Tianeptine, sold under the brand names Stablon, Tatinol, and Coaxil among others, is an

atypical ''Atypical'' is an American comedy-drama television series created by Robia Rashid for Netflix. The series takes place in Connecticut, and focuses on the life of 18-year-old Samuel "Sam" Gardner ( Keir Gilchrist), who is autistic. The first sea ...

tricyclic antidepressant Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains ...

which is used mainly in the treatment of

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...

, although it may also be used to treat

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

asthma Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...

, and

irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by a group of symptoms that commonly include abdominal pain, abdominal bloating, and changes in the consistency of bowel movements. These symptoms may ...

. Tianeptine has antidepressant and

anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...

effects with a relative lack of

sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...

anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central nervous system, central and peripheral nervous system. These agents inhibit the parasympatheti ...

, and

cardiovascular In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s. It has been found to act as an atypical

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the

μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical ...

with clinically negligible effects on the δ- and

κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP for its ligand ketazocine, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four re ...

s. This may explain part of its antidepressant and anxiolytic effects; however, it is thought that tianeptine also modulates

glutamate receptor Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate (the conjugate base of glutamic acid) is abundant in the human body, but particularly in the nervous system ...

s, and this may also explain tianeptine's antidepressant/anxiolytic effects. Tianeptine was discovered and patented by the French Society of Medical Research in the 1960s. It was introduced for medical use in

France France, officially the French Republic, is a country located primarily in Western Europe. Overseas France, Its overseas regions and territories include French Guiana in South America, Saint Pierre and Miquelon in the Atlantic Ocean#North Atlan ...

in 1983. Currently, tianeptine is approved in France and manufactured and marketed by Laboratories

Servier Servier Laboratories (French: Laboratoires Servier, often abbreviated to Servier) is an international Pharmaceutical industry, pharmaceutical company governed by a non-profit foundation, with its headquarters in France (Suresnes). The consolida ...

SA; it is also marketed in a number of other European countries under the trade name Coaxil as well as in Asia (including

Singapore Singapore, officially the Republic of Singapore, is an island country and city-state in Southeast Asia. The country's territory comprises one main island, 63 satellite islands and islets, and one outlying islet. It is about one degree ...

) and Latin America as Stablon and Tatinol but it is not available in

Australia Australia, officially the Commonwealth of Australia, is a country comprising mainland Australia, the mainland of the Australia (continent), Australian continent, the island of Tasmania and list of islands of Australia, numerous smaller isl ...

Canada Canada is a country in North America. Its Provinces and territories of Canada, ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, making it the world's List of coun ...

New Zealand New Zealand () is an island country in the southwestern Pacific Ocean. It consists of two main landmasses—the North Island () and the South Island ()—and List of islands of New Zealand, over 600 smaller islands. It is the List of isla ...

Italy Italy, officially the Italian Republic, is a country in Southern Europe, Southern and Western Europe, Western Europe. It consists of Italian Peninsula, a peninsula that extends into the Mediterranean Sea, with the Alps on its northern land b ...

or the

United Kingdom The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Northwestern Europe, off the coast of European mainland, the continental mainland. It comprises England, Scotlan ...

. In the US, it is an unregulated drug sold under several names and some of these products have been found to be adulterated with other

recreational drugs Recreation is an activity of leisure, leisure being discretionary time. The "need to do something for recreation" is an essential element of human biology and psychology. Recreational activities are often done for enjoyment, amusement, or plea ...

. It is commonly known by the nickname "gas station heroin".

Medical uses

Depression and anxiety

Tianeptine shows efficacy against serious depressive episodes (

major depression Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...

), comparable to

amitriptyline Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat major depressive disorder, and a variety of pain syndromes such as neuropathic pain, fibromyalgia, migraine and tension headac ...

imipramine Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression. It is also effective in treating anxiety and panic disorder. Imipramine is taken by mouth. Common s ...

and

fluoxetine Fluoxetine, sold under the brand name Prozac, among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used for the treatment of major depressive disorder, Anxiety disorder, anx ...

, but with significantly fewer side effects. It was shown to be more effective than maprotiline in a group of people with co-existing depression and anxiety. Tianeptine also displays significant

properties and is useful in treating a spectrum of anxiety disorders including

panic disorder Panic disorder is a mental disorder, specifically an anxiety disorder, characterized by reoccurring unexpected panic attacks. Panic attacks are sudden periods of intense fear that may include palpitations, sweating, shaking, shortness of breath ...

