Cobra Venom and Epilepsy: From 1910 Reports to Ion Channels

TL;DR

• In the early 1900s, physicians experimented with injecting snake venom (crotalin) to treat epilepsy, but rigorous observations showed it did not cure seizures ^{1 2}.
• A 1914 study found rattlesnake venom not only failed to help epileptic patients but could worsen their convulsions ². By the 1930s, controlled trials confirmed no lasting benefit from venom injections in epilepsy ¹.
• Interest shifted as some venoms showed other medical uses: by 1936, cobra venom was reported to produce significant pain relief in cancer patients, heralding venoms’ potential as analgesics ³.
• Modern research has isolated many venom peptides that target specific ion channels in nerves, enabling potent pain relief and anticonvulsant effects. For example, black mamba peptides (“mambalgins”) block acid-sensing channels to produce morphine-level analgesia without opioids ^{4 5}.
• Venoms are now seen as a rich source of neurological drugs: a cone snail toxin was developed into the FDA-approved pain drug ziconotide ⁶, and spider-venom peptides are in development for drug-resistant genetic epilepsies ^{7 8}.

“…the much vaunted crotalin or snake venom have thus far been unsuccessful as to a cure.”
— John C. Schwartz, Ohio Hospital for Epileptics report (1920) ¹

Early 20th-Century Experiments with Snake Venom for Epilepsy#

In an era with few effective epilepsy treatments, some doctors turned to exotic remedies. Around 1910, Philadelphia physician Thomas J. Mays began championing the use of rattlesnake venom (known as crotalin) as an experimental therapy for epilepsy ⁹. Mays and a few contemporaries believed that injecting minute doses of snake venom might somehow reduce the frequency or severity of seizures. This bold idea likely drew on the principle that a potent poison in small doses could have counterintuitive healing effects – a form of early hormesis or even a quackish echo of homeopathy. With epilepsy largely uncontrolled (bromides offered only partial relief), the prospect of shock therapy via animal toxin captured attention. Early case reports from Mays claimed anecdotal improvements, which spurred further trials in the 1910s.

However, when put to the test under clinical observation, snake venom therapy largely disappointed. In 1914, C.L. Jenkins and A.S. Pendleton of the Ohio State Hospital for Epileptics reported on “Crotalin in epilepsy”, publishing their findings in JAMA. Their verdict was discouraging: patients receiving rattlesnake venom extract did not improve; in fact, “the convulsions of epileptics are increased by its use and it has no beneficial effect” on their condition ². Other physicians in Europe had similar null results – e.g. S. Fackenheim in 1912 and A. Prévost in 1913 tried snake venoms without seeing cures ¹⁰. By 1920, an official report from the Ohio epilepsy colony ruefully noted that “innumerable treatments… and the much vaunted crotalin or snake venom” had “thus far been unsuccessful as to a cure” ¹. In other words, despite early hype, snake venom had failed to stop epileptic seizures.

The final nail in the coffin came with more systematic trials in the 1930s. Doctors administered diluted pit viper venom (from water moccasins) to multiple institutionalized epilepsy patients over weeks, carefully tracking outcomes. These controlled studies found no significant reduction in seizures relative to baseline ¹. Some patients suffered allergic reactions or local tissue damage from the injections, adding risk with no reward. As effective barbiturate drugs (phenobarbital) and new anticonvulsants emerged in the 1910s–1930s, the medical community abandoned snake venom as an epilepsy remedy. What began as a daring idea of “fighting fire with fire” – using a neurotoxin to quell neural storms – turned out to be a dead end for epilepsy.

Table 1 – Notable Early Trials of Snake Venom in Epilepsy

Despite the failure in epilepsy, these early 20th-century experiments were not entirely in vain. They introduced the idea that animal venoms could interact with the nervous system – for harm or potential healing – and spurred pharmacologists to investigate venom components more closely. Notably, while snake venom injections didn’t cure seizures, some physicians observed other intriguing effects. D. I. Macht’s team found that cobra venom had a remarkable analgesic (pain-deadening) action when given to patients with terminal cancer pain ³. By 1936, cobra venom was “emphatically” hailed as a potent analgesic that “promises to be of use in the symptomatic treatment of cancer” ³. This was a striking contrast: a substance infamous for causing agony could, in controlled doses, relieve suffering. Thus, the snake venom saga pivoted from epilepsy to pain management, hinting that venoms harbored pharmacologically active molecules worth harnessing.

