Originally used by African tribes in trials of crime and witchcraft, the alkaloid physostigmine mainly serves today as an antidote to drug poisoning. Safer drugs have mostly replaced it for treating glaucoma, Alzheimer’s, delayed stomach emptying, and the autoimmune disease myasthenia gravis. Learn more about physostigmine, its uses, adverse effects, and newer alternatives.

Disclaimer: By writing this post, we are not recommending this drug. Some of our readers requested that we commission a post on it and we are providing a summary of the information available in the scientific literature.



  • An effective antidote to anticholinergic drugs
  • A wide spectrum of activity on the nervous system


  • Several daily doses required due to its fast breakdown
  • Toxic only slightly above therapeutic doses (narrow therapeutic index)
  • Multiple side effects and drug interactions

What Is Physostigmine?

Physostigmine, also known as eserine and Antilirium, is an alkaloid originally obtained from the Calabar bean. This bean is the seed of a plant (Physostigma venenosum) native to tropical Africa [1+].

In the old Calabar region (currently in East Nigeria), this bean was used in trials of crime. Witchcraft suspects were forced to ingest it and only those who survived (usually by vigorously vomiting) were considered innocent [1+, 2+].

After British missionaries and explorers arrived in Calabar in the mid 19th century, some were curious to find out what makes this bean so special. They decided to send some of the mysterious beans back to Europe. This allowed scientists to study the plant, isolate its active compound, and identify its effects.

Early research uncovered that physostigmine acts to [1+, 2+]:

  • Constrict pupils and relax eye muscles
  • Slow the heart rate
  • Increase salivary, bronchial, and stomach secretions
  • Stimulate bowel movements
  • Relax blood vessels

Its overall effects closely resemble those of acetylcholine, the main neurotransmitter of the parasympathetic, rest-or-digest nervous system. Today we know that indeed, physostigmine is a strong “parasympathomimetic” and acts as a reversible acetylcholinesterase (enzyme that breaks down acetylcholine) inhibitor. In modern medicine, it is mainly used as an antidote to drug poisoning with anticholinergic drugs, for glaucoma, and to accelerate recovery after surgery [2+].

Based on its effects on the eyes, the first clinical use of physostigmine in the late 19th century was for glaucoma [2+].

As an Antidote

Only later on, physostigmine started to be used as an antidote to poisoning from several other drugs, including the alkaloids in deadly nightshade (atropine in Atropa belladonna) and Jimsonweed (scopolamine or hyoscine) [1+, 2+].

Its use dropped dramatically in the 1980s after two people developed heart failure from being treated with physostigmine for antidepressant overdose. Despite these rare cases, physostigmine is still considered an effective and safe antidote to anticholinergic poisoning. Recent observational studies on almost 1,400 people support its use for this purpose [3+, 4, 5].

Physostigmine Mechanism of Action (MoA)

AChE Inhibition

Acetylcholine is the main neurotransmitter of the parasympathetic system, which opposes the action of the fight-or-flight, sympathetic system. In the brain, acetylcholine stimulates memory and cognitive processes. Outside the brain, it activates muscles and aids digestion [6, 7, 8+].

After acetylcholine achieves its effects, an enzyme called acetylcholinesterase quickly breaks it down. Physostigmine binds to acetylcholinesterase and inactivates it, increasing acetylcholine levels and prolonging the effects of acetylcholine in the body [9, 10].

Specifically, physostigmine is a reversible acetylcholinesterase (AChE) inhibitor, which means that it binds to the enzyme only temporarily. Reversible AChE inhibitors such as donepezil and galantamine are used to treat Alzheimer’s Disease and improve cognitive dysfunction [9+].

In comparison, irreversible inhibitors are usually too toxic to have any therapeutic value. They are mostly used as insecticides while others were employed in chemical warfare in the past [9+].

Blood-Brain Barrier

Physostigmine can cross the blood-brain barrier, which means that it can block acetylcholinesterase both inside and outside the brain. Its synthetic analogs (neostigmine and pyridostigmine), on the other hand, can’t cross this barrier and are active only outside the brain [11, 8+].

