Tofranil (Imipramine) is an antidepressant used for the treatment of major depression and functional enuresis in children (bedwetting). Although it has been associated with relieving depression, it has also been successfully used to alleviate suicidal tendencies. Chemically it belongs to the dibenzazepine family.

History of Tofranil (Imipramine)

Imipramine, the active drug in Tofranil, was developed in the 1950s. It was the first drug in the tricyclic antidepressant (TCA) family. Imipramine made two fundamental contributions to the development of psychiatry: one was the dramatic change it brought to the psychiatric care of those experiencing depression, and the other of a purely pharmacological nature, permitting, among other things, the development of a hypotheses of depressive disorders.

How Does Tofranil Work?

The mechanism of action of this medication is similar to that of other tricyclic antidepressants. Its antidepressant activity is thought to relate primarily to its inhibition of serotonin and norepinephrine reuptake. Tofranil has more serotonin effects initially; its metabolite, Norpramin, then balances this effect with more norepinephrine transport inhibition. On the other hand, Tofranil is highly anticholinergic and is a relatively effective serotonin reuptake inhibitor. It also has moderate activity for alpha-1 adrenoreceptors and Histamine-1 receptors.


This drug is a dibenzazepine derivative of tricyclic antidepressants. It is off-white in color and crystalline in nature. It is available as a hydrochloride. It is odorless and has a pKa value of 9.5. On exposure to light, Tofranil turns yellow and can result in the loss of potency. It is stable in a pH range of 4–5.

Dosage FAQs

  • What is a safe dose of this drug?
    • Depression: For symptoms associated with depression, a dose of Tofranil, initially, is 75 mg. This dose can be increased to 150 mg to 200 mg maximum for individuals who are not under hospitalization, and 300 mg maximum if the person in treatment is under hospital care. This medication may be given at bedtime, as a single dose of 150 mg. For the elderly, the dose should be reduced to 10 mg initially, and may be increased to 30 mg to 50 mg per day.
    • Nocturnal enuresis (nighttime bed wetting): Although this medication is not recommend for children under 16 years of age, in some cases it may be used to treat excessive bedwetting. It is used for a maximum of three months. It is administered at a dose of 25 mg for children from seven to eight years of age. Children from eight to 11 years receive 25 mg to 50 mg, and for children over 11 years, doses between 50 mg and 75 mg at bedtime are recommended. If therapy must be continued after three months, a full physical examination should be performed.
  • Is it safe to use this drug if I am pregnant or become pregnant?
    There is no data available for Tofranil’s use in pregnancy. As a result, the U.S. Food and Drug Administration (FDA) has not assigned it to a pregnancy category. Although the drug may be secreted in the mother’s milk, the use of drug during pregnancy depends on the mother’s need for it and the risk to benefit ratio has to be determined.
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    How is this drug processed in my body?
    This drug has a rapid absorption rate and a long half of about nine to 24 hours. It is metabolized in the liver and is converted to its active metabolite, Norpramin. Norpramin has a half-life of 14 to 62 hours. The bioavailability of Tofranil is 40% and volume of distribution is around 15 to 30 L/kg. Tofranil is highly protein bound (84%) and reaches its peak plasma concentration in about two to three hours.
  • How can I get the most out of my treatment with this drug?
    Tofranil was designed to treat symptoms associated with depression, which is also a condition treated regularly with various types of psychotherapy. If you are prescribed this drug for depression, consider finding a therapist or counselor with whom you can develop a good therapeutic relationship and complement your treatment with psychotropic medication. A therapist may be able to help you work on underlying issues contributing to your symptoms of depression, help you build a good self-care routine to prevent symptoms from returning, and help you develop healthy coping strategies should symptoms arise or become triggered.

Possible Side Effects

The primary and most common adverse effects of TCAs are the anticholinergic effects. These include:

  • Dry mouth
  • Constipation
  • Urinary retention
  • Blurred vision
  • Confusion

Since this medication is a tertiary amine, these effects are more severe than with the secondary amine tricyclic antidepressants, such as Norpramin. Tofranil is also a potential blocker of the alpha receptors, thus it also produces orthostatic hypotension—the medical term for the dizzy feeling you get when you stand up too quickly. It can also cause weight gain, sedation, and changes in heart rate. 

Adverse Drug Interactions

This drug, like other TCAs, has several important drug interactions of which to be aware. If you are prescribed this medication, ensure that your pharmacist and/or doctor shares the following drug interaction safety information:

  • Alcohol: Alcohol increases the sedative effects of this medication.
  • Monoamine Oxidase Inhibitors (MAOIs): Treatment with this medication should not be started until two weeks after stopping treatment with MAOIs. Conversely, MAOIs should not be started until one to two weeks after stopping Tofranil.  
  • Antiepileptic agents: This medication decreases the antiepileptic effects of such medications.
  • Antihistamine: There is an increase in the sedative effects due to the increased muscarinic effects when both drugs are administered together.
  • Anxiolytics and hypnotics: There is an increase in sedative effects during concurrent administration.
  • Barbiturates: This medication antagonizes the anticonvulsant effects of barbiturates.
  • Nitrates: The effect of nitrates is decreased when administered with this medication because of the dry mouth side effect of Tofranil.
  • Antihypertensive: Hypotensive effects are increased when mixed with this drug.
  • Sibutramine: Tofranil and sibutramine combined severely increase the risk of developing serotonin syndrome, which is a potentially fatal condition.

Safe Withdrawal from Tofranil

Although this drug is not classified as addictive, stopping treatment with it abruptly may cause uncomfortable withdrawal symptoms including nausea, headache, fatigue, and general malaise. If you need to stop taking this medication, work out a safe plan with your doctor to taper off your dosage gradually. This will go a long way toward reducing the severity and occurrence of withdrawal symptoms.


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  2. Moller, H.J. (2006). Evidence for beneficial effects of antidepressants on suicidality in depressive patients: A systematic review. European Archives of Psychiatry and Clinical Neuroscience, 256(6), 329.
  3. Nestler, E.J. et al. (2002). Neurobiology of depression. Neuron, 34(1), 13.
  4. Stahl, S.M. (2000). Essential psychopharmacology: Neuroscientific basis and practical applications. 2nd ed. New York: Cambridge University Press: 135–295.
  5. Stimmel, G.L. (1995). How to counsel patients about depression and its treatment. Pharmacotherapy, 15(6 pt 2), 100S–104S.

Page content reviewed by James Pendleton, ND.