Venlafaxine (Effexor)

Venlafaxine in Brief
  • Generic name: Venlafaxine hydrochloride
  • Brand names: Effexor, Effexor XR
  • Therapeutic class: Antidepressant
  • Pharmacologic class: Serotonin-Norepinephrine Reuptake Inhibitor (SNRI), bicyclic phenyetilamine derivative
  • FDA Approved:
    Immediate-release formulation: December 28, 1993
    Extended-release formulation: October 20, 1997
  • Chemical Formula: C17H27NO2
  • Pregnancy Category: C
  • Habit forming? Not known
  • Originally discovered: 1980s, Wyeth, USA Denmark

Based on "Essential Psychopharmacology"
written by Stephen M. Stahl, MD, PhD


Venlafaxine was first synthesized in the early 1980s by researchers at Wyeth Pharmaceuticals. Wyeth scientists -- John Yardley, Morris Husbands, and Eric Muth -- recognized venlafaxine’s promise as an important antidepressant and pressed forward with its development. Wyeth launched venlafaxine for the treatment of depression in the United States in early 1994 under the trade name Effexor.


The medicine was originally launched in an immediate release formulation. The extended-release (XR) formulation was approved by the FDA in 1997. The advantage of the XR formulation, besides once-daily dosing, is a slightly lower rate of nausea during the beginning of therapy.

Generic formulations of venlafaxine immediate-release entered the market in 2007.

FDA approved indications

  • Major depressive disorder
  • Generalized anxiety disorder (GAD)
  • Social anxiety disorder
  • Panic disorder

Off-label & Investigational uses

  • post-traumatic stress disorder (PTSD) 15
  • migraine prophylaxis16
  • fibromyalgia17
  • tension-type headache18
  • chronic pain syndromes19
  • premenstrual dysphoric disorder (PMDD)20
  • diabetic neuropathy21
  • hot flashes22
  • bipolar depression24
  • chronic fatigue syndrome
  • irritable bowel syndrome (IBS)
  • attention-deficit hyperactivity disorder (ADD/ADHD) 25
  • cocaine dependence26

Venlafaxine for fibromyalgia
Venlafaxine is a promising treatment for fibromyalgia symptoms. Venlafaxine 75 mg/day appears to be effective in alleviating the pain and disability associated with fibromyalgia17, 38. This effect seems to be independent of its anxiolytic and antidepressant properties. Blockade of both norepinephrine and serotonin reuptake might be more effective than blockade of either neurotransmitter alone in the treatment of fibromyalgia.

Analgesic potential of Venlafaxine
Venlafaxine is gaining interest as a potential treatment for various pain syndromes. This medication combines the norepinephrine-reuptake inhibiting effects of TCAs with the serotonin-reuptake inhibiting effects of the SSRIs, without the anticholinergic side effects. It appers to be effective in diabetic neuropathy and neuropathic back pain21,32. Venlafaxine is modestly effective in the treatment of atypical facial pain33. The results of clinical study have shown long-term efficacy and effectiveness of venlafaxine XR for treatment of chronic pain with associated major depressive disorder34.

Venlafaxine "pros" and "cons"


  • Venlafaxine appears more effective than SSRIs, and at least as effective as tricyclic antidepressants, in the treatment of major depression36
  • Often effective for depression unresponsive to SSRIs 2,7
  • High therapeutic success rate5
  • Effective for treatment-resistant depression6
  • Quick onset of antidepressant and anxiolytic activity28,29
  • Higher remission rates than with fluoxetine and paroxetine13
  • Memory improving effects27
  • Provides protection against a renewed occurrence of depressive symptoms (recurrence prevention)
  • Low potential for pharmacokinetic drug interactions due to minimal inhibition of liver CYP450 isoenzymes


