Venlafaxine is an FDA-approved antidepressant for the treatment of major depression, generalized anxiety disorder, social anxiety disorder, and panic disorder. However, research has shown that venlafaxine is also effective in other diseases and disorders. Read on to find out how this drug works in your body and the possible side effects accompanying venlafaxine use.

Disclaimer: By writing this post, we are not recommending this drug. Some of our readers who were already taking the drug requested that we commission a post on it, and we are simply providing information that is available in the clinical and scientific literature. Please discuss your medications with your doctor.

What is Venlafaxine?

Venlafaxine (commonly known as Effexor) is an antidepressant used to treat depression, anxiety, and panic attacks.

Venlafaxine belongs to a group of drugs known as selective serotoninnorepinephrine reuptake inhibitors (SNRIs). In essence, this means that venlafaxine prevents the neurons in the brain from taking up released serotonin and norepinephrine. Consequently, this results in increased levels of serotonin and norepinephrine in the body and brain [1].

Since the introduction of venlafaxine in 1994, it has become a commonly prescribed antidepressant for depression, anxiety, and panic attacks. However, venlafaxine is also reported to have beneficial effects on other conditions, which will be discussed further in this article.

Mechanism of Action

To date, the exact relationship between the biology of the depressed brain and how antidepressants work to bring about their therapeutic effects is not completely understood [2].

However, studies have shed light on what antidepressants, like venlafaxine do to our brains. Since venlafaxine falls under the selective serotonin-norepinephrine reuptake inhibitors (SNRIs), the primary mechanisms of action of venlafaxine are as follows:

1) Increases Serotonin

Venlafaxine increases the level of serotonin by binding to the reuptake protein (SLC6A4), which is responsible for clearing away released serotonin at the synapse [3, 4].

This is the primary mechanism of action of venlafaxine since it binds most strongly to the serotonin reuptake proteins [4].

2) Increases Norepinephrine

Venlafaxine binds to and inhibits the norepinephrine reuptake protein (SLC6A2) and hence, increases levels of norepinephrine at the synapse [4, 5, 6].

A higher dose of venlafaxine is required to increase norepinephrine levels. In a study (randomized controlled trial) of 32 healthy male subjects over a period of 2 weeks, venlafaxine was found to exert its effects through increasing both serotonin and norepinephrine levels in a sequential manner [7].

3) Increases Dopamine

Although venlafaxine also binds to the dopamine reuptake protein (DAT), it does not bind as strongly as it does to serotonin and norepinephrine proteins. Therefore, the inhibition of dopamine by venlafaxine is less potent [8].

The pharmacological and clinical relevance of dopamine reuptake inhibition is not entirely understood.

Uses of Venlafaxine

1) Helps Combat Major Depression

Venlafaxine is an approved treatment for major depression along with the other antidepressants such as tricyclic antidepressants (TCAs), which are an older type of medication.

In the first clinical trial (double-blind randomized controlled trial) of 60 patients with major depression, the group receiving venlafaxine significantly improved their depression scores at low, medium, and high doses, and the highest dose resulted in improvement just 2 weeks after therapy, as compared to the placebo group [9].

In another clinical trial (double-blind randomized controlled trial) of 194 patients with major depression, taking venlafaxine considerably improved depressive symptoms compared to the placebo group. It was both effective and well-tolerated [10].

Since then, multiple studies have shown how effective an antidepressant venlafaxine is, not only compared to placebo but also in comparison with older antidepressants, such as fluoxetine [11, 12, 13, 14, 15, 16].

2) May Help Combat Bipolar Disorder

Depressive episodes occurring in bipolar disorder patients considerably decrease the quality of life.

In a clinical trial (single-blind randomized controlled trial) of 60 bipolar patients on mood stabilizing drugs, venlafaxine treatment for 6 weeks significantly reduced depressive symptoms. Additionally, venlafaxine was effective and safe as a treatment option for depressive episodes in bipolar patients [17].

A recent clinical trial (double-blind randomized controlled trial) compared the effectiveness of venlafaxine to lithium monotherapy (only using a single drug for treatment purposes) in 65 venlafaxine-treated and 64 lithium-treated bipolar patients for 12 weeks. Venlafaxine treatment produced a greater decline in depressive symptoms compared to lithium, indicating that short-term venlafaxine therapy is an effective option for depressive episodes in bipolar patients [18].