Uses of Physostigmine

1) As an Antidote to Drug Poisoning

Acetylcholine Inhibitors (Anticholinergics)

Acetylcholine inhibitors (anticholinergics) are drugs that block the activity of acetylcholine receptors in the central and peripheral nervous systems. They are used for conditions such as urinary incontinence, chronic obstructive pulmonary disease (COPD), Parkinson’s disease, asthma, and as antidotes to pesticide poisoning (organophosphates) [12+].

However, anticholinergic overdose can cause serious health complications such as [12+]:

  • Delirium, hallucinations, and confusion
  • Anxiety, agitation, and insomnia
  • Irregular heart rate
  • Seizures and coma

Altogether, these symptoms are caused by anticholinergic toxicity and frequently lead people who overdose with acetylcholine inhibitors to the emergency department [13].

Physostigmine prevents acetylcholine breakdown, which reverses the symptoms of anticholinergic overdose [13].

Physostigmine has been successfully used to reverse the overdose symptoms from the following anticholinergics:

  • Plant alkaloids (atropine, scopolamine, hyoscyamine, solanine) [14+, 15, 16, 17+, 18, 19, 20]
  • Antipsychotic medication (olanzapine) [21, 22]
  • Anti-Parkinson’s medication (benztropine) [23+, 24+, 25]
  • Antidepressants (tricyclics imipramine, amitriptyline, doxepin) [26+, 27, 28+]
  • Antihistamines (promethazine, cimetidine, orphenadrine) [29, 30+, 31+, 32, 33]
  • Muscle relaxants (cyclobenzaprine) [34, 35+]

Benzodiazepines such as diazepam, midazolam, and lorazepam can be used as alternatives to physostigmine. However, in an observational study on over 50 people, physostigmine was more effective than benzodiazepines at controlling agitation and delirium, caused fewer complications, and sped up recovery [36].

In another study on over 800 people with anticholinergic poisoning, benzodiazepines were most commonly used (29%) followed by physostigmine (12%) or a combination of both (9%). Physostigmine is mostly used for poisoning by pure anticholinergics while benzodiazepines were preferred for mixed drug poisoning [37].

Physostigmine is also valuable for diagnosing anticholinergic poisoning since it can quickly reverse the symptoms [38+].

Irreversible AChE Inhibitors (Organophosphorus Compounds)

Compounds in this category are widely used but highly poisonous insecticides (organophosphates). Others are nerve agents that were used as weapons of chemical warfare. Persian Gulf War veterans frequently develop an illness caused by exposure to these toxic chemicals with weakness, depression, pain, poor memory, and poor balance [39, 40].

All organophosphorus compounds are irreversible AChE inhibitors and as such are extremely toxic substances. They permanently bind to acetylcholinesterase, resulting in a buildup of acetylcholine that can cause seizures, breathing problems, and damage to multiple organs. Physostigmine reversibly and weakly binds to acetylcholinesterase, which protects this enzyme from the more dangerous effects of organophosphates [41+].

In animal studies, physostigmine reduced the toxicity of organophosphate compounds such as:

  • Nerve agents (soman, sarin) [42, 43]
  • Pesticides [44, 45, 46, 47, 48]
  • Glaucoma drugs (echothiophate, diisopropyl fluorophosphate) [46, 49]

The protective effect can be increased in combination with other anticholinergics such as:

  • Anti-Parkinson drugs (Artane, procyclidine) [50, 51, 52]
  • Plant alkaloids (atropine, scopolamine) [53+, 54, 55, 56]

Drugs that restore AChE activity (oximes) by detaching the bound organophosphates can also be part of the strategy to combat toxicity [57, 58].

The combination of physostigmine and scopolamine provides good protection against the poisoning from nerve agents like soman. However, unpredictable stress conditions lowered its efficacy in guinea pigs, suggesting that it may not be the best choice on the battlefield [59, 60, 41+].