  • High risk of withdrawal syndrome. Withdrawal symptoms occur rapidly and may be very severe 3. Withdrawal symptoms may occur after missing a single dose due to venlafaxine's short half-life.
  • High rate of treatment emergent mania and hypomania 23
  • More toxic than SSRIs in overdose. Toxicity appears to be higher than with other SSRIs, with a fatal toxic dose closer to that of the tricyclic antidepressants 4, 10. Doses of 900 mg or more are likely to cause moderate toxicity.
  • Elevation of blood pressure 37. The risk of sustained high blood pressure increases from 3% to 7% at dosages of 100-225 mg/day (for IR formulation) and to 13% at dosages above 300 mg/day 11. In the studies of the XR formulation with maximum dosage of 225 mg/day, the increased risk was only 3%.
  • Highest rate of nausea and vomiting 30
  • Highest risk of suicide 31

Mechanism of action

Venlafaxine is a phenethylamine bicyclic derivative. It blocks the reuptake of serotonin, noradrenaline and, to a lesser extent, dopamine. The reuptake effects of venlafaxine are dose dependent. At low doses (< 150 mg/day) it acts only on serotonergic transmission, like the SSRIs. At moderate doses (>150 mg/day) venlafaxine acts on serotonergic and noradrenergic systems, whereas at high doses (>300 mg/day) it affects serotonergic, noradrenergic and dopaminergic neurotransmission 14.

The combination of the effects on the reuptake mechanisms appears to be responsible for the antidepressant action of the drug.

Venlafaxine has negligible affinity for muscarinic, adrenergic, or histamine receptors.

Analgesic action
Venlafaxine has an analgesic effect that is independent of its antidepressant activity. The results of clinical studies suggest that the opioidergic system has a role in the analgesic effect of venlafaxine 8. Antinociceptive effect of venlafaxine is influenced by opioid receptor subtypes (mu-, kappa1- kappa3- and delta-opioid receptor subtypes) combined with the alpha2-adrenergic receptor. This opioid profile may be one of the explanations to venlafaxine efficacy in severe depression, unlike the SSRIs and other antidepressants which lack opioid activity 9. Time to clear out of the system

Venlafaxine has elimination half-life about 5 ± 2 hours and its active metabolite O-desmethylvenlafaxine (ODV) has a half-life of about 11 ± 2 hours. It may take 4 to 5 days for venlafaxine to clear out of the system.

The clearance of venlafaxine is slightly (15%) lower following multiple doses than following a single dose.

Onset of action

Steady-state concentrations of both venlafaxine and ODV in plasma were attained after approximately 3 days of multiple dose therapy.

While most people taking venlafaxine become aware of some lessening of depression within two to four weeks, there are some who experience relief within the first week and others who only experience relief after a couple of months of therapy.

Venlafaxine (Effexor) withdrawal

Abrupt discontinuation and even gradual tapering of venlafaxine is associated with high incidence of withdrawal symptoms. Severe discontinuation reactions may make cessation of the drug extremely difficult. Venlafaxine discontinuation symptoms include:

  • agitation
  • anorexia
  • anxiety
  • confusion
  • coordination impaired
  • diarrhea
  • dizziness
  • dry mouth
  • dysphoric mood
  • fasciculation
  • fatigue
  • headaches
  • hypomania
  • insomnia
  • nausea
  • nervousness
  • nightmares
  • shock-like sensations
  • somnolence
  • sweating
  • tremor
  • vertigo
  • vomiting

In order to minimise the chance of withdrawal problems, it is suggested that venlafaxine should be withdrawn very gradually by reducing the dose very slowly over a period of weeks, or months in cases where the symptoms are severe.

Venlafaxine & alcohol

Venlafaxine has not been shown to increase the impairment of mental and motor skills caused by alcohol.

Venlafaxine (Effexor) abuse & dependence

Venlafaxine is not a controlled substance. It has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. While venlafaxine has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials.

However, there is some evidence that large doses of venlafaxine may produce amphetamine-like effects 35. So, when treating patients with a history of alcohol or drug abuse, physicians should consider the potential of venlafaxine for abuse.