However, venlafaxine use may increase the risk of bipolar patients experiencing hypomania or mania, also known as “mood switch.” In a 10-week clinical trial (double-blind randomized controlled trial), 174 bipolar patients were administered one of 3 antidepressants: bupropion, sertraline, or venlafaxine, along with mood-stabilizing drugs. There was a significantly increased risk of switching to hypomania or mania in patients who took venlafaxine compared to bupropion or sertraline [19].

3) Reduces Neuropathic Pain

Neuropathic pain is caused by damage to the nerves. This pain is of a chronic nature and often persists for months and years, which severely decreases the patients’ quality of life [20].

Although using antidepressants for neuropathic pain is not an approved treatment in most countries, they are still prescribed for pain relief associated with neuropathic pain [20].

In a clinical trial (double-blind randomized controlled trial) of 13 patients who suffered from neuropathic pain after undergoing treatment for breast cancer, venlafaxine reduced the average pain intensity (reported by patients) and maximum pain intensity (reported retrospectively by a computer program) compared to the placebo group [21].

Another clinical trial (double-blind randomized controlled trial) was carried out in 150 patients who experienced neuropathic pain after breast cancer surgery. Venlafaxine significantly decreased the incidence of chronic pain and its intensity 6 months later, compared to the placebo group [22].

However, larger clinical trials are needed to evaluate the effectiveness of venlafaxine as a treatment option for neuropathic pain, especially considering the limited drug options available for this condition [23].

4) Effective Against Migraines

Migraines are characterized by chronic headaches on one side of the head that can have an adverse negative effect on everyday life.

Sixty migraine patients were administered venlafaxine or placebo in a study (double-blind randomized controlled trial). The venlafaxine-treated group reported fewer headaches than the placebo group [24].

Venlafaxine was also effective in reducing vertigo-related symptoms in vestibular migraines [25].

5) Reduces the Incidence of Tension-Type Headaches

Tension-type headaches are persistent headaches, although they are typically less disabling than migraines. They are more common in the general population with a 38% yearly prevalence and have a considerable negative impact if they occur frequently [26].

In a study (double-blind randomized controlled trial) of 60 tension-type headache patients, 34 patients were administered venlafaxine and 26 received a placebo treatment for 12 weeks. Venlafaxine reduced the number of days with headaches compared to placebo, suggesting that it may be an effective and safe treatment option for this condition [27].

6) Improves Behavioral Symptoms in Autism

Autism is a neurodevelopmental disorder that is characterized by 3 core behavioral symptoms: Lack of social skills, impaired communication skills, and repetitive behaviors [28].

In a pilot study of 10 autistic subjects (8 children and adolescents, 2 adults), 6 subjects responded positively to venlafaxine at low doses, and treatment was well tolerated. The study also reports that venlafaxine improved all 3 behavioral symptoms of autism [29].

Another study (double-blind randomized controlled trial) compared the effectiveness of venlafaxine in autistic patients receiving venlafaxine, with 7 autistic patients receiving a placebo treatment for a period of 56 days. Despite the small number of patients involved, venlafaxine significantly improved behavioral abnormalities in autistic patients compared to placebo; however, larger studies are required to confirm this [30].

7) Helps Combat Vasomotor Symptoms of Menopause

Menopause is the transitional time in a woman’s life when the ovaries stop releasing eggs and menstrual periods stop. One of the most commonly reported menopausal symptoms as hot flashes or night sweats, which falls under the umbrella of vasomotor symptoms of menopause. These symptoms greatly reduce the quality of life for women [31, 32].

Hot flashes are also a problem for women with a history of breast cancer and men undergoing androgen-deprivation therapy for the treatment of advanced prostate cancer [33, 34].

In a pilot study in 28 women with a history of breast cancer who received low doses of venlafaxine over a period of 4 weeks, 58% of patients had a greater than 50% reduction in the frequency and severity of hot flashes [34].

These initial observations led to more studies reporting that venlafaxine is an effective treatment for managing hot flashes in breast cancer survivors [35, 36, 37, 38, 39].

Venlafaxine is also a successful treatment for hot flashes in otherwise healthy women. In a study (randomized controlled study) of 80 postmenopausal women lasting 12 weeks, the venlafaxine-treated group showed a notably decreased mean hot flash scores compared to the placebo group. Also, 93% of women in the venlafaxine group chose to continue treatment after the completion of the study. [40].