The synthetic physostigmine analog pyridostigmine is the drug approved by the FDA to prevent damage caused by the nerve agent soman [59, 60, 41+].

2) Recovery after Surgery

Several drugs used for general anesthesia are anticholinergics. They can cause adverse effects such as sleepiness, depression, agitation, and confusion after surgery. Physostigmine injections reversed these symptoms in 10 studies of over 800 people [61, 62, 63, 64, 65, 66, 36, 67+, 68, 69+].

Children often awake in a state of violence and agitation after surgery (called emergence excitement). In 2 clinical trials on almost 300 children, infused physostigmine reduced these symptoms [70+, 71].

After surgery, physostigmine applied on the skin or injected reduced pain, the need for morphine, and lowered an inflammatory protein (IL-1beta) in two clinical trials on over 100 people [72, 73].

Sedatives used during surgery can cause breathing cessation (apnea). In a clinical trial on 10 people, physostigmine reduced this complication, especially in a person with a history of sleep apnea [74].

3) Glaucoma

Glaucoma is an eye disease commonly caused by high eye pressure that can damage eye nerves and lead to a loss of vision [75+].

Physostigmine has been used since the late 19th century to improve glaucoma. It activates the muscles that help remove built-up fluids from the eye, reducing high eye pressure. Its effects have been confirmed in two clinical trials on 40 healthy people [2+, 76, 77].

Although physostigmine is available as an ointment and eye solution for glaucoma, it has largely been replaced by another alkaloid with fewer side effects (pilocarpine) and other newer drugs [2+, 78+].

4) Cognitive Function

Healthy People

In 3 clinical trials on 61 healthy people, physostigmine improved perception, long-term memory, and working memory [79, 80, 81].

Physostigmine also improved memory and learning in multiple studies in healthy animals [82+, 83, 84, 85, 86, 87, 88, 89].

Alzheimer’s Disease

Acetylcholine levels and activity decline in people with Alzheimer’s disease. Acetylcholinesterase blockers increase acetylcholine in the brain and are commonly used to reverse memory loss and other symptoms of the disease [90+, 91].

In 7 clinical trials on 75 people with Alzheimer’s disease, physostigmine infusions enhanced memory, coordination, and brain activity [92, 93, 94+, 95, 96, 97, 98].

Among ~2,500 people with Alzheimer’s disease, physostigmine slightly improved symptoms in about one-third. These responders underwent another 3 clinical trials, in which oral physostigmine for up to 6 months prevented memory and cognitive worsening [99, 100, 101].

However, physostigmine was abandoned and substituted by safer and longer-acting synthetic derivatives (such as tacrine, rivastigmine, galantamine, and donepezil) [102+].

Other Conditions

Physostigmine (sometimes combined with lecithin) improved memory loss caused by brain injuries and infections in a trial on 36 people and in 6 case studies. However, it failed to improve memory in another clinical trial on 24 people with memory loss [103, 104, 105, 106+, 107, 108+, 109+].

Physostigmine also relieved manic symptoms in 20 people with bipolar disorder or schizophrenia [110+, 24+, 111, 112].

5) Myasthenia Gravis Symptoms

Myasthenia gravis is a rare autoimmune disease that affects only 0.02% of the US population. It’s caused by the destruction of acetylcholine receptors, which results in extreme muscle weakness [113].

In 1934, the Scottish doctor Mary Walker noticed that myasthenia gravis had similar symptoms to poisoning with the South American alkaloid curare, for which physostigmine is used as an antidote. She gave physostigmine and a synthetic analog (Prostigmin) to three people with myasthenia gravis and both drugs temporarily improved the symptoms [114+, 115+].

Physostigmine vs Pyridostigmine

Today, immunosuppressants are the first-line for reducing autoimmune damage in myasthenia gravis while acetylcholinesterase blockers can be added to relieve some symptoms. Pyridostigmine is longer-acting, safer, and preferred over physostigmine [113].

