
In the world of emergency and prehospital medicine, Ketamine is the ultimate multi-tool of medications—pain relief? Check. Sedation? Check. Bronchodilation? Check. Seizure coverage? Check. Journey into a dissociative state? Check. It's no wonder emergency medicine is drooling over this drug. Unfortunately, so are some of our patients.

While ketamine’s versatility makes it an MVP, it does harbor some interesting side effects like hypersalivation. If you’re anything like me (and you probably are since you’ve found yourself on FOAMfrat’s website), you can’t just accept this as a fact of pharmacology. We’re a professional field of grown-up toddlers relentlessly asking, “But why? Why does ketamine do this? Why is hypersalivation even a thing?” So I looked it up – here it is.
AP101
The autonomic nervous system is divided into the sympathetic and parasympathetic branches, with the former being classically associated with your “fight or flight” responses like increased heart rate and blood pressure, alertness, and sharpened cognitive function and the latter being associated with the “rest and digest” functions such as saliva and bile production. Under normal conditions, input from both sides is constantly balanced to maintain homeostasis and carry out involuntary bodily functions.
There are three major salivary glands: the parotid, submandibular, and sublingual glands. Both autonomic branches innervate the salivary glands. They receive parasympathetic input from the facial and mandibular nerves, while sympathetic input travels from thoracic spinal nerves (specifically, the superior cervical ganglion).

The parasympathetic system has primary control over the amount of saliva produced, and the sympathetic nervous system governs the protein content and viscosity of saliva.
Parasympathetic Activity
Parasympathetic neurons have specialized receptors known as muscarinic receptors, which bind acetylcholine and modulate parasympathetic input. You’ve probably heard about these receptors in the setting of cholinergic toxicity - where an overabundance of acetylcholine binding triggers a massive parasympathetic response. We see increased salivation as one of those characteristic symptoms due to increased salivary gland stimulation.

Ketamine is actually a competitive antagonist to muscarinic receptors. Simply put, Ketamine blocks acetylcholine from binding and prevents the brain and spinal cord from receiving parasympathetic input. This is similar to how Atropine works to treat cholinergic toxicity. Based on this, it doesn’t really make sense that Ketamine would cause hypersalivation, does it? You would expect them to be dry.
How does Ketamine cause hypersalivation, then? The answer is simple.

Just kidding.
Sympathetic Activity
It’s actually overactivation of the sympathetic nervous system that causes hypersalivation with Ketamine administration. Sympathetic neurons have adrenergic receptors which bind catecholamines like norepinephrine (among others, but we’re dealing specifically with norepinephrine here). To transmit a signal, presynaptic neurons dump a bunch of norepinephrine into the synaptic cleft, where they bind to open adrenergic receptors on the post-synaptic neuron and trigger an impulse.

After the impulse has been sent, Norepinephrine unbinds from the receptor and is reabsorbed by the presynaptic neuron to module sympathetic input. That process is known as reuptake. Ketamine inhibits norepinephrine reuptake.
While sequestered in the synaptic cleft, norepinephrine continues to trigger impulses down the neuron. The result is over-activation of the sympathetic nervous system, and while the SNS doesn't actually play a direct role in the amount saliva production, it does influence protein content and viscosity of saliva. It also causes smooth muscle contraction around the salivary glands, which pushes stored saliva into the salivary ducts. The result: thick secretions that could obscure your view during an airway attempt, increase risk of aspiration, or require constant suctioning.
Conclusion + Note about Atropine
Hypersalivation is a fairly uncommon complication and is more often seen with higher (sedation) doses of Ketamine. Like most other side effects, it’s more likely to occur when Ketamine is pushed too fast and overwhelms the receptors.
Key takeaway: push ketamine slowly.
If you type any rendition of “Ketamine and Hypersalivation” into Google, you’ll come across some literature discussing Atropine as a preventative measure, especially in pediatrics. However, because hypersalivation originates from the sympathetic nervous system in this case, and Atropine plays on the parasympathetic nervous system, it’s not likely to make a difference.
References
Alhajj M, Babos M. Physiology, Salivation. [Updated 2023 Jul 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK542251/
Ghannam MG, Singh P. Anatomy, Head and Neck, Salivary Glands. [Updated 2023 May 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538325/
Kohrs, Rainer MD; Durieux, Marcel E. MD. Ketamine: Teaching an Old Drug New Tricks. Anesthesia & Analgesia 87(5):p 1186-1193, November 1998. | DOI: 10.1213/00000539-199811000-00039
Mion G, Villevieille T. Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS Neurosci Ther. 2013 Jun;19(6):370-80. doi: 10.1111/cns.12099. Epub 2013 Apr 10. PMID: 23575437; PMCID: PMC6493357.
Zhou J-s, Peng G-f, Liang W-d, Chen Z, Liu Y-y, Wang B-y, Guo M-l, Deng Y-l, Ye J-m, Zhong M-l and Wang L-f (2023) Recent advances in the study of anesthesia-and analgesia-related mechanisms of S-ketamine. Front. Pharmacol. 14:1228895. doi: 10.3389/fphar.2023.1228895