Further reading


  • 1. U.S. FDA. Venlafaxine Prescribing Information.
  • 2. Poirier MF, Boyer P. Br J Psychiatry. 1999 Jul;175:12-6. PubMed
  • 3. Daniel M. Campagne. Venlafaxine and Serious Withdrawal Symptoms: Warning to Drivers MedGenMed. 2005; 7(3): 22. PubMed
  • 4. Whyte IM, Dawson AH, Buckley NA. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. QJM. 2003 May;96(5):369-74. PubMed
  • 5. Bauer M, Tharmanathan P, Volz HP, Moeller HJ, Freemantle N. The effect of venlafaxine compared with other antidepressants and placebo in the treatment of major depression: a meta-analysis. Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):172-85. PubMed
  • 6. de Montigny C, Silverstone PH, Debonnel G, Blier P, Bakish D. Venlafaxine in treatment-resistant major depression: a Canadian multicenter, open-label trial. J Clin Psychopharmacol. 1999 Oct;19(5):401-6. PubMed
  • 7. Kaplan EM. Efficacy of venlafaxine in patients with major depressive disorder who have unsustained or no response to selective serotonin reuptake inhibitors: an open-label, uncontrolled study. Clin Ther. 2002 Jul;24(7):1194-200. PubMed
  • 8. Gultekin H, Ahmedov V. Role of the opioidergic system and nitric oxide in the analgesic effect of venlafaxine. Yakugaku Zasshi. 2006 Feb;126(2):117-21. PubMed
  • 9. Schreiber S, Bleich A, Pick CG. Venlafaxine and mirtazapine: different mechanisms of antidepressant action, common opioid-mediated antinociceptive effects--a possible opioid involvement in severe depression? J Mol Neurosci. 2002 Feb-Apr;18(1-2):143-9. PubMed
  • 10. Nicholas A Buckley, Peter R McManus. Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of United Kingdom mortality data. BMJ. 2002 December 7; 325(7376): 1332–1333. PubMed
  • 11. Thase ME. Effects of venlafaxine on blood pressure: a meta-analysis of original data from 3744 depressed patients. J Clin Psychiatry. 1998 Oct;59(10):502-8. PubMed
  • 12. Markowitz JS, Patrick KS. Venlafaxine-tramadol similarities. Med Hypotheses. 1998 Aug;51(2):167-8. PubMed
  • 13. Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry. 2001 Mar;178:234-41. PubMed
  • 14. Redrobe JP, Bourin M, Colombel MC, Baker GB. Dose-dependent noradrenergic and serotonergic properties of venlafaxine in animal models indicative of antidepressant activity. Psychopharmacology (Berl). 1998 Jul;138(1):1-8. PubMed
  • 15. Gelenberg AJ, Lydiard RB, Rudolph RL, Aguiar L, Haskins JT, Salinas E. Efficacy of venlafaxine extended-release in nondepressed outpatients with generalized anxiety disorder: A 6-month randomized controlled trial. JAMA. 2000 Jun 21;283(23):3082-8. PubMed
  • 16. Ozyalcin SN, Talu GK, Kiziltan E, Yucel B, Ertas M, Disci R. The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache. 2005 Feb;45(2):144-52. PubMed
  • 17. Sayar K, Aksu G, Ak I, Tosun M. Venlafaxine treatment of fibromyalgia. Ann Pharmacother. 2003 Nov;37(11):1561-5. PubMed
  • 18. Zissis NP, Harmoussi S, Vlaikidis N, Mitsikostas D, Thomaidis T, Georgiadis G, Karageorgiou K. A randomized, double-blind, placebo-controlled study of venlafaxine XR in out-patients with tension-type headache. Cephalalgia. 2007 Apr;27(4):315-24.PubMed
  • 19. Galvez R, Caballero J, Atero M, Ruiz S, Romero J. Venlafaxine extended release for the treatment of chronic pain. Actas Esp Psiquiatr. 2004 Mar-Apr;32(2):92-7. PubMed
  • 20. Freeman EW, Rickels K, Yonkers KA, Kunz NR, McPherson M, Upton GV. Venlafaxine in the treatment of premenstrual dysphoric disorder. Obstet Gynecol. 2001 Nov;98(5 Pt 1):737-44. PubMed
  • 21. Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain. 2004 Aug;110(3):697-706. PubMed
  • 22. Evans ML, Pritts E, Vittinghoff E, McClish K, Morgan KS, Jaffe RB. Management of postmenopausal hot flushes with venlafaxine hydrochloride: a randomized, controlled trial. Obstet Gynecol. 2005 Jan;105(1):161-6. PubMed
