Can Deplin Cause Agitation? Understanding the Risk and How to Respond

January 10, 2026 •

4 min read

Clinical reports and anecdotal evidence confirm that agitation can be a side effect of taking Deplin (L-methylfolate), particularly when starting treatment or at higher doses. Understanding this potential risk is crucial for anyone using this medicinal supplement to augment their antidepressant therapy.

Quick Summary

Deplin, an L-methylfolate supplement, may trigger agitation, anxiety, or irritability in certain individuals. This can be caused by increased neurotransmitter activity, particularly at higher doses, and requires consultation with a doctor for dose adjustment or cessation.

Key Points

Agitation is a confirmed side effect: Clinical reports indicate that agitation, anxiety, and irritability are known potential side effects of Deplin (L-methylfolate).
Mechanism involves neurotransmitters: Agitation can result from an overly rapid or significant increase in neurotransmitter levels (serotonin, dopamine, norepinephrine) caused by L-methylfolate.
Higher doses increase risk: The risk of experiencing agitation is higher with larger doses, such as 15 mg, compared to lower, more gradual doses.
Specific risk factors exist: Individuals with specific MTHFR genetic variants or underlying bipolar disorder may be more susceptible to this side effect.
Consult a doctor immediately: If agitation occurs, it is crucial to speak with a healthcare provider, who may recommend dosage adjustment or discontinuation.
Agitation typically resolves: Case studies show that the agitation induced by L-methylfolate often resolves within a few days of stopping the supplement.

Is Agitation a Known Side Effect of Deplin?

Yes, agitation is a recognized potential side effect of Deplin, which is the brand name for L-methylfolate. While many people tolerate the supplement well, some report experiencing irritability, anxiety, and increased restlessness shortly after beginning treatment. The reaction appears to be more common with higher doses, such as 15 mg daily, and in individuals with specific genetic variations or pre-existing conditions like bipolar disorder. Case studies have documented instances where patients on L-methylfolate experienced uncharacteristic agitation and irritability that resolved quickly after discontinuing the supplement.

The Neurochemical Mechanism Behind L-Methylfolate-Induced Agitation

The potential for Deplin to cause agitation is linked to its primary function in the body. L-methylfolate is the active form of folate that can cross the blood-brain barrier. It plays a critical role in the synthesis of monoamine neurotransmitters, including serotonin, dopamine, and norepinephrine. For individuals who are 'undermethylators' or have certain genetic predispositions, such as MTHFR gene variants that affect enzyme activity, the introduction of high-dose L-methylfolate can cause a sudden, significant increase in these neurotransmitters. While increased neurotransmitter activity is the intended effect for treating depression, an overly rapid or pronounced increase can lead to a state of over-stimulation, which manifests as agitation, anxiety, irritability, or even hypomania or mania in susceptible individuals.

Factors That Increase the Risk of Deplin-Related Agitation

Several factors can influence a person's risk of experiencing agitation while taking Deplin:

Dosage: Higher doses of L-methylfolate (e.g., 15 mg) are more likely to cause adverse effects like agitation compared to lower doses. In some cases, a high dose can overwhelm the body's systems, leading to over-methylation and subsequent over-stimulation.
Individual Sensitivity and Genetics: Genetic variations in the MTHFR gene can affect how a person processes folate. Those with decreased MTHFR enzyme activity may respond more strongly to L-methylfolate supplementation, sometimes leading to an imbalance that causes agitation. Conversely, other genetic factors related to neurotransmitter pathways might also play a role.
Underlying Bipolar Disorder: L-methylfolate has been shown to potentially induce manic or hypomanic symptoms in individuals with or susceptible to bipolar disorder. Since agitation is a common symptom of mania, this population is at a higher risk.
Drug Interactions: Taking Deplin in combination with other medications that affect serotonin, dopamine, or norepinephrine levels can exacerbate side effects. Antidepressants, particularly SSRIs, are often augmented with Deplin, and the combination may increase the risk of over-stimulation or, in rare cases, serotonin syndrome.

What to Do If You Experience Agitation on Deplin

If you find that Deplin is making you feel agitated, restless, or irritable, it's essential to take action carefully and under medical supervision. Never stop taking your medication abruptly without consulting your doctor.

