Clomipramine Drug Interactions You Need to Know About

Clomipramine (brand name Anafranil) is an effective medication for OCD and other conditions, but it interacts with a surprisingly long list of other drugs, supplements, and even some foods. Some of these interactions can be dangerous.

This guide explains which interactions matter most, what to avoid, and what information your doctor needs before prescribing Clomipramine.

How Drug Interactions Work with Clomipramine

Clomipramine interacts with other substances in two main ways:

1. Pharmacodynamic interactions — When two drugs affect the same body systems. For example, combining Clomipramine with another serotonin-boosting drug can cause too much serotonin to build up (serotonin syndrome).
2. Pharmacokinetic interactions — When another drug changes how your body processes Clomipramine. Clomipramine is broken down in the liver by specific enzymes (mainly CYP2D6 and CYP1A2). Drugs that block these enzymes can cause Clomipramine levels to rise, increasing the risk of side effects.

Understanding how Clomipramine works can help you understand why these interactions matter.

Medications That Interact with Clomipramine

Dangerous Combinations (Avoid)

MAO Inhibitors (MAOIs) — This is the most dangerous interaction. Combining Clomipramine with an MAOI (such as phenelzine, tranylcypromine, or selegiline) can cause serotonin syndrome, hypertensive crisis, seizures, and death. A 14-day washout period is required between stopping an MAOI and starting Clomipramine, and vice versa. This also applies to linezolid (an antibiotic) and intravenous methylene blue, which have MAOI activity.

High-Risk Combinations (Use with Extreme Caution)

Other serotonergic drugs — Combining Clomipramine with other medications that increase serotonin significantly raises the risk of serotonin syndrome. These include:

• SSRIs (Fluoxetine, Sertraline, Paroxetine, Fluvoxamine, Citalopram, Escitalopram)
• SNRIs (Venlafaxine, Duloxetine, Desvenlafaxine)
• Triptans (Sumatriptan, Rizatriptan — used for migraines)
• Tramadol
• Lithium
• Buspirone

If switching from an SSRI to Clomipramine, your doctor should allow adequate washout time. Fluoxetine, in particular, has a very long half-life and requires a longer washout.

CYP2D6 inhibitors — These drugs slow down the enzyme that breaks down Clomipramine, causing it to accumulate in your body:

• Fluoxetine (Prozac)
• Paroxetine (Paxil)
• Quinidine
• Bupropion (Wellbutrin)

If you must take one of these with Clomipramine, your doctor may need to reduce your Clomipramine dose significantly.

CYP1A2 inhibitors — These also increase Clomipramine levels:

• Fluvoxamine (Luvox) — this is a particularly potent inhibitor and can dramatically raise Clomipramine levels
• Ciprofloxacin (an antibiotic)

QT-prolonging drugs — Clomipramine can affect your heart's electrical rhythm. Taking it with other drugs that prolong the QT interval increases the risk of dangerous heart arrhythmias:

• Certain antipsychotics (Haloperidol, Ziprasidone)
• Certain antibiotics (Erythromycin, Moxifloxacin)
• Certain antiarrhythmics (Amiodarone, Sotalol)
• Methadone

Moderate Interactions

• Anticholinergic drugs — Taking Clomipramine with other anticholinergic medications (like Diphenhydramine/Benadryl, Oxybutynin, or certain antipsychotics) can worsen side effects like dry mouth, constipation, urinary retention, and confusion.
• CNS depressants — Benzodiazepines, opioids, sleep aids, and muscle relaxants combined with Clomipramine increase sedation and the risk of respiratory depression.
• Cimetidine — This heartburn medication can increase Clomipramine blood levels.
• Enzyme inducers — Phenobarbital, carbamazepine, and rifampin can decrease Clomipramine levels, potentially making it less effective.
• Thyroid medications — Interactions may affect both drug efficacy and side effects.
• Sympathomimetics — Drugs like epinephrine and norepinephrine (including those in dental anesthetics) can have enhanced cardiovascular effects with Clomipramine.
• Warfarin — Clomipramine may alter the blood-thinning effect of warfarin, requiring more frequent INR monitoring.

Supplements and Over-the-Counter Drugs

Don't assume that "natural" means safe to combine with Clomipramine:

• St. John's Wort — This herbal supplement increases serotonin and can cause serotonin syndrome when combined with Clomipramine. Avoid it completely.
• 5-HTP and L-Tryptophan — These serotonin precursor supplements also increase serotonin syndrome risk.
• Diphenhydramine (Benadryl) — Adds to anticholinergic side effects. Avoid using it regularly as a sleep aid while on Clomipramine.
• Pseudoephedrine and phenylephrine — Decongestants found in cold medications can interact with Clomipramine's effects on norepinephrine.
• Melatonin — Generally considered safe, but can add to drowsiness.

Food and Drink Interactions

• Alcohol — Significantly increases sedation and CNS depression. Avoid or strictly limit alcohol while taking Clomipramine.
• Grapefruit juice — May increase Clomipramine levels by inhibiting CYP enzymes. It's best to avoid regular consumption of grapefruit or grapefruit juice.
• Caffeine — Not a direct interaction, but high caffeine intake can worsen anxiety and tremor, which are already potential Clomipramine side effects.

What to Tell Your Doctor

Before starting Clomipramine, make sure your doctor knows about:

• Every medication you take — prescription and over-the-counter, including eye drops, inhalers, and topical creams
• All supplements and herbal products — especially St. John's Wort, 5-HTP, and any "mood support" supplements
• Recent medication changes — particularly if you've recently stopped an MAOI or SSRI
• Recreational drug use — MDMA (ecstasy/molly) is a potent serotonin releaser and is extremely dangerous to combine with Clomipramine
• Upcoming medical procedures — your anesthesiologist needs to know you're on a TCA, as dental anesthetics and certain surgical medications can interact
• Genetic testing results — if you know you're a CYP2D6 poor metabolizer, this affects how your body handles Clomipramine

Keep an updated medication list and bring it to every appointment. This simple step prevents many dangerous interactions.

Final Thoughts

Clomipramine's interaction profile is one of the reasons it requires careful medical supervision. The most important thing you can do is be completely transparent with your doctor about everything you're taking — prescribed or not.

If you're currently taking Clomipramine and need to start a new medication, always check with your prescriber or pharmacist first. And for more information about Clomipramine, including side effects and dosing, explore our other guides. If you're having trouble finding Clomipramine at your pharmacy, Medfinder can help you check stock near you.