Hormonal therapy (estrogen) has been the gold standard for women dealing with menopausal symptoms like hot flashes. However, hormonal therapy is not suited to every woman due to associated risks [32].

A study (double-blind randomized controlled trial) of 339 postmenopausal women for 8 weeks reported that venlafaxine (non-hormonal therapy) was just as effective as estrogen hormonal therapy in reducing hot flashes [41].

8) Effective Against Anxiety Disorders

Anxiety disorders are a group of mental health disorders characterized by excessive anxiety, worry, and fear. They are pervasive in nature with a lifetime prevalence of 25% in industrialized areas [42, 43].

Anxiety disorder is an umbrella term that primarily includes generalized anxiety disorder (GAD), social anxiety disorder (SAD), specific phobias, and panic disorder (PD) [44].

Venlafaxine is an approved treatment for all 3 of these conditions [45].

Helps Combat Generalized Anxiety Disorder

Venlafaxine was the first antidepressant drug to receive regulatory approval to treat generalized anxiety disorder, which is described as having constant excessive worry about everyday happenings for most than 6 months [46, 45].

In 2 short-term studies (both double-blind randomized controlled trials) of 8 weeks in 365 and 370 patients without major depression, venlafaxine significantly reduced anxiety and tension scores compared to placebo treatment. In most clinical trials, venlafaxine was a safe and effective treatment for generalized anxiety disorder [47, 48].

In 2 long-term studies (both double-blind randomized controlled trials) of 28 and 24 weeks in 251 and 541 patients with generalized anxiety disorder, venlafaxine treatment considerably improved anxiety symptoms compared to placebo, starting as early as the second week of treatment. This suggests that venlafaxine is a safe and well-tolerated long-term treatment for up to 6 months for generalized anxiety disorder [49, 50, 51].

Helps Combat Social Anxiety Disorder

Social anxiety, also known as social phobia, is when a person experiences feelings of anxiety and worry in everyday social situations and as a result, feels self-conscious.

Venlafaxine was more effective than placebo in reducing social anxiety symptoms (as measured by the Liebowitz Social Anxiety Scale) in 272 patients for 12 weeks (double-blind randomized controlled trial) [52].

Multiple studies (all studies were double-blind randomized controlled trials) have demonstrated the safety and effectiveness of venlafaxine as a treatment for social anxiety disorder, even as a long-term option [53, 54].

Two other clinical trials (double-blind randomized controlled trial) also compared paroxetine (antidepressant of the selective serotonin reuptake inhibitor class) and venlafaxine to placebo treatments in 389 and 413 patients with social anxiety disorder for 12 weeks. Venlafaxine was just as effective as paroxetine in decreasing anxiety symptoms and was superior to the placebo treatment [55, 56].

Helps Combat Panic Disorder

Panic disorder is a chronic and recurring disorder characterized by out-of-the-blue panic attacks which negatively impact an individual’s wellbeing.

In a study (double-blind randomized controlled trial), 653 patients suffering from panic disorder were given either venlafaxine at a low and high dose, paroxetine, or placebo treatment for 12 weeks. Venlafaxine at both doses reduced the frequency of full-symptom panic attacks compared to the placebo group when measured at the end of 12 weeks, highlighting that venlafaxine is an effective short-term treatment for panic disorders [57].

In another placebo-controlled study (double-blind randomized controlled trial) of 361 panic disorder patients, venlafaxine-treated patients were more responsive to medication and showed greater remission (no panic disorder symptoms) rates than placebo-treated patients at the end of the study. Venlafaxine treatment also improved anticipatory anxiety, fear, and avoidance symptoms [58, 59].

Venlafaxine was effective in preventing relapse in panic disorder patients after treatment [60].

9) Improves OCD Symptoms

Obsessive Compulsive Disorder (OCD) is a common mental health disorder where an individual has unwanted thoughts or ideas (obsessions) that compels them to carry out certain activities repeatedly (compulsions).

In 2 relatively small studies (a single-blind randomized controlled trial and a double-blind randomized controlled trial) of 73 and 150 OCD patients, the effectiveness of venlafaxine was tested against standard treatment options for OCD, clomipramine (tricyclic antidepressant), and paroxetine (antidepressant of the selective serotonin reuptake inhibitor class) respectively. Venlafaxine was as effective as clomipramine with fewer side effects. Venlafaxine and paroxetine had similar effects on improving symptoms of OCD after 12 weeks of treatment [61, 62].

