dementia. The greatest increases in risk were reported to come from antidepressant, anti-Parkinsonian, or bladder-function-targeting drugs in particular [18].
Side-Effects on The Cardiovascular System
According to one study, a 10µg (10 microgram) infusion dose of the anticholinergic atropine was reported to elevated the resting heart rates of nine adult males by as much as 25-30 beats per minute (BPM). Additionally, some of the subjects were observed to have elevated blood pressure for up to several days after the initial treatment, suggesting a potential negative long-term or chronic after-effect from this drug [19].
Relatedly, one animal study has reported that several anticholinergic muscle-relaxing drugs commonly used during anesthesia — including pancuronium, vecuronium, and mivacurium — led to significantly increased heart rates when administered to rats, which further suggests potential negative cardiovascular side-effects from these drugs [20].
May Affect Cognition in the Elderly
According to one 7-year-long study in 3,434 elderly participants (65 or older), the use of multiple anticholinergics at once may increase the risk of dementia [21].
Relatedly, according to a relatively small-scale study comparing 12 young and 15 elderly adults, the use of the anticholinergic drug mecamylamine was reported to lead to slower information processing and reduced cognitive performance on memory-based tasks in the elderly group — but not in the younger group [22].
In another longitudinal study of 1,780 elderly individuals, anticholinergics were reported to reduce cognitive performances on certain cognitive tests evaluating visual memory and verbal fluency [23].
Cases of anticholinergic toxicity have been reported to cause a variety of adverse side-effects including increased heart rate (tachycardia), blurred vision, impaired digestion, impaired cognitive function and memory processing, and reduced heat intolerance — all of which are symptoms that can be especially dangerous for older patients in particular [13, 24].
Finally, another study reported that 10mg of mecamylamine may have caused impairments in learning and memory tasks amongst elderly patients, but not in younger subjects. According to one other study, a combination of pancuronium with high-dose fentanyl anesthesia increased heart rate and blood pressure in 12 patients undergoing heart surgery [22, 25].
Anticholinergic Syndrome
The term “anticholinergic syndrome” refers to the potential toxic effects produced by exceeding the recommended dose of anticholinergics. Its symptoms can include accelerated heartbeat (tachycardia), overheating (hyperthermia), drowsiness, blurred vision, dry skin and mouth, and occasionally even more severe symptoms, such as hallucinations and seizures [26].
Although it can be caused by over-use of anticholinergic drugs, anticholinergic syndrome is also commonly observed following surgical procedures involving the use of general anesthetics such as atropine and scopolamine. In these cases, the symptoms can include difficulty breathing, general impairment of brain function, and altered cognitive processing [27].
Anticholinergic Poisoning
According to one review, certain anticholinergic drugs — such as atropine — have been reported to cause a variety of potentially toxic side-effects when administered at dosages exceeding 75-100mg. However, the most severe side-effects typically occur at much higher doses, such as 450mg per person [28].
For example, uncontrolled or excessive consumption of the plant Atropa Belladonna — also known as “Deadly Nightshade” — has been reported to lead to anticholinergic poisoning. According to case reports from 50 different patients, some of the symptoms of such poisoning can include meaningless speech, hallucinations, flushing, memory loss, increased heart rate, irregular breathing, and even coma [4, 29].
High blood levels of tricyclic antidepressants (TCAs) can also cause anticholinergic poisoning, including the previously-mentioned symptoms. However, there have also been 19 documented cases of overdose that led to comas — 16 of which required emergency respiratory support (such as machine-assisted breathing), and 2 of which led to the death of the patients [30].
Potential Antidotes to Anticholinergic Poisoning
The alkaloid compound physostigmine salicylate is sometimes used by medical professionals as an antidote to anticholinergic poisoning. For example, some studies have reported that a dose as small as 2mg may potentially counteract some of anticholinergic poisoning’s side-effects, such as breathing difficulties, hallucinations, variable heart rates, dry skin, and coma [31, 32].