6) Dry Mouth

When not enough saliva is being produced, the mouth becomes dry. This makes chewing, swallowing, and talking difficult and increases the risk of mouth infections, cavities, and bad breath [116+].

In two clinical trials on 15 healthy people, a gel and a spray with physostigmine stimulated the salivary glands in the mouth to make more saliva. A mouth rinse and a gel with physostigmine relieved the feeling of dryness in two additional clinical trials on 31 people with dry mouth. The formulations were applied on the inside lining of the lip [117, 118, 117, 119].

In ferrets, a physostigmine solution increased saliva when applied to the inside of the mouth [120].

7) Uncontrollable Movement (Ataxia)

Ataxia is the lack of voluntary muscle coordination. It most often results from damage to a specific brain area that controls balance and voluntary muscle movement (the cerebellum) [121].

Physostigmine improved movement coordination in 5 clinical trials on almost 100 people given orally or as an infusion. However, physostigmine tablets and patches had no effects in two other trials on 25 people [122, 123, 124+, 125, 126, 127, 128].

8) Sleep Apnea

Sleep apnea is a disorder that causes breathing to continually stop and start during sleep. Physostigmine infusions given over 7 hours reduced sleep apnea by about 20% in a trial on 10 men. Its effects would need to be confirmed in larger long-term studies [129].

9) Delayed Stomach Emptying (in animals)

Delayed stomach emptying (gastroparesis) is when the stomach doesn’t empty as quickly as it should. Slow emptying of the stomach causes nausea, vomiting, bloating, early satiety, weight loss, acid reflux, and stomach pain. Sometimes it results from chronic health conditions, stomach surgery, or chemotherapy [130, 131+].

In several animal studies, physostigmine improved digestion by increasing gut flow. This could reduce symptoms of delayed stomach emptying such as nausea [132, 133, 134+, 135, 136].

Due to the digestive adverse effects that physostigmine can cause, delayed stomach emptying is normally improved with safer drugs. These include the following [130, 131+]:

  • Anti-nausea drugs (metoclopramide, domperidone)
  • Antibiotics (erythromycin, azithromycin)
  • Drugs that stimulate gut flow (metoclopramide, domperidone)
  • Appetite-stimulating drugs (relamorelin)
  • Drugs used to treat gastroesophageal reflux (revexepride)

Physostigmine Side Effects

Oral and injected physostigmine frequently causes digestive problems such as [99, 100]:

  • Nausea and vomiting
  • Diarrhea
  • Lack of appetite
  • Indigestion
  • Stomach pain

Additional side effects include [99+, 137+]:

  • Dizziness and weakness
  • Sweating
  • Slow or irregular heart rate
  • Increased blood pressure
  • Shortness of breath
  • Seizures
  • Nightmares and odd dreams

Physostigmine applied to the eyes may cause the following adverse effects [78+]:

  • Headaches
  • Nearsightedness (myopia) and blurred vision
  • Retinal detachment
  • Inflammation of the conjunctiva, cornea, and iris

Physostigmine (22 μg/kg) caused depressive symptoms in a clinical trial on 9 healthy people. In another trial on 45 people, a lower dose (14 μg/kg) caused depression only in those with borderline personality disorder [138, 139].

Safety of Physostigmine

Physostigmine is very toxic and has a narrow therapeutic index/range. Even small oral doses can be deadly (below 5 mg/kg for a 70 kg person) [140].

Physostigmine injections and eye solutions are normally sold as physostigmine salicylate and may contain sodium bisulfite as an additive, so they should not be used by people allergic to salicylates or sulfites [140, 141, 142].

Physostigmine should be used with caution in people with the following conditions as it may cause disease worsening [143, 144, 145, 140]:

  • Asthma
  • Bladder or bowel obstruction
  • Diabetes
  • Heart disease
  • Parkinson’s disease
  • Gangrene, a type of tissue death caused by a loss of blood flow

Just as physostigmine crosses the blood-brain barrier, it can also cross the placenta and damage unborn babies. However, its potential benefits in case of poisoning may warrant its use. For instance, physostigmine was used in approximately 4% of the cases in roughly 100 pregnant women with acetylcholine inhibitor poisoning [146].