Venom Peptides and Ion Channels: Modern Therapeutics Emerge#

Fast-forward to the 21st century, and the legacy of those early trials lives on in an unexpected way. Scientists now recognize animal venoms as rich libraries of ion-channel modulators – molecules evolved to precisely disrupt nerve signals in prey or predators. These toxins, refined by evolution, can selectively bind to neural receptors and channels, making them valuable leads for new drugs. A recent comprehensive review notes that venoms from snakes, spiders, scorpions, bees, wasps, and cone snails all contain compounds with anticonvulsant effects, often by targeting specific ion channels involved in seizures ^{10 11}. What was once a fringe idea – venom as medicine – is now an entire field of biomedicine (venomics) turning deadly peptides into cures.

One area of breakthrough is pain management. Venom peptides have yielded analgesics that match or exceed morphine in potency without the same side effects. A dramatic example is the discovery of mambalgins – a new class of three-finger peptide toxins from the Black mamba snake. Researchers in 2012 showed that mambalgin peptides can abolish pain by inhibiting acid-sensing ion channels (ASICs) in neurons ^{12 5}. In mouse studies, mambalgin delivered potent analgesia comparable to high-dose morphine yet caused no respiratory depression and minimal tolerance ^{4 5}. This opioid-free painkiller mechanism, directly inspired by snake venom, opened the door to novel analgesic drugs. While mambalgins are still in preclinical development, the concept is proven: nature’s toxins can be tamed to relieve pain. In fact, an earlier venom-derived drug is already saving lives: ziconotide, a synthetic version of a cone snail toxin, was approved in 2004 as a last-resort pain medication. Ziconotide blocks neuronal calcium channels to shut down pain signals, a strategy born from snail venom’s paralytic powers ⁶. These successes in pain treatment vindicate the medical promise of venom components.

Venom molecules are also being pursued as antiepileptic agents, especially for forms of epilepsy that current drugs fail to control. Many venoms target ion channels (sodium, calcium, potassium, GABA receptors, etc.) that govern neuronal excitability – the very circuits that go awry in seizures. For example, α-cobratoxin, a neurotoxin from cobra venom, was found to inhibit T-type calcium channels in neurons, which are implicated in epilepsy and neuropathic pain ^{13 14}. This toxin (better known for causing paralysis by blocking acetylcholine receptors) surprisingly triggers a cascade via muscarinic receptors that dampens low-voltage calcium currents, effectively calming overactive neurons ^{13 14}. Such a mechanism could inform new anticonvulsant drug development. Likewise, venom researchers have characterized spider peptides that modulate voltage-gated sodium channels very precisely. Some of these spider-venom peptides can prevent epileptic seizures in animal models by blocking the hyperactive sodium channels that drive uncontrolled firing ¹⁰. These insights are not just theoretical – they are moving toward the clinic.

A cutting-edge initiative comes from a team in Australia, where venom-derived peptides are being tailored to genetic epilepsies. By using venom peptides that correct the specific ion channel dysfunctions in certain rare epileptic syndromes, researchers aim to create precision anti-seizure drugs. Prof. Glenn King’s lab has developed spider venom peptides that showed efficacy in preclinical models of Dravet syndrome and other refractory epilepsies ^{7 8}. To speed up translation, these venom peptides are even being tested on patient-derived “mini-brains” (brain organoids), which can demonstrate effectiveness in human neural tissue before actual trials ^{7 8}. This personalized medicine approach – matching a venom peptide to a patient’s ion channel mutation – would have sounded like science fiction to doctors in Mays’s time. Yet it flows logically from a century of progress in neuropharmacology and toxin science.

Venom research has also led to discoveries about epilepsy mechanisms. An intriguing case is the coral snake toxin unraveled in 2015, which targets GABA_A receptors. Unlike most snake venoms that cause paralysis or bleeding, the redtail coral snake produces a toxin that locks open GABA_A receptor channels, effectively silencing inhibitory signals and precipitating fatal seizures in prey ^{15 16}. This was the first known natural toxin to hit GABA receptors, and it gave scientists a powerful tool to probe the role of GABA in seizure control. By studying how the coral snake’s toxin induces seizures (by preventing GABA receptors from closing), researchers can better understand certain epileptic conditions and potentially design antidotes or therapeutics that modulate GABA channels in the opposite way. In short, venoms have become invaluable probes of the nervous system, illuminating pathways that standard drug libraries might overlook.