However, larger clinical trials are needed to confirm the beneficial effects of taking venlafaxine as a treatment for OCD [63].

10) Improves PTSD Symptoms

Venlafaxine was more effective than placebo in a study (double-blind randomized controlled trial) of 329 post-traumatic stress disorder (PTSD) patients. Venlafaxine significantly reduced PTSD symptoms (as measured by the Clinician-Administered Posttraumatic Stress Disorder Scale score) after 24 weeks of treatment [64].

Another study (double-blind randomized controlled trial) in 538 PTSD patients reported that venlafaxine significantly improved symptoms of PTSD at the end of 12 weeks of treatment compared to the placebo-treated group [65].

11) Reduces Pain in Fibromyalgia

In a pilot study of 15 patients suffering from fibromyalgia, venlafaxine considerably decreased pain and disability associated with fibromyalgia after 12 weeks of treatment [66].

Relief from fibromyalgia-associated pain and improvement in disease symptoms is thought to be due to an increase in both serotonin and norepinephrine levels, and this is exactly what venlafaxine does.

More studies are required to further investigate the beneficial effects of venlafaxine in fibromyalgia.

12) May Reduce Inflammation

The effectiveness of venlafaxine as an anti-inflammatory agent has been explored in animal studies, especially considering the beneficial effects it has had on reducing neuropathic and fibromyalgia-associated pain.

In a rat model of inflammation (carrageenan-induced paw edema), venlafaxine had strong anti-inflammatory effects [67].

In a rat model of IBD, venlafaxine was given to normal and depressed rats. It reduced inflammatory injury caused by IBD in both normal and depressed rats, suggesting that venlafaxine may be useful for its anti-inflammatory effects [68].

13) May Improve Memory

Memory impairments are also observed in depressed patients and hence, it becomes useful to know the effect of antidepressants on memory.

In 74 bipolar disorder patients and 113 schizophrenia patients, increased blood levels of venlafaxine were significantly associated with better verbal memory (memory for words and language). However, these results need to be replicated using other patient samples. [69].

Venlafaxine was found to improve working memory (short-term or recent memory) and spatial memory (memory for recording objects in an individual’s environment) in rats, even after a single drug injection [70, 71, 72].

Side Effects of Venlafaxine & Precautions

Like most drugs, there are certain side effects observed in some patients taking venlafaxine. Some of these side effects may disappear with time as the body adjusts to the medication. Venlafaxine represents one of the drugs in the second generation of antidepressants that have fewer side effects than first-generation antidepressants. The common and rare side effects of venlafaxine are listed below [73, 74, 75].

Common Side Effects

  • Nausea
  • Headaches
  • Insomnia/experiencing trouble sleeping
  • Drowsiness
  • Sweating
  • Nervousness
  • Dry mouth
  • Dizziness
  • Constipation
  • Lack of energy
  • Blurred vision
  • Loss of appetite
  • Decreased sex drive
  • Erectile dysfunction
  • Impotence
  • Numbness/tingling

Rare Side Effects

  • Suicidal thoughts
  • Irritability
  • A feeling of uncontrollable euphoria/excessive excitement
  • High fever
  • Shortness of breath
  • Irregular heartbeat
  • Chest pains
  • Restlessness
  • Muscle pain/weakness
  • Increased blood pressure
  • Abnormal bleeding
  • Severe dizziness/feeling of passing out
  • Yellow eyes/skin
  • Menstrual changes like heavy bleeding/spotting/bleeding between periods
  • Difficult/painful urination
  • Seizures
  • Eye pain/changes in vision/swelling or redness in and around the eye

Withdrawal Symptoms

Withdrawal symptoms may appear in patients who intentionally or unintentionally discontinue venlafaxine therapy without medical consultation.

A study reported that withdrawal symptoms appeared in the 3 days after discontinuation of venlafaxine therapy in 7 out of 9 (78%) patients that took venlafaxine compared to 2 out of 9 (22%) patients that were on a placebo treatment. Hence, it is suggested to gradually taper off the dose of venlafaxine to minimize any risk of developing withdrawal symptoms [76].