Physostigmine may cross into the milk, although no human or animal studies have confirmed this. It should only be used by breastfeeding women if the benefits outweigh the risks.

Physostigmine Drug Interactions  

Physostigmine blocks the action of acetylcholine inhibitors, such as drugs that are used for [12+]:

  • Urinary incontinence (oxybutynin, tolterodine, trospium chloride)
  • Breathing disorders (ipratropium, tiotropium)
  • Parkinson’s disease (benztropine, procyclidine)
  • Psychosis and behavioral disorders (clozapine, olanzapine, quetiapine, haloperidol)
  • Depression (amitriptyline, doxepin, imipramine, paroxetine)
  • Allergies (diphenhydramine, dimenhydrinate, cimetidine, promethazine)

The effects of physostigmine are blocked by glucocorticoids, steroid drugs used to lower inflammation. These include [147, 148+]:

  • Betamethasone
  • Cortisone
  • Deflazacort
  • Dexamethasone
  • Prednisone
  • Triamcinolone

Physostigmine may interact with cannabis. In a trial on 5 people who took in 20 – 40 mg of THC, the main psychoactive compound in cannabis, physostigmine decreased eye redness and lowered increased heart rate but increased sleepiness [149].

Physostigmine Dose & Formulations

Physostigmine is available in the following forms:

  • Vials: 0.4 – 1 mg/mL physostigmine salicylate [150+]
  • Eyedrops: 0.25% physostigmine sulfate or 8 mg/mL physostigmine salicylate [151, 77]
  • Ointment: 0.25 – 1% physostigmine sulfate [152+]

The recommended doses in case of poisoning with acetylcholine blockers are [150+]:

  • Pediatrics: 0.02 mg/kg (up to 0.5 mg) infused over 3 minutes every 10 – 15 minutes
  • Adolescents/Adults: 0.5 – 2 mg/kg infused over 2 – 5 minutes every 10 – 15 minutes

For improving recovery after surgery, the following doses are used:

  • Pediatrics: 20 – 30 μg/kg injected immediately after awakening [70+, 71]
  • Adolescents/Adults: a single injected dose of 1 – 2 mg [153+]

Some types of glaucoma improve with 0.25% physostigmine applied up to 3x/day, although other drugs such as pilocarpine are preferred [2+, 78+].

Genetics Related to Physostigmine

Physostigmine blocks acetylcholinesterase by binding to an amino acid that is required to break down acetylcholine (Ser203). People with a different amino acid in this position may be less susceptible to the effects of physostigmine [8+, 154+].

Mutations in other amino acids required for acetylcholinesterase to break down acetylcholine (Gly121, Gly122, Ala204, Glu334, and His447) or those that affect the size of molecules the enzyme can bind to (Phe295 and Phe297) may also alter physostigmine’s effectiveness [155, 154+].

Limitations and Caveats

Among the effects of physostigmine on recovery after surgery, only the improvement of breathing cessation hasn’t been investigated in a sufficiently large number of people.

Its effects on cognitive function in people without Alzheimer’s disease, dry mouth, and uncontrolled movement have only been inconsistently tested on a small number of people. Physostigmine improved uncontrolled movement in some studies but failed to do so in others.

Only animal studies have investigated physostigmine’s ability to prevent poisoning by organophosphate compounds and improve delayed stomach emptying.

Natural Alternatives

Several natural substances work in the same way as physostigmine. As a result, some of these natural alternatives may have similar uses or offer parallel health benefits.

You should always consult your doctor before changing or stopping your medications. It’s also a good idea to let your doctor know of any supplements you are currently taking.

1) Caffeine

Many of us are all too familiar with the effects of caffeine.

But did you know that caffeine also blocks acetylcholinesterase?