According to a case study of a single patient, physostigmine reportedly reversed the symptoms of antimuscarinic poisoning in one 13-year old who accidentally overdosed on diphenhydramine, along with other medications [33].
Drug Interactions
In addition to possible adverse side-effects, anticholinergic drugs can also potentially have a variety of complex and negative interactions with other drugs and medications. Moreover, the specific effects that these interactions can cause may be highly specific to the particular type of anticholinergic drug being used, as well as exactly what compound it is being combined with [34, 35].
As always, the best way to minimize the risk of experiencing adverse drug-drug interactions is to keep your doctor fully informed of any medications you are currently taking, as well as any other pre-existing health conditions you may have, and any other health-relevant lifestyle and dietary factors that could potentially impact your treatment. Only a fully-qualified medical professional has the necessary scientific background and clinical training to help you navigate the possible therapeutic benefits and risks associated with a particular course of treatment.
Therefore, the information below should not ever be used as a replacement for conventional medical care. Additionally, if you think you may be experiencing any of the side-effects discussed below, it is extremely important to seek out medical care as soon as possible.
With those important points in mind, let’s see what some of the latest science has to say about some of the other substances and medications that anticholinergics can potentially interact with!
Anticholinergics and Antipsychotic Medications
According to one study of 104 schizophrenic patients, the combination of antipsychotic medications and anticholinergics has been reported to impair certain cognitive functions, such as information processing and verbal memory. Additionally, these negative cognitive effects appear to become both stronger and more likely at increasing dosages of anticholinergics [16].
Anticholinergics and Dementia Medications
According to some studies, anticholinergics may interact with a number of relatively common anti-dementia drugs, such as donepezil. Additionally, some researchers have raised concerns that the use of anticholinergic medications in the elderly may increase a person’s long-term risk of developing dementia with age [36, 37, 34].
However, the exact magnitude and overall likeliness of this risk is not yet known for certain — and neither are the potential underlying mechanisms. While more research will be needed to verify and flesh out these preliminary findings, some caution may be advised for older individuals in the meantime.
Anticholinergics and Cholinesterase Inhibitors
Cholinesterase inhibitors are drugs that prevent the action of the enzyme cholinesterase, which is responsible for breaking down the neurotransmitter acetylcholine throughout the body and brain. These drugs therefore generally increase overall acetylcholine levels, and are sometimes used by medical professionals to treat some of the symptoms of Alzheimer’s disease [38].
Since these medications have the opposite effect of anticholinergics, taking these types of drugs together can cause them to directly interfere with each other, thus reducing their efficacy, as well as potentially leading to a variety of more complex and unpredictable effects [38].
Anticholinergics and Diabetes Medications
According to some early medical reports, anticholinergic medications may interfere with some common anti-diabetic drugs, such as metformin. Although the exact mechanisms are still unclear, some researchers believe that anticholinergics may increase the levels of sugar (glucose) in the blood, which would directly cancel out the therapeutic effects of anti-diabetes medications [39].
Doxylamine succinate vs Diphenhydramine
Diphenhydramine and doxylamine succinate (DS) are two relatively common antihistamine drugs that have been reported to have some anticholinergic effects. They are each available in several over-the-counter forms, and are commonly taken to alleviate the symptoms of several common illnesses, such as allergies and the common cold [40].
However, while they may each involve some anticholinergic mechanisms, there are some subtle differences between them that may affect how effective they are for different conditions.
Diphenhydramine
Diphenhydramine is an older antihistamine that also has anticholinergic effects. It is the main ingredient of the over-the-counter medication Benadryl, a sedating allergy medication [40].
Diphenhydramine is generally reported to provide rapid relief from acute allergic reactions to foods and other potential environmental irritants. According to one study in 70 allergy patients, diphenhydramine (1 mg/kg) reportedly relieved the symptoms of an allergic reaction at the same rate as a newer antihistamine called cetirizine (0.25 mg/kg). However, cetirizine was not reported to cause some of the side-effects associated with diphenhydramine, such as drowsiness, sedation, and impaired movement [41, 42].