Modern pharmacology thus sees venoms not as poisons but as blueprints. Each component in a venom acts on a specific biological target; our job is to isolate those molecules and refine them into safe drugs. Dozens of venom-derived drug candidates are in the pipeline for pain, epilepsy, autoimmune diseases, and more. The journey that began with snake handlers injecting crotalin into hapless patients has come full circle in a much more sophisticated form. Now, the question is not whether venoms can heal – it’s how to harness their healing power most effectively. The story of cobra and rattlesnake venom in epilepsy, once a cautionary tale of quackery, is now part of a larger narrative: nature’s toxins as tomorrow’s cures.

FAQ#

Q1. Did doctors really try snake venom as an epilepsy treatment?
A: Yes. In the 1910s, some physicians (notably Dr. Thomas Mays) injected small doses of rattlesnake venom – called crotalin – into epilepsy patients, hoping to prevent seizures. Trials soon showed it was ineffective and sometimes even worsened seizures ^{2 1}.

Q2. What is “crotalin” in medical history?
A: Crotalin was the name for a crude extract of rattlesnake venom used experimentally in the early 20th century as a supposed epilepsy remedy. Doctors of that era tried crotalin injections in epilepsy, but it did not cure the condition ¹.

Q3. Are any venom-based drugs used for seizures or pain today?
A: Yes – venom peptides are an emerging source of medicines. For example, ziconotide, derived from cone snail venom, is an FDA-approved drug for severe chronic pain that works by blocking nerve calcium channels ⁶. While no snake venom drug for epilepsy is on the market yet, scientists are developing spider- and snake-venom peptides to target the ion channel defects in difficult epilepsy cases ⁷.

Q4. How can a snake venom peptide relieve pain without dangerous side effects?
A: Venom peptides can be highly specific to certain nerve receptors. One snake peptide, mambalgin, binds only to acid-sensing ion channels involved in pain signaling. It blocks pain transmission as effectively as morphine but doesn’t affect opioid receptors or breathing ^{4 5}. This specificity lets it kill pain without the respiratory depression or addiction risk of opioids.

Footnotes#

Sources#

1. Mays, T. J. “The Rattlesnake-Venom Treatment of Epilepsy.” Journal of the American Medical Association LX(11) (1913): 847. (Letter to the Editor) ⁹.
2. Jenkins, C. L., & Pendleton, A. S. “Crotalin in Epilepsy.” Journal of the American Medical Association 63(20) (1914): 1749–1750. doi:10.1001/jama.1914.02570200043011 ².
3. Schwartz, John C. Annual Report of the Ohio Hospital for Epileptics (Columbus, OH: 1920), p. 28. Quoted in Loring & Hermann, History of Epilepsy Neuropsychology (Oxford, 2012) ¹.
4. Macht, David I. “Experimental and Clinical Study of Cobra Venom as an Analgesic.” Proceedings of the National Academy of Sciences USA 22(1) (1936): 61–71. doi:10.1073/pnas.22.1.61 ³.
5. Diochot, S. et al. “Black mamba venom peptides target acid-sensing ion channels to abolish pain.” Nature 490(7421) (2012): 552–555. doi:10.1038/nature11494 ^{12 5}.
6. Zhang, Ling, et al. “Alpha-cobratoxin inhibits T-type calcium currents through muscarinic M4 receptor and G_o-protein βγ subunits–dependent PKA pathway in dorsal root ganglion neurons.” Neuropharmacology 62(2) (2012): 1062–1072. doi:10.1016/j.neuropharm.2011.10.017 ^{13 14}.
7. Kolf, Catherine. “Researchers unlock secret of reclusive coral snake’s deadly venom.” Johns Hopkins University News (February 10, 2015) ^{15 16}.
8. Zainal Abidin, S. A., et al. “Animal Venoms as Potential Source of Anticonvulsants.” F1000Research 13:225 (2024): 15 pages. doi:10.12688/f1000research.147027.1 ^{10 11}.
9. University of Queensland. “Developing venom-based epilepsy drugs using lab-grown organs.” IMB UQ News (Sept 25, 2024) ^{7 8}.
10. Research!America. “Did You Know? The Leap from Snails to Pain Management.” Research!America Blog (Aug 18, 2025) ⁶.