While caffeine is a weaker inhibitor than physostigmine, it may still offer some of the same health benefits [156, 157].

For example, a review of clinical trials found that caffeine improves performance in simple and complex tasks. They also found improvements in alertness and executive control [158].

Another large review of 25 clinical trials identified improvements to attention, reaction time, and problem-solving in sleep-deprived individuals [159].

Caffeine may also help prevent Alzheimer’s and Parkinson’s disease. Studies suggest that regular caffeine intake may lower the risk of developing these conditions [160, 158].

One observational study of 1409 people found that people who drank 3 5 cups of coffee per day had the lowest risk of developing Alzheimer’s [161].

However, there are a few important caveats.

The scientific evidence is not clear-cut. A number of clinical trials have not found the same cognitive improvements [162, 163].

Also, caffeine’s effect on cognition is likely due to more than just acetylcholinesterase inhibition. Research shows that caffeine’s neuroprotective effects are, in part, due to interaction with adenosine receptors [164, 158].

2) Caffeic Acid

Caffeic acid is a natural compound found in many plants and foods, such as tomatoes, carrots, and wine [165].

Caffeic acid is also found in coffee, which is how it got its name. Despite the name similarity, caffeic acid is actually unrelated to caffeine [166].

Research shows that caffeic acid is an acetylcholinesterase inhibitor, like physostigmine [157].

Studies have found that caffeic acid improves learning and cognitive function in rats with Alzheimers disease [165, 167, 168].

A different study shows that caffeic acid has a synergistic effect with donepezil, a medication commonly used for Alzheimer’s [169].

On top of that, caffeic acid may have antioxidant and anti-inflammatory properties [170, 171].

3) Rosmarinic Acid

Rosmarinic acid, which was first discovered in rosemary, is a natural compound found in a variety of plants [172].

The chemical structure of rosmarinic acid is very similar to caffeic acid. It also acts as an acetylcholinesterase inhibitor [172].

A study in rats found that rosmarinic acid improves learning and memory [173].

Other studies suggest that it also has anti-oxidative, anti-inflammatory, and antiviral effects [174, 175].

It could also reduce blood pressure and protect against seizures in mice [176, 177].

4) Huperzine A

Club moss (Huperzia serrata) contains a compound called Huperzine A that has several potential health effects [178].

Huperzine A is a reversible acetylcholinesterase inhibitor. It also blocks the NMDA receptor [178, 179].

A review of 6 clinical trials including 454 people examined the effects of Huperzine A on Alzheimer’s disease. They found improvements in cognitive function and daily activity. A different review of 20 trials revealed similar results [180, 181].

However, both reviews warn that the included studies were of poor quality and that larger, better-designed trials are needed [180, 181].

Huperzine A may also protect against organophosphate poisoning and help with the symptoms of myasthenia gravis [179, 182, 183].

5) Alpha-Pinene

Alpha-pinene (or α-pinene) is a compound found in the essential oils of many plants, including pine needles and rosemary [184].

Like physostigmine, alpha-pinene inhibits acetylcholinesterase [185].

A cell study discovered that alpha-pinene can protect against aspirin toxicity [186].

A different study in mice found it also protects against stomach ulcers caused by alcohol and indomethacin, an NSAID drug [187].

Other studies suggest that alpha-pinene may also have anti-oxidative and anti-inflammatory properties [188, 189].

Other Natural Alternatives

There are many natural compounds that can potentially block acetylcholinesterase [190].

In fact, one study identified over 200 plantderived compounds with acetylcholinesterase inhibiting properties [191].

Although the majority have not been properly evaluated, there is great potential in this area of study [190].

About the Author

Mathew Eng, PharmD


Mathew received his PharmD from the University of Hawaii and undergraduate degree in Biology from the University of Washington.

Mathew is a licensed pharmacist with clinical experience in oncology, infectious disease, and diabetes management. He has a passion for personalized patient care and believes that education is essential to living a healthy life. His goal is to motivate individuals to find ways to manage their chronic conditions.

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