Physical withdrawal symptoms of discontinuing venlafaxine therapy include [77, 78, 79, 80]:

  • Headaches
  • Nausea
  • Diarrhea
  • Sweating
  • Increased blood pressure
  • Vertigo
  • Irritable Mood
  • ‘Pins and needles’ sensation
  • Restlessness
  • Fatigue

Mental withdrawal symptoms of stopping venlafaxine therapy include [77, 78, 79, 80]:

  • Visual and auditory hallucinations
  • Bizarre dreams
  • Feelings of dissatisfaction and agitation
  • Delirium
  • Electric shock-like sensations/brain zaps
  • Worsening of depressive symptoms

Warnings and Cautions of Venlafaxine

1) Use Has a High Risk of Developing Withdrawal Symptoms

There is a high risk of experiencing adverse events or withdrawal symptoms after abruptly discontinuing venlafaxine therapy for as little as 12 hours.

Withdrawal symptoms may occur in patients who were taking either a low, moderate, or high dose of venlafaxine.

The accompanying dizziness, disorientation, and impaired coordination as part of the withdrawal symptoms can severely interfere with an individual’s ability to carry out everyday tasks such as driving a car [81].

2) Use Has a Risk of Causing Treatment-Emergent Mania

Venlafaxine is associated with a high risk of causing mania in short- and long-term treatment of bipolar disorder when used as an adjunct to standard mood stabilizers [82].

It is reported to have an increased risk of developing treatment-emergent mania compared to other antidepressants, such as bupropion and sertraline [83].

3) Use Is More Toxic in Overdose

Venlafaxine ranks higher in the fatal toxicity index (measured by deaths per million prescriptions) than other serotonin-norepinephrine reuptake inhibitors and is similar in toxicity to less toxic tricyclic antidepressants (first generation of antidepressants) [84].

Seizures occurred in 7/51 (14%) of patients who suffered a venlafaxine overdose of more than 900 mg. Venlafaxine was also more likely to cause toxicity in an overdose because of high levels of serotonin in the body [85].

4) Use May Increase Blood Pressure

A meta-analysis of 3,744 depressed patients reported that taking venlafaxine caused significant temporary and sustained increases in blood pressure in a dose-dependent manner [86].

In a study (double-blind randomized controlled trial) of 54 young healthy adults, venlafaxine treatment resulted in significantly increased blood pressure parameters, such as systolic blood pressure (SBP), resting and standing diastolic blood pressure (DBP), and heart rate, compared to pregabalin and placebo-treated adults [87].

Hence, blood pressure should be monitored in patients undergoing venlafaxine treatment.

5) Use Is Associated with Higher Suicide Risk

Venlafaxine use was consistently related to a higher risk of suicide in 219,088 patients compared with 3 other antidepressants of the selective serotonin reuptake inhibitor (SSRI) and tricyclic antidepressant class (citalopram, fluoxetine, and dothiepin) as part of a retrospective study [88].



People are who sensitive or allergic to venlafaxine, desvenlafaxine (another serotonin-norepinephrine reuptake inhibitor drug that is similar to venlafaxine), or any other excipients (substances that are present in the medication along with the drug) should refrain from using venlafaxine.

Concomitant Use with Monoamine Oxidase Inhibitors (MAOIs)

The concomitant use of venlafaxine with Monoamine Oxidase Inhibitors (MAOIs, used to treat neuropsychiatric disorders and neurodegenerative diseases) is contraindicated since both drugs result in elevated serotonin levels. This may lead to potentially toxic serotonin syndrome [89, 90].

It is not advisable to start any MAOI treatment 7 days after discontinuing venlafaxine treatment due to the increased risk of serotonin syndrome [90].

The effects of MAOIs in the brain may persist for a while after their discontinuation. Hence, venlafaxine medication is also contraindicated within 14 days of discontinuing treatment with MAOIs [91, 92].

Pregnancy and Breastfeeding

A clinical report describes a newborn developed temporary but severe heart complications and the suspected cause of the complication was the maternal use of venlafaxine during pregnancy [93].

On the other hand, multiple meta-analyses report that venlafaxine use in pregnancy is not associated with developing birth defects in newborns [94, 95, 96].

A large-scale study of the Nordic population, including 2.3 million living singletons, also reports of no association between venlafaxine use in pregnancy and developing heart-related birth defects [97].

Studies in rats and rabbits have not reported birth defects on a higher-than-recommended venlafaxine dosage. However, animal studies are not always predictive of human response and thus, venlafaxine should only be used during pregnancy if the potential benefits outweigh the potential risks.

Venlafaxine is found in breastmilk in small amounts, however, complications are rare. Caution is always good while taking any medication while breastfeeding and you should speak to your doctor about your options [98].

