Toxicoses in Animals From Amphetamines and ADHD Drugs in Animals

Immediate-release amphetamines and methylphenidate are rapidly absorbed in the GI tract, reaching peak plasma concentrations in 1–3 hours. Extended-release, controlled-release, and transdermal patches have a slower rate of absorption and a relatively longer half-life.

Amphetamines are lipid soluble and rapidly cross the blood-brain barrier, with CSF concentrations reaching 80% of the plasma concentration. In addition, amphetamines are distributed to the kidney, liver, and lungs. Amphetamines and methylphenidate are metabolized in the liver and eliminated in the urine. Amphetamines have active metabolites; methylphenidate does not.

The half-life of amphetamines depends on the urinary pH; with an alkaline pH, the half-life is prolonged, and as urine pH decreases, the rate of excretion increases. When the urine pH is 7.5, elimination in dogs takes approximately 6 hours. When the urine pH is 6, elimination is complete in approximately 3–4 hours.

The minimum lethal dose for amphetamine sulfate in dogs is 20–27 mg/kg, PO. The LD₅₀ for most amphetamines is 10–23 mg/kg, PO. Although the LD₅₀ for methylphenidate has not yet been established, Beagles that received a dose of 20 mg/kg, PO, every 24 hours for 90 days survived (1).

Atomoxetine is well absorbed from the GI tract, with a bioavailability in dogs of approximately 74%. The bioavailability in cats is unknown. Atomoxetine readily crosses the blood-brain barrier; Its onset of action is rapid (30 minutes to 2 hours), and the duration of action is fairly long (12–24 hours). In dogs, atomoxetine is metabolized in the liver and is excreted approximately equally in the urine and feces (biliary excretion).

Amphetamines stimulate the central and peripheral nervous systems. They increase the amounts of catecholamines at nerve endings by increasing the release of norepinephrine and inhibiting its reuptake and metabolism. Amphetamines also increase the activity of dopamine and induce the release of epinephrine, serotonin, and histamine. Increased CNS levels of dopamine produce euphoria.

Seizures in intoxicated animals could be due to neuronal death from the interaction between amphetamines and receptors for N-methyl-d-aspartate (NMDA). Tachycardia and arrhythmias are due largely to the sympathomimetic effects of amphetamine ingestion.

Similarly, methylphenidate inhibits the reuptake of dopamine, resulting in increased dopaminergic activity in the brain.

The complete mechanism of action of atomoxetine is unclear; it might be due to the inhibition of presynaptic norepinephrine reuptake. Atomoxetine is selective for norepinephrine transporters but not for neurotransmitter receptors.

The most commonly reported clinical signs of amphetamine or methylphenidate intoxication are restlessness, agitation, hyperactivity, aggression, mydriasis, circling, head bobbing, vocalization, ataxia, seizures, and death. Clinical signs of restlessness and agitation associated with amphetamine salt ingestion occur at 0.09 mg/kg. PO, and more severe signs occur as ingested amounts increase. Hyperthermia (at 0.2 mg/kg, PO) can occur secondary to seizures or serotonin release. Tachycardia (at 0.2 mg/kg, PO) and arrhythmias, as well as hypertension and, more rarely, hypotension, have all been reported. Tremors have been reported at 0.7 mg/kg, PO; seizures have been reported at 1.3 mg/kg, PO (2). Death results from respiratory failure, with DIC, cerebrovascular hemorrhages, lactic acidosis, and cardiac failure in some cases.

Clinical signs associated with methylphenidate ingestion occur at higher doses: hyperthermia and tachycardia at 0.3 mg/kg, PO; vocalization at 0.8 mg/kg, PO; hypertension at 0.85 mg/kg, PO.

Although not validated for animal use, some of the rapid human point-of-care (POC) urine spot tests can be useful in the diagnosis of amphetamine intoxication. They are not useful for methylphenidate intoxication.

Most amphetamines and related drugs or their metabolites, as well as methylphenidate, are readily detectable in plasma or urine by the use of gas chromatography–mass spectrometry (GC/MS) or liquid chromatography–mass spectrometry (LC/MS).

Clinical signs associated with atomoxetine toxicosis include GI signs (at 0.4 mg/kg, PO, in dogs and at 0.7 mg/kg, PO, in cats) and stimulatory signs (at 2.2 mg/kg, PO, in both dogs and cats) (2).

In dogs, clinical signs of atomoxetine toxicosis reported in one large study included mydriasis, hyperactivity, vomiting, tachycardia, hypersalivation, lethargy, agitation, ataxia, hyperthermia, behavioral changes, diarrhea, head bobbing, polydipsia, and trembling. Cats in the same study developed hypersalivation, mydriasis, tachycardia, disorientation, hiding behavior, and tremors (2).

The diagnosis of atomoxetine toxicosis is based on presence of the drug in the household and a history of ingestion. No human rapid-spot urine tests are currently available for atomoxetine. As with amphetamines, GC/MS or LC/MS can be useful in making the diagnosis; however, the length of time to perform these tests precludes their use in treatment.

Induction of emesis is generally not recommended for patients that have ingested immediate-release amphetamine and methylphenidate products, because of the rapid onset of clinical signs.

Clinically normal patients that have ingested a long-acting or extended-release product might benefit from induction of emesis followed by a dose of activated charcoal with a cathartic (AC+C), with care taken to monitor for hypernatremia. Gastric lavage with a cuffed tube may be performed in patients that are unable to vomit or that have ingested a large amount. AC+C should be administered before the tube is removed. There is no antidote.