Contact Your Healthcare Provider: This is the most crucial step. Report your symptoms to the prescribing doctor immediately. They will assess your situation and determine the appropriate course of action.
Dosage Adjustment: Your doctor may recommend a significant reduction in your dosage. In some cases, a lower dose (e.g., starting with a fraction of the full dose) can prevent the over-stimulation that causes agitation.
Temporary Discontinuation: Your doctor might advise you to temporarily stop taking Deplin to see if the symptoms subside. If the agitation improves quickly after cessation, it strengthens the likelihood that the supplement was the cause.
Evaluate Other Medications: A review of all medications and supplements is necessary to identify any potential interactions that might be contributing to the agitation.
Wait for Acclimation: In some cases, side effects are temporary and may resolve as your body adjusts to the supplement. However, this should only be pursued with your doctor's guidance, especially for significant agitation.

L-Methylfolate vs. Standard Folic Acid

Understanding the difference between L-methylfolate (the active ingredient in Deplin) and standard folic acid is key to understanding potential side effects.


Feature	L-Methylfolate (Deplin)	Standard Folic Acid
Form	Bioactive, primary form in circulation.	Synthetic, inactive form.
Processing	Does not require conversion by the MTHFR enzyme.	Requires conversion by the MTHFR enzyme, which can be impaired by genetic variants.
Effect on Agitation	Can cause agitation, especially at higher doses, due to direct monoamine synthesis modulation.	High doses of standard folic acid might obscure a vitamin B12 deficiency, potentially leading to neurological issues that could cause irritability, though less directly linked to agitation than L-methylfolate.
Use in Depression	Used as an augmenting agent for antidepressants, particularly in patients with genetic predispositions.	Primarily used to prevent folate deficiency; less effective for augmenting antidepressants in those with conversion issues.
Risk of Overdose	Overdose is unlikely to be life-threatening but can cause mood changes like agitation.	High doses can cause various side effects and potentially increase cancer risk over time.

Conclusion

While a powerful tool for augmenting antidepressant treatment, the medicinal supplement Deplin can cause agitation in some individuals. This is often linked to its role in rapidly increasing monoamine neurotransmitter levels in the brain, with higher doses, genetic factors, and underlying conditions like bipolar disorder all playing a role. If you experience unusual irritability or agitation while on Deplin, it is vital to consult your healthcare provider promptly. They can help you adjust your dosage, evaluate alternative treatments, and ensure your safety. Never attempt to self-adjust your medication. By working closely with a doctor, you can navigate the benefits and risks of using L-methylfolate to manage your mental health. For more detailed clinical information on this topic, consider reviewing the case vignettes published in Psychiatric Times.

Frequently Asked Questions

Yes, some individuals report increased anxiety and restlessness as a side effect of Deplin. This is often linked to the same over-stimulation of neurotransmitters that can cause agitation.

Deplin provides L-methylfolate, which helps produce neurotransmitters like serotonin, dopamine, and norepinephrine. In some people, particularly at higher doses, this can lead to an overproduction or rapid increase, causing over-stimulation and agitation.

Individuals with certain MTHFR gene variants have decreased enzyme activity, affecting their ability to convert standard folate to L-methylfolate. When supplementing with high-dose L-methylfolate, they may experience a stronger effect and be more susceptible to agitation.

While agitation can be a side effect, it is not typically a sign of an allergic reaction. Allergic reactions would more likely involve skin rash, itching, hives, or swelling. However, any concerning symptoms should be discussed with a doctor.

If you experience agitation from Deplin, you should contact your doctor. They may advise you to stop the medication, reduce the dose, or adjust your treatment plan. Do not make changes to your medication without medical guidance.

In reported cases, agitation caused by L-methylfolate resolved within a few days of discontinuing the supplement. However, the duration can vary depending on the individual and the severity of the reaction.

Not necessarily, but it is a possibility. L-methylfolate can trigger manic or hypomanic symptoms in people with underlying bipolar disorder. Experiencing agitation should prompt a careful evaluation by your doctor to determine the cause.