Drug Interactions

Venlafaxine and Drugs That Increase Serotonin

Since venlafaxine increases the levels of serotonin in the user’s body, the concurrent use of other drugs that boost serotonin levels results in overstimulation. Concomitant use of venlafaxine and drugs that increase serotonin in the body may lead to the development of serotonin syndrome [90].

The following drugs have been reported to interact with venlafaxine, resulting in serotonin syndrome:

  • Linezolid (an antibiotic that is also a monoamine oxidase inhibitor) [99, 100]
  • Lithium [101, 102, 103]
  • Mirtazapine [104, 105]
  • St John’s wort (herbal product) [106]
  • Tramadol [105]
  • Tranylcypromine [107, 108]
  • Trazodone [109]
  • Triptans (drugs used to treat migraine headaches) [110]

Venlafaxine and Drugs Interfering with Hemostasis

Serotonin that is released from platelets has an impact on the processes involved in hemostasis (stopping bleeding from damaged blood vessels). Venlafaxine use reduces the serotonin concentration inside platelets and hence, impairs the clustering of platelets [90, 111].

As a result, venlafaxine use in combination with non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin may increase the incidence of bleeding events, especially in the upper gut [112].

Venlafaxine treatment along with certain anticoagulant drugs (acenocoumarol and warfarin) also increases the risk of bleeding events [113, 114].

Dosages of Venlafaxine

All venlafaxine doses are administered orally, in a single dose with food in the morning or evening. The recommended dosages for which venlafaxine is approved by the Food and Drug Administration (FDA) are described below:

Major Depression and Generalized Anxiety Disorder

Most patients begin with a venlafaxine dose of 75 mg/day (recommended dosage), which is administered as a single dose.

Some patients start at 37.5 mg/day of venlafaxine until the patient’s body adjusts to the medication, and then the dosage is increased to the recommended 75 mg/day.

However, patients that are not experiencing benefits from the recommended venlafaxine dose may be prescribed a higher dose of 225 mg/day, which is the maximum dose.

Social Anxiety Disorder

The recommended venlafaxine dosage is 75 mg/day administered as a single dose. There is no evidence that a higher venlafaxine dose results in any additional benefits.

Panic Disorder

Panic disorder patients start off on a recommended venlafaxine dosage of 37.5 mg/day for a week before increasing the dosage, 75 mg in each instance at intervals of a minimum of 7 days, to a maximum venlafaxine dosage of 225 mg/day.

Genetics Related to Venlafaxine


The CYP2D6 gene codes for a liver enzyme that is primarily responsible for breaking down venlafaxine into a compound called O-desmethylvenlafaxine (ODV). This compound is equally as potent and is also marketed as a drug called desvenlafaxine [115, 116].

Individuals can be poor metabolizers (2 inactive copies of the CYP2D6 gene), meaning that they have a decreased capacity to break down venlafaxine. In contrast, individuals can be ultrarapid metabolizers (more than 2 copies of functional CYP2D6 variants), meaning that they have an increased capacity to break down venlafaxine [117].

Since both compounds have similar potency, being either a poor or an ultrarapid metabolizer doesn’t have a great impact on the effectiveness of the drug. However, poor metabolizers may experience more side effects [118].


The CYP2C19 gene codes for a liver enzyme that is involved in the breakdown of venlafaxine to O-desmethylvenlafaxine (ODV) [116].

CYP2C19 also converts venlafaxine to another minor by-product called N-desmethylvenlafaxine (NDV) [119].

People can be poor or ultrarapid metabolizers based on the genetic composition of CYP2C19. Genetic variability amongst individuals can impact the total concentrations of venlafaxine and ODV in a user’s body and hence, should be factored in when deciding venlafaxine dosage [120, 121].


The ABCB1 gene encodes a transporter protein (P-gp) in the blood-brain barrier, which is responsible for the transport of various compounds, including drugs and hormones, to and from the brain. This transporter protein pumps out venlafaxine from the brain and hence, controls venlafaxine levels inside the brain.

Genetic variations in the ABCB1 gene could influence the levels of venlafaxine available inside the brain as well as the clinical response in patients. An important variant of the ABCB1 gene is rs2032583, which consists of the C and T variants. A study found that people with at least one C variant (either CC or CT variant) were 7.72 times more likely to show full resolution of depressive symptoms after 4 weeks of venlafaxine treatment compared to people who are carriers of the TT variants [122].


The SLC6A2 gene encodes the norepinephrine transporter, which is responsible for the reuptake of norepinephrine in the brain and is the target where venlafaxine acts to increase norepinephrine levels.

A study of 243 Chinese patients diagnosed with major depression found that variants in the SLC6A2 gene (rs28386840, rs1532701, rs40434, rs13333066, rs187714) were associated with increased likelihood of achieving full resolution of depressive symptoms after 8 weeks of venlafaxine treatment [123].

However, other studies report a lack of association between genetic variations in the SLC6A2 gene and the response to venlafaxine [124, 124].


The SLC6A4 gene encodes the serotonin transporter that controls serotonin levels in the brain and is the primary target for venlafaxine to bring about its effect.

In 56 major depression and bipolar disorder patients suffering from depressive episodes, a variant in the SLC6A4 gene (rs25531) was associated with poor treatment response to venlafaxine after 4 weeks [124].

Another study reported that the same variant could be predictive of the patient response to venlafaxine therapy [125].

Natural Options

A number of plant-derived compounds have antidepressant effects. However, few of these natural alternatives work in the same way as venlafaxine.

In the following list, we identify natural antidepressants that can block the reuptake of both serotonin and norepinephrine, just like venlafaxine.

Check out this post for a complete list of natural ways to improve depression

Remember: You should always consult your doctor before changing or stopping your medications.

It’s also important to let your doctor know of all the supplements you are currently taking to avoid any potential interactions.

1) St John’s Wort

St John’s wort (Hypericum perforatum) is a medicinal plant that has been used since the Middle Ages. Today, it is mostly known for its antidepressant effects [126].

St John’s wort works in multiple ways. It blocks the reuptake of serotonin, norepinephrine, dopamine, and GABA. MAO inhibition also contributes to its anti-depressant effects [127, 128].

Multiple comprehensive reviews have examined the role of St John’s wort in depression. A large majority of studies seem to agree: St John’s wort is just as effective for depression as many commonly prescribed antidepressants. It also causes far fewer side effects [129, 130].

There are a couple of caveats, however.

St John’s wort only works for mild-to-moderate depression. It’s unclear if it can help with severe depression or suicide risk [129, 130].

There are also many serious drug and food interactions with St John’s wort. You should consult your doctor before using it to avoid any issues [131].

2) Resveratrol

Resveratrol is a plant compound found in many foods, such as red wine, berries, and peanuts [132].

It’s associated with a variety of health benefits, including antioxidant, anti-inflammatory, and anti-cancer effects [132].

Animal studies suggest that resveratrol can inhibit the reuptake of serotonin and norepinephrine, much like venlafaxine. It may also block the enzyme MAO, which is how some older antidepressants work [133, 134].

Resveratrol reduces symptoms of depression, anxiety, and PTSD, according to a number of animal studies [135, 136, 137, 138].

However, the health benefits in humans are not as clear.

A recent analysis was performed on 4 clinical trials totaling 225 people. They found that resveratrol does not affect depression, anxiety, or anger. There was one benefit – resveratrol significantly reduces fatigue [139].

3) Saffron

From the flower of the Crocus sativus plant comes the spice saffron. Commonly used as a seasoning and coloring agent, saffron may have several health benefits as well [140].

Saffron is just as effective as some commonly prescribed medications for the treatment of mild-to-moderate depression. This is according to a recent review of 11 clinical trials [141].

A different review of 12 studies found that saffron improves depression, premenstrual symptoms, sexual dysfunction, and excessive snacking behaviors [142].

Other studies suggest that saffron may also help with anxiety, mood, and postpartum depression [143, 144, 145, 146].

Saffron’s antidepressant effects likely stem from norepinephrine and serotonin reuptake inhibition, similar to venlafaxine [147].

Partner Resources

If you’re interested in natural and more targeted ways of improving your mood, we at SelfHacked recommend checking out this mood wellness report. It gives genetic-based diet, lifestyle and supplement tips that can help improve your mood. The recommendations are personalized based on your genes.

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About the Author

Mathew Eng, PharmD


Mathew received his PharmD from the University of Hawaii and an undergraduate degree in Biology from the University of Washington.

Mathew is a licensed pharmacist with clinical experience in oncology, infectious disease, and diabetes management. He has a passion for personalized patient care and believes that education is essential to living a healthy life. His goal is to motivate individuals to find ways to manage their chronic conditions.

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