, as evidenced by a study in which those administered 35% CO₂ gas ( carbogen) on

paroxetine Paroxetine ( ), sold under the brand name Paxil among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used to treat major depressive disorder, obsessive-compulsive disorder, o ...

or tianeptine therapy showed equivalent panic-blocking effects. Like many antidepressants (including

bupropion Bupropion, formerly called amfebutamone, and sold under the brand name Wellbutrin among others, is an atypical antidepressant that is indicated in the treatment of major depressive disorder, seasonal affective disorder, and to support smo ...

, the

selective serotonin reuptake inhibitors Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by blo ...

, the serotonin-norepinephrine reuptake inhibitors,

moclobemide Moclobemide, sold under the brand names Amira, Aurorix, Clobemix, Depnil and Manerix among others, is a reversible inhibitor of monoamine oxidase A (RIMA) drug primarily used to treat Clinical depression, depression and social anxiety. It is not ...

and numerous others) it may also have a beneficial effect on cognition in people with depression-induced cognitive dysfunction. A 2005 study in Egypt showed tianeptine to be effective in men with depression and

erectile dysfunction Erectile dysfunction (ED), also referred to as impotence, is a form of sexual dysfunction in males characterized by the persistent or recurring inability to achieve or maintain a Human penis, penile erection with sufficient rigidity and durat ...

. Tianeptine has been found to be effective in depression, in people with

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

, and with

post-traumatic stress disorder Post-traumatic stress disorder (PTSD) is a mental disorder that develops from experiencing a Psychological trauma, traumatic event, such as sexual assault, domestic violence, child abuse, warfare and its associated traumas, natural disaster ...

for which it was as safe and effective as fluoxetine and moclobemide.

Other uses

A clinical trial comparing its efficacy and tolerability with amitriptyline in the treatment of

showed that tianeptine was at least as effective as amitriptyline and produced fewer prominent adverse effects, such as dry mouth and constipation. Tianeptine has been reported to be very effective for

. In August 1998, Dr. Fuad Lechin and colleagues at the

Central University of Venezuela Central is an adjective usually referring to being in the center of some place or (mathematical) object. Central may also refer to: Directions and generalised locations * Central Africa, a region in the centre of Africa continent, also known as ...

Institute of Experimental Medicine in

Caracas Caracas ( , ), officially Santiago de León de Caracas (CCS), is the capital and largest city of Venezuela, and the center of the Metropolitan Region of Caracas (or Greater Caracas). Caracas is located along the Guaire River in the northern p ...

published the results of a 52-week

randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical ...

of asthmatic children; the children in the groups who received tianeptine had a sharp decrease in clinical rating and increased lung function. Two years earlier, they had found a close, positive association between free serotonin in plasma and severity of asthma in symptomatic persons. As tianeptine was the only agent known to both reduce free serotonin in plasma and enhance uptake in platelets, they decided to use it to see if reducing free serotonin levels in plasma would help. By November 2004, there had been two double-blind placebo-controlled crossover trials and an under-25,000 person open-label study lasting over seven years, both showing effectiveness. Tianeptine also has

anticonvulsant Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...

and

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

effects, and a clinical trial in Spain that ended in January 2007 has shown that tianeptine is effective in treating pain due to

fibromyalgia Fibromyalgia (FM) is a functional somatic syndrome with symptoms of widespread chronic pain, accompanied by fatigue, sleep disturbance including awakening unrefreshed, and Cognitive deficit, cognitive symptoms. Other symptoms can include he ...

. Tianeptine has been shown to have efficacy with minimal side effects in the treatment of

attention-deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...

Contraindications

Known contraindications include the following: * Hypersensitivity to tianeptine or any of the tablet's

excipients An excipient is a substance formulated alongside the active ingredient of a medication. They may be used to enhance the active ingredient’s therapeutic properties; to facilitate drug absorption; to reduce viscosity; to enhance solubility; to i ...

Side effects

Compared to other

s, it produces significantly fewer cardiovascular,

(like dry mouth or constipation),

and appetite-stimulating effects. Unlike other tricyclic antidepressants, tianeