Tianeptine Side Effects: Risk of Liver-Injury and Addiction

Tianeptine side effects are considered mild and tolerable in comparison to many other antidepressants. The incidence of very serious tianeptine side effects like liver injury and addiction are rare.

For example, the rate of tianeptine abuse is 0.1% – 0.3% among patients prescribed tianeptine in France. In comparison, the CDC estimates that there are over 5 million prescription painkiller users in the United States, accounting for 1.6% of the entire US population.

An advantage of tianeptine’s side effect profile is that tianeptine is not sedating, does not induce anticholinergic effects (e.g., dry mouth), and lacks cardiovascular side effects like hypertension [^1].

One double-blind, placebo controlled trial of tianeptine in healthy volunteers reported that tianeptine did not produce orthostatic hypotension (a potentially dangerous drop in blood pressure on standing), increase heart rate, cause ECG changes, alter cardiac conduction time, or impair cardiac output.

Tianeptine is a prescription drug in Europe approved for the treatment of major depressive disorder.  Due to its unregulated status, tianeptine is marketed and sold as a nutraceutical or nootropic drug to individuals without a prescription in the United States.

Antidepressant vs Tianeptine Side Effects

Antidepressant side effects are frequently cited as a common reason for lack of patient compliance. Most patients who discontinue antidepressant therapy do so because of side effect intolerance. Hence, identifying antidepressants with a more favorable side effect burden is an important step in optimizing the treatment of depression.

In general, the side effect burden of antidepressants is ranked as follows:

Monoamine oxidase inhibitors > tricyclics > SNRIs > SSRIs

where monoamine oxidase inhibitors (MAOIs) have the most budensome side effects. To some extent, side effect tolerability is a question of individual preference. Some patients may not mind observing a tyramine restricted diet, which is necessary to safely take MAOIs, but be unwilling to tolerate the sexual side effects of SSRIs.

Despite its classification as a tricyclic, tianeptine’s side effect profile is markedly unlike other tricyclic antidepressants (TCA) [^2].

Other TCAs are strongly anticholinergic (resulting in dry mouth, constipation and mild memory impairment). They’re also proconvulsant – they tend to decrease the seizure threshold – as well as sedating, appetite-stimulating, and can cause orthostatic hypotension. Orthostatic hypotension is a potentially dangerous drop in blood pressure that occurs on standing.

Tianeptine lacks the typical side effects of TCAs

Despite tianeptine’s structural similarity to other antidepressants, tianeptine’s distinct mechanism of action partially explains tianeptine’s less severe side effects. The antidepressant effect of TCAs has been attributed to increased serotonin and norepinephrine caused by decreasing the re-uptake (removal) of these neurotransmitters, as well as acetylcholine receptor blockade.

However, Tianeptine’s mechanism of action has remained more elusive. An emerging view is that Tianeptine “works” by activating mu-opioid receptors, modulating glutamate, and reversing stress induced synaptic remodeling.

Unlike other tricyclics which can induce seizures even at therapeutic doses, Tianeptine has been deemed safe to use in patients with epilepsy. [^20]

Coaxil (Tianeptine) Package Insert

According to the package insert, Tianeptine is associated with the following adverse effects:

Extrasystole, trembling, tightness of the throat, vomiting, myalgia, precordialgia, nightmares, respiratory, headaches, dizziness, upsets, flatulence, faintness, discomfort, abdominal pain, lumbago, insomnia, asthenia, nausea, dryness of the mouth, anorexia, tachycardia, gastralgia, and drowsiness.

Common Tianeptine Side Effects


Headache (up to 18%) Common (>1% frequency)
Dizziness (up to 10%) Common (>1% frequency)
Insomnia/nightmares (up to 20%) Common (>1% frequency)
Drowsiness (up to 10%) Common (>1% frequency)
Dry mouth (up to 20%) Common (>1% frequency)
Constipation (up to 15%) Common (>1% frequency)
Nausea Common (>1% frequency)
Abdominal pain Common (>1% frequency)
Weight gain (~3%) Common (>1% frequency)
Agitation Common (>1% frequency)
Anxiety/irritability Common (>1% frequency)
Bitter taste Uncommon (0.1-1% frequency)
 Flatulence Uncommon (0.1-1% frequency)
 Gastralgia Uncommon (0.1-1% frequency)
 Blurred vision Uncommon (0.1-1% frequency)
 Muscle aches Uncommon (0.1-1% frequency)
 Premature ventricular contractions Uncommon (0.1-1% frequency)
 Micturition disturbances Uncommon (0.1-1% frequency)
 Palpitations Uncommon (0.1-1% frequency)
 Orthostatic hypotension Uncommon (0.1-1% frequency)
 Hot flushes Uncommon (0.1-1% frequency)
Tremor Uncommon (0.1-1% frequency)
 Hepatitis Rare (
Hypomania Rare (
Euphoria Rare (
 ECG changes Rare (
 Pruritus/allergic-type skin reactions Rare (
 Protracted muscle aches Rare (
General fatigue Rare (

Tianeptine and Hepatotoxicity (Liver Injury)

Perlemuter’s review of antidepressant-induced liver injury[ref]Voican CS, Corruble E, Naveau S, Perlemuter G. Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry. 2014;171(4):404-15.[/ref] reported that tianeptine, along with iproniazid, nefazodone, phenelzine, imipramine, amitriptyline, duloxetine, bupropion, trazodone, and agomelatine, were associated with a higher risk of liver injury. These drugs (including tianeptine) had a higher hepatotoxic potential in comparison to SSRIs.

Hepatotoxicity (liver failure) is in usually unpredictable and idiosyncratic. Interestingly, it is unrelated to drug dosage.

It usually takes about several days to 6 months after initiating antidepressant therapy for hepatitis to manifest. Antidepressant-induced liver injury, when it involves fulminant liver failure, is life-threatening.

Tianeptine-induced hepatoxicity is rare. Moreover, Perlemuter’s review has been criticized for being limited by publication bias (physicians tend to publish more severe case reports) and failing to account for the prescribing frequency of various antidepressants.

Tianeptine Abuse and Dependence

From 1989 to 2004, 141 cases of tianeptine abuse were reported in France. This corresponds with an incidence of about 0.1-0.3%. In 2007, tianeptine’s manufacturer Servier modified the drug insert due to problems with tianeptine abuse. Tianeptine is restricted in Singapore because of its abuse potential, while France began treating tianeptine as a controlled substance-requiring a secure prescription form like prescription narcotics.

Tianeptine Is a Direct Mu-Opioid Agonist

The abuse potential of tianeptine is almost certainly related to its activation of mu-opioid receptors in the brain. Tianeptine dependence and withdrawal mimics the withdrawal symptoms associated with conventional painkillers, albeit to a lesser degree.

In 2014, Sames D et. al. of Columbia University[^18] used a radioligand binding assay to characterize tianeptine’s receptor binding affinities. They reported that tianeptine is an efficacious mu-opioid receptor agonist (Ki = 383 +/- 183nM), also affecting delta-opioid receptors to a lesser extent . Tianeptine was inactive at kappa-opioid receptors.

If you’re interested in the pharmacology of tianeptine, Sames’ paper, published in Nature, is an excellent read.

The authors suggest that tianeptine’s anxiolytic and antidepressant effects may be attributed to tianeptine’s opioid binding. Other opioids have been noted to elicit antidepressant effects, and have controversially been used off-label for treatment-resistant depression.

“Doctor shopping” refers to the patient behavior of simultaneously consulting many physicians in a short time span, which is linked to substance abuse. One study reported that tianeptine had a high “doctor shopping indicator” compared to other antidepressants, suggestive of an above-average abuse potential.[^19]

One paper, sensationalistically entitled “Addictive potential of Tianeptine – the threatening reality” (19801742) described 24 male patients who abused tianeptine. The average daily dose was 40 tablets (500 mg) administered intravenously. The authors linked the abuse potential with tianeptine’s opioid activity and dopamine release in the nucleus accumbens. Another study[^21] found that a single high dose of tianpetine does not induce a psychostimulant effect in healthy volunteers compared to methylphenidate (Ritalin). This result suggests the abuse potential of tianeptine is unlikely to be dopamine-related.

A single administration of a supratherapeutic dose of tianeptine does not induce psychostimulant effect in young healthy volunteers in contrast to methylphenidate at a therapeutic dose. These findings suggest an absence of psychostimulant liability of tianeptine in a therapeutic situation.[^21]

[^1]: Delalleau B, Dulcire C, Le moine P, Kamoun A. Analysis of the side effects of tianeptine. Clin Neuropharmacol. 1988;11 Suppl 2:S83-9.

[^2]: Delalleau B, Dulcire C, Le moine P, Kamoun A. Analysis of the side effects of tianeptine. Clin Neuropharmacol. 1988;11 Suppl 2:S83-9.

[^18]: Gassaway MM, Rives ML, Kruegel AC, Javitch JA, Sames D. The atypical antidepressant and neurorestorative agent tianeptine is a μ-opioid receptor agonist. Transl Psychiatry. 2014;4:e411.

[^20]: Moon J, Jung KH, Shin JW, et al. Safety of tianeptine use in patients with epilepsy. Epilepsy Behav. 2014;34:116-9.

[^21]: Bernard K, Penelaud PF, Mocaër E, Donazzolo Y. Absence of psychostimulant effects of a supratherapeutic dose of tianeptine: a placebo-controlled study versus methylphenidate in young healthy volunteers. J Clin Psychopharmacol. 2011;31(4):441-8.

[^19]: Rouby F, Pradel V, Frauger E, et al. Assessment of abuse of tianeptine from a reimbursement database using ‘doctor-shopping’ as an indicator. Fundam Clin Pharmacol. 2012;26(2):286-94.

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