In another placebo-controlled study in elderly insomnia patients, 50 mg of diphenhydramine was reported to reduce the number of nightly awakenings significantly more than an inactive placebo treatment. However, it was not reported to significantly affect either sleep onset or sleep quality [43, 44].
Doxylamine Succinate
Doxylamine succinate (DS) is an antihistamine available over-the-counter, and is a common ingredient of many sleep aids, such as Noctyl, Nytol, and Restaid, as well as in several decongestant medications [45].
Doxylamine succinate is commonly used for the treatment of the common cold. According to one study in 688 sick patients, 4 daily dosages of 7.5 mg of DS was reported to successfully reduce the cold symptoms of sneezing and runny nose. The incidence of sedative side-effects was also reported to be lower than those from earlier studies of the effects of other antihistamines on the common cold [46].
The OTC medication Diclegis (doxylamine succinate), when combined with vitamin B6, was reported to improve nausea and vomiting symptoms in one randomized control trial (RCT) study of 131 pregnant women. According to this study’s authors, its effects were noticeable within 3 days of treatment [47].
25 mg of Doxylamine succinate (25 mg) — either administered alone or in combination with acetaminophen (paracetamol / Tylenol) — was reported to improve sleep, sensations of well-restedness, and even reduced pain in comparison to placebo, according to a study of 2,931 post-surgery patients. However, the combination therapy led to the greatest improvement in sleep [48].
Side-Effects of Diphenhydramine & Doxylamine
According to one review, over-the-counter medications containing diphenhydramine or doxylamine may be potentially unsafe for use by elderly individuals. This is because they can potentially impair memory and information processing, as well as cause dizziness or impair vision [49, 50].
In one study in 16 male participants, diphenhydramine was reported to cause side-effects of drowsiness, reduced alertness, and also had undesired sedative effects [51].
Additive Effects of Anticholinergics
According to one review, anticholinergic drugs may increase the risk of dementia in some users. While the overall magnitude of this risk and the potential mechanisms involved are still unclear, according to this review’s authors, anticholinergics that act primarily on the central nervous system (CNS; consisting of the brain and spinal cord) may carry the relatively greatest risk. Some researchers believe that such risks may possibly arise due to the ability of these drugs to contribute to widespread and/or chronic inflammation throughout the CNS [35].
According to one 4-year-long longitudinal study in 6,912 participants, anticholinergics may be associated with chronic impairments in diverse cognitive functions including verbal fluency, visual memory, and executive function. Importantly, these potential effects appeared to be correlated with the overall number and dose size of anticholinergics used, which suggests that this risk may be directly related to the overall amount of anticholinergics taken over time [52].
Nonetheless, these findings are still relatively preliminary, and much more research will still be needed to verify these potential risks, as well as to identify the possible mechanisms involved.
Genetic Factors That May Influence Anticholinergics
In general, a person’s overall levels and activity of acetylcholine — as well as the total number of receptors they have for it — are influenced by a large number of potential genes. Therefore, a person’s genetics may have a significant influence on how they respond to acetylcholine-based medical treatments, such as anticholinergics.
According to some preliminary genetics studies, certain genetic variants in nicotinic receptor genes (such as the CHRNA3 gene) may be associated with a greater risk of developing chronic obstructive pulmonary disease (COPD). For example, according to one study comparing over 3,400 COPD patients against 11,000 healthy controls, one specific variant in particular — the ‘A’/’T’ allele of SNP rs1051730 — may be associated with increased general risk of COPD (regardless of smoking history) [53].
Carriers of the epsilon-4 (“e4”) allele of the APOE gene have also been reported to experience worse cognitive function after receiving anticholinergic medication, as compared to people without this specific genetic variant. For example, one preliminary small-scale study reported that over the course of 3 weeks of treatment with 2.0 mg of the anticholinergic trihexyphenidyl, carriers of the e4 APOE allele were reported to score relatively lower on memory and information processing tests, compared to people without this specific genetic variant [54].
