Does Acyclovir Cause Confusion? Understanding the Link to Neurotoxicity

October 9, 2025 •

4 min read

While considered a very safe medication for most people, a systematic review of cases published in the literature found that nearly 74% of neurotoxicity cases linked to antivirals involved acyclovir. This rare but serious side effect can cause confusion, among other neuropsychiatric symptoms, especially in high-risk patients.

Quick Summary

Acyclovir can, in rare instances, lead to confusion as a symptom of neurotoxicity, particularly in older adults and those with impaired kidney function. This complication arises from the accumulation of the drug and its metabolites in the body. Symptoms typically reverse upon discontinuing the medication, sometimes aided by dialysis in severe cases.

Key Points

Acyclovir can cause neurotoxicity: While rare, acyclovir can lead to neurotoxicity, with confusion as a primary symptom.
Renal impairment is the main risk factor: Impaired or end-stage kidney function prevents the body from properly clearing the drug and its toxic metabolite, leading to accumulation.
Older adults are more sensitive: Elderly patients are particularly vulnerable to the central nervous system effects of acyclovir, even without severe renal impairment.
Neurotoxicity symptoms include more than confusion: Other signs can include agitation, hallucinations, dizziness, tremors, and seizures.
Symptoms are often reversible: Discontinuing the medication is the primary treatment, and for severe cases, hemodialysis can rapidly reverse the toxic effects.
Diagnosis is clinical: Recognizing the symptoms in a high-risk patient is key to diagnosis, as confirmatory lab tests may be delayed or unavailable.

The Mechanism of Acyclovir Neurotoxicity

Acyclovir, a widely used antiviral, has a high affinity for central nervous system (CNS) tissues and is primarily eliminated from the body through the kidneys. In patients with compromised renal function, this clearance process is inefficient, leading to the accumulation of the drug and its neurotoxic metabolite, 9-carboxymethoxymethylguanine (CMMG). As CMMG levels rise in the blood and cerebrospinal fluid, it can trigger neuropsychiatric symptoms, including confusion.

Unlike many other drugs, the neurotoxicity associated with acyclovir is dose-dependent, meaning that higher drug concentrations increase the risk of adverse effects. While neurotoxicity is a well-documented risk, it is important to remember that it is not a common side effect and typically only occurs when the drug is improperly dosed for a patient with underlying risk factors.

Who Is at Risk for Acyclovir-Induced Confusion?

Several factors can increase a patient's vulnerability to acyclovir-induced confusion and other neurotoxic effects. Recognizing these risk factors is crucial for healthcare providers and patients alike to ensure safe and effective treatment.

Elderly patients: Older adults are more susceptible to the CNS effects of acyclovir, including agitation, dizziness, and confusion, even with normal renal function.
Impaired renal function: Patients with chronic or acute kidney disease, including those with end-stage renal disease, are at significantly higher risk. The reduced ability to clear the drug leads to its accumulation.
High or unadjusted doses: Administering a dose that is not properly adjusted for a patient's level of renal function can cause an overdose and increase toxicity risk.
Dehydration: Reduced fluid intake can decrease kidney function and concentrate the drug in the bloodstream, raising the risk of side effects.
Pre-existing neurological issues: Certain nervous system problems can be worsened by acyclovir.

Recognizing the Symptoms: Beyond Confusion

While confusion is a prominent symptom of acyclovir neurotoxicity, it often presents alongside a constellation of other neuropsychiatric issues. The onset of these symptoms is typically rapid, often occurring within 24 to 72 hours of initiating or continuing the medication.

Spectrum of Neuropsychiatric Symptoms

Confusion: Disorientation and difficulty with clear thinking.
Agitation and Altered Consciousness: Restlessness, extreme irritability, drowsiness, or a decreased level of awareness.
Hallucinations: Seeing or hearing things that are not there.
Tremors and Unsteady Movements: Involuntary shaking and difficulty with coordination (ataxia).
Speech Difficulties: Trouble speaking or slurred speech (dysarthria).
Seizures: Involuntary body convulsions.
Delirium or delusions: Including rare instances of Cotard's syndrome, or "death delusions," where a patient is convinced they are dead.

Distinguishing from Viral Encephalitis

In patients being treated for a herpesvirus infection involving the central nervous system (e.g., herpes encephalitis), it can be challenging to differentiate between worsening viral infection and acyclovir-induced neurotoxicity. However, acyclovir neurotoxicity often has a more rapid onset (around 3 days) compared to viral encephalitis and can be identified by the absence of typical encephalitis signs like high fever or specific focal neurologic findings. Specialized testing for the CMMG metabolite in cerebrospinal fluid can also assist in diagnosis.

Comparing Acyclovir Neurotoxicity with Common Side Effects

It is important for patients and caregivers to differentiate between the serious but rare symptoms of neurotoxicity and the more common, generally less severe side effects of acyclovir. The following table provides a comparison.


Feature	Neurotoxicity Symptoms	Common Side Effects
Onset	Acute, often within 24-72 hours	Can occur at any point during treatment
Symptom Type	Psychiatric and neurological (e.g., confusion, hallucinations, tremors)	General constitutional (e.g., nausea, diarrhea, headache)
Underlying Cause	Accumulation of acyclovir and its metabolite (CMMG)	Direct drug effect or viral illness symptoms
Resolution	Reversible upon drug discontinuation; may require medical intervention	Often improves over time or with symptomatic treatment
Severity	Can be severe, requiring immediate medical attention	Usually mild to moderate
Risk Factors	Renal impairment, advanced age, dehydration	Minimal specific risk factors for general side effects

Diagnosis and Management

Diagnosing acyclovir-induced neurotoxicity is a clinical process that relies on recognizing the signs and symptoms in at-risk individuals. If a patient receiving acyclovir develops new or worsening neuropsychiatric symptoms, especially confusion, a healthcare provider should have a high suspicion for toxicity.

Key steps for management include:

Drug Discontinuation: The most critical step is to immediately stop administering acyclovir. In many cases, the symptoms will resolve completely once the drug is cleared from the body.
Monitoring: Close observation of the patient's neurological status is necessary to track improvement and ensure symptoms resolve.
Hemodialysis: For severe cases, particularly in patients with end-stage renal disease, hemodialysis can be highly effective. It helps to rapidly clear the acyclovir and CMMG metabolites from the bloodstream. Studies have shown that even a single session can significantly improve symptoms.

Conclusion

Yes, acyclovir can cause confusion, but it is a rare side effect associated with drug-induced neurotoxicity. The most significant risk factor is impaired kidney function, which leads to the accumulation of the drug and its toxic metabolite in the body. Elderly patients and those who are dehydrated are also at increased risk. If you or someone you know experiences confusion, hallucinations, or other unusual neurological symptoms while taking acyclovir, it is crucial to seek immediate medical attention. The condition is often reversible with prompt recognition and management, most importantly, discontinuing the medication. With proper monitoring and dosage adjustments, especially for at-risk individuals, acyclovir remains a safe and effective antiviral medication. For further details on acyclovir safety, consult reliable medical sources like those provided by the Mayo Clinic.

Frequently Asked Questions

Acyclovir-induced confusion is considered a rare adverse effect. The incidence is low, and most patients tolerate the medication without this complication. However, it is more frequent in specific high-risk populations, particularly older adults and those with renal impairment.

The primary cause is the accumulation of acyclovir and its metabolite, 9-carboxymethoxymethylguanine (CMMG), in the body, especially within the central nervous system. This buildup typically happens when a patient has impaired kidney function, which prevents the drug from being cleared properly.

Doctors can differentiate between the two by considering the clinical presentation and risk factors. Acyclovir toxicity often appears more quickly (within days) and can be characterized by specific neuropsychiatric symptoms like hallucinations and death delusions, along with normal cerebrospinal fluid results. Viral encephalitis is often accompanied by fever and a distinct set of neurological signs.

If you experience confusion or other neurological symptoms while taking acyclovir, you should contact your doctor or seek emergency medical attention immediately. The medication will likely need to be discontinued to prevent further toxicity.

The main treatment for acyclovir neurotoxicity is to stop the medication. For severe cases, particularly in patients with kidney problems, hemodialysis can be used to remove the drug from the body more quickly. The condition is often reversible once the drug is cleared.

Yes, other CNS side effects include agitation, dizziness, hallucinations, tremors, seizures, and altered levels of consciousness. Some patients may also experience more specific symptoms, such as speech difficulties or unusual delusions.

While it is far more common in those with kidney impairment, cases of acyclovir neurotoxicity have been reported in patients with seemingly normal renal function. This highlights the importance of vigilance in all patients taking the medication, especially if they are elderly or have other comorbidities.