Phenothiazine tranquilizers such as acepromazine (0.55–1.1 mg/kg, IV, IM, or SC) or chlorpromazine (0.5 mg/kg, IV or IM, slowly to effect) (2) work well to control the CNS effects of amphetamine and ADHD drug toxicoses. Diazepam is not recommended as a first choice, because it can cause a paradoxical reaction and exacerbate clinical signs. Other anticonvulsants, such as propofol (2–8 mg/kg, IV slowly to effect [25% of total dose every 30 seconds until desired effect is achieved], and prepare to intubate) (3), levetiracetam (30–60 mg/kg, IV) (4), or phenobarbital (3–4 mg/kg, IV) (5) should be administered.

Acidifying the urine by administering ammonium chloride (25–50 mg/kg, PO, every 6 hours [100–200 mg/kg, PO, every 24 hours, divided into 4 doses]) or ascorbic acid (20–30 mg/kg, PO, SC, IM, or IV) can enhance amphetamine elimination in the urine (2); however, this treatment is not recommended if the patient is acidotic or has rhabdomyolysis.

Cyproheptadine (in dogs: 1.1 mg/kg, PO or per rectum, every 4–6 hours until resolution of clinical signs; in cats: 2–4 mg/cat, PO or per rectum, every 4–6 hours until resolution of clinical signs) may be administered to treat serotonin syndrome (6). Heart rate and rhythm, body temperature, and electrolytes should be monitored and any abnormalities treated as needed.

Typically, cardiac arrhythmias resolve in response to the treatment of CNS signs. Administration of a beta blocker like propranolol is controversial because it can produce coronary artery spasms and vasoconstriction; therefore, propranolol should not be administered to hypertensive patients (2).

Emesis may be induced in clinically normal patients that have ingested atomoxetine if it is done within 30 minutes after ingestion and the airway of the patient can be protected. A dose of AC+C may be administered when the patient is done vomiting, provided that the sodium concentration is monitored for hypernatremia.

Alternatively, gastric lavage with a cuffed tube should be performed if the patient is unable to vomit or has ingested a large overdose. A dose of AC+C should be placed in the stomach before the tube is removed. 

Further treatment of atomoxetine toxicosis is supportive and includes IV fluids, diphenhydramine (2 mg/kg, IM) for dysphoria (2), and any of the following antiemetics for tremors: 

• maropitant(1 mg/kg, SC, IV, or PO) (7, 8)

• ondansetron (0.5–1 mg/kg, IV or PO) (9, 10)

• diazepam(0.5 mg/kg, IV; or 1 mg/kg per rectum) as needed (11)

• methocarbamol (55–220 mg/kg, IV, given slowly to effect, with the rate of infusion not to exceed 2 mL/min (2); or 50–100 mg/kg, PO, every 6–8 hours as needed, not to exceed 330 mg/kg per day (6))

Housing the patient in a dark, quiet environment will decrease CNS stimulation, and carrying out thermoregulation procedures such as running fans and applying cooling vests and/or ice blankets to treat hyperthermia will make the patient more comfortable and less likely to have additional adverse clinical signs.

• Also see pet owner content regarding poisonings from illicit and abused drugs.

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2. Stern L, Schell M. Management of attention-deficit disorder and attention deficit/hyperactivity disorder drug intoxication in dogs and cats. Vet Clin North Am Small Anim Pract. 2018:48(6):959-968. doi:10.1016/j.cvsm.2018.07.007

3. Munguia GG, Brooks AC, Thomovsky SA, Thomovsky EJ, Rincon A, Johnson PA. Emergency approach to acute seizures in dogs and cats. Vet Sci. 2024;11(6):277. doi:10.3390/vetsci11060277

4. Stabile F, De Risio L. Response to levetiracetam treatment and long-term follow-up in dogs with reactive seizures due to probable exogenous toxicity. Front Vet Sci. 2021;8:773942. doi:10.3389/fvets.2021.773942

5. Pei Z, Zhang X. Methamphetamine intoxication in a dog: case report. BMC Vet Res. 2014;10:139. doi:10.1186/1746-6148-10-139

6. Fitzgerald KT, Bronstein AC. Adderall® (amphetamine-dextroamphetamine) toxicity. Top Companion Anim Med. 2013;28(1):2-7. doi:10.1053/j.tcam.2013.03.002

7. Ramsey DS, Kincaid K, Watkins JA, et al. Safety and efficacy of injectable and oral maropitant, a selective neurokinin 1 receptor antagonist, in a randomized clinical trial for treatment of vomiting in dogs. J Vet Pharmacol Ther. 2008;31(6):538-543. doi:10.1111/j.1365-2885.2008.00992.x

8. Harris S, McMichael MA, Harmon R, Boothe D. Case report: successful intravenous lipid emulsion therapy for canine amphetamine toxicosis. Front Vet Sci. 2022;9:938021. doi:10.3389/fvets.2022.938021

9. Zersen KM, Molli A, Weisbeck BG, et al. Plasma concentrations of oral ondansetron in hospitalized dogs exhibiting clinical signs of nausea. Vet Sci. 2024;11(3):112. doi:10.3390/vetsci11030112

10. Foth S, Meller S, Kenward H, et al. The use of ondansetron for the treatment of nausea in dogs with vestibular syndrome. BMC Vet Res. 2021;17:222. doi:10.1186/s12917-021-02931-9

11. Oster E, Čudina N, Pavasović H, et al. Intoxication of dogs and cats with common stimulating, hallucinogenic and dissociative recreational drugs. Vet Anim Sci. 2023;19:100288. doi:10.1016/j.vas.2023.100288