  • 23. Leverich GS, Altshuler LL, Frye MA, Suppes T, et al. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression. Am J Psychiatry. 2006 Feb;163(2):232-9.
  • 24. Amsterdam JD, Wang G, Shults J. Venlafaxine monotherapy in bipolar type II depressed patients unresponsive to prior lithium monotherapy. Acta Psychiatr Scand. 2010 Mar;121(3):201-8.
  • 25. Findling RL, Schwartz MA, Flannery DJ, Manos MJ. Venlafaxine in adults with attention-deficit/hyperactivity disorder: an open clinical trial. J Clin Psychiatry. 1996 May;57(5):184-9. PubMed
  • 26. McDowell DM, Levin FR, Seracini AM, Nunes EV. Venlafaxine treatment of cocaine abusers with depressive disorders. Am J Drug Alcohol Abuse. 2000 Feb;26(1):25-31. PubMed
  • 27. Nowakowska E, Kus K, Florek E, Czubak A, Jodynis-Liebert J. The influence of tobacco smoke and nicotine on antidepressant and memory-improving effects of venlafaxine. Hum Exp Toxicol. 2006 Apr;25(4):199-209. PubMed
  • 28. Hackett D. Venlafaxine XR in the treatment of anxiety. Acta Psychiatr Scand Suppl. 2000;(406):30-5. PubMed
  • 29. Entsuah R, Derivan A, Kikta D. Early onset of antidepressant action of venlafaxine: pattern analysis in intent-to-treat patients. Clin Ther. 1998 May-Jun;20(3):517-26. PubMed
  • 30. F R Mackay, N R Dunn, R M Martin, G L Pearce, S N Freemantle, R D Mann. Newer antidepressants: a comparison of tolerability in general practice. Br J Gen Pract. 1999 November; 49(448): 892–896. PubMed
  • 31. Rubino A, Roskell N, Tennis P, Mines D, Weich S, Andrews E. Risk of suicide: retrospective cohort study. BMJ. 2007 Feb 3;334(7587):242. PubMed
  • 32. Sumpton JE, Moulin DE. Treatment of neuropathic pain with venlafaxine. Ann Pharmacother. 2001 May;35(5):557-9. PubMed
  • 33. Forssell H, Tasmuth T, Tenovuo O, Hampf G, Kalso E. Venlafaxine in the treatment of atypical facial pain: a randomized controlled trial. J Orofac Pain. 2004 Spring;18(2):131-7. PubMed
  • 34. Bradley RH, Barkin RL, Jerome J, DeYoung K, Dodge CW. Efficacy of venlafaxine for the long term treatment of chronic pain with associated major depressive disorder. Am J Ther. 2003 Sep-Oct;10(5):318-23. PubMed
  • 35. A Case of Venlafaxine Abuse. Volume 348:764-765 February 20, 2003 Number 8. New England Journal of Medicine. NEJM
  • 36. Bauer M, Tharmanathan P, Volz HP, Moeller HJ, Freemantle N. The effect of venlafaxine compared with other antidepressants and placebo in the treatment of major depression: a meta-analysis. Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):172-85
  • 37. Diaper A, Rich AS, Wilson SJ, et al. Changes in cardiovascular function after venlafaxine in healthy volunteers: a double-blind, placebo-controlled study of orthostatic challenge, blood pressure and heart rate. Hum Psychopharmacol. 2013 Aug 16. PubMed
  • 38. Hsiao MC. Effective treatment of fibromyalgia comorbid with premenstrual dysphoric disorder with a low dose of venlafaxine. Prim Care Companion J Clin Psychiatry. 2007;9(5):398.

Published: March 31, 2008
Last updated: October 21, 2017

Interesting facts

Venlafaxine facts
  • Venlafaxine belongs to the phenylthylamine class, which includes amphetamine, methylendioxymethamphetamine (MDMA), and methamphetamine. This chemical structure likely lends to its activating properties, however some patients find Venlafaxine highly sedating despite its more common stimulatory effects.
  • Venlafaxine and tramadol share a number of molecular and pharmacological features that may allow for broader and overlapping indications. Certain patients with coexisting depression and pain syndromes could potentially be treated with a single agent 12.

More Facts
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