However, it is important to keep in mind that — like the majority of all genetics studies — these findings are only reporting statistical associations. In other words, just having a “risk allele” does not necessarily mean that a person will ultimately have or develop any particular trait or health condition.
“Natural” Anticholinergics
According to some preliminary research, there may be a wide variety of different substances and compounds that can potentially influence acetylcholine levels and activity. Generally speaking, these commonly work either by imitating it, or blocking its effects [55].
However, whether consuming the foods and supplements below can actually result in clinically-meaningful increases or decreases in overall acetylcholine activity is still an open question. While there is some early research with promising results so far, a lot more research will be needed to fully confirm these effects in healthy human users — and so far there is otherwise “insufficient evidence” to come to any firm conclusions about the effects of these substances on acetylcholine activity, or overall health.
Therefore, these early findings should be taken with a grain of salt until more extensive research is done to figure out their full effects, and the possible mechanisms involved.
With that in mind, let’s see what some of the latest science has to say about some nutritional compounds and dietary supplements that may influence the levels or activity of acetylcholine!
Compounds That May Increase the Effects of Acetylcholine
INSUFFICIENT EVIDENCE:
Substances and compounds that amplify or enhance the effects of acetylcholine are sometimes referred to as acetylcholine agonists. Some such compounds include:
- Nicotine: Nicotine binds to nicotinic receptors, increases their number, and stimulate the release of acetylcholine. However, continuous exposure to nicotine can slow down the effects, which may explain why chronic smokers gradually develop tolerance and a need for increasing amounts of nicotine over time [56, 57, 58].
- Lipoic Acid: Lipoic acid has been reported to increase the levels of acetylcholine in rats with dementia, and has also been tentatively associated with improved memory in these animals. It has also been reported to reduce the number of reactive oxygen species that can cause inflammation in the brain [59]. However, these findings have only been reported in animals so far, which means it’s still unknown whether any similar effects would also be seen in healthy human users until much more additional research is done.
- Piracetam: According to a review of 19 clinical studies, piracetam was reported to slightly improve memory and other cognitive functions in the elderly. It also reportedly improved memory in 123 children after undergoing anesthesia [60, 61]. Nonetheless, it is still unclear whether any “cognitive-enhancing” (“nootropic”) effects would be seen in healthy human users, and more research will be needed to explore this properly.
Compounds That May Reduce the Effects of Acetylcholine
INSUFFICIENT EVIDENCE:
Substances and compounds that suppress or reduce the effects of acetylcholine are sometimes referred to as acetylcholine antagonists. Some such compounds include:
- Forskolin: Forskolin is a natural compound derived from the Coleus plant, and has been reported to desensitize acetylcholine receptors and block their activity in one preliminary animal study in rats [62].
- Kava: a flower from the Pacific Islands, Kava has been reported to reduce muscle activity in rats. It also partially blocks nerve signals that cause muscle contractions in frogs [63].
- Botulin: Botulin is a bacterial toxin that blocks the release of acetylcholine from nerve endings. In fact, this is how Botox injections work: injecting low doses of this bacteria causes facial muscles to be paralyzed, thereby potentially reducing the appearance of fine lines and wrinkles in the skin above them [64].
- Curare: traditionally made by South American indigenous tribes from diverse plants, curare binds to the nicotinic receptors and reduces acetylcholine levels. It can completely paralyze muscles by blocking nerve signals, which eventually can lead to death (due to the inability to breathe, which requires muscle activity) [65, 66].
- Glycine: According to one preliminary animal study, the amino acid glycine has been reported to increase the amount of acetylcholinesterase in the spinal cords of mice, which causes more acetylcholine to be broken down. However, too much can lead to excess stimulation and nerve exhaustion [67, 68].
- Various herbs: leaves from the plant Atropa Belladonna, or “Deadly Nightshade,” have been traditionally brewed in tea and used as a remedy for bowel issues in certain cultures. Flowers of the Datura species and the Mandrakes have also been historically used as folk remedies for asthma and bronchitis. However, when ingested excessively, they can be highly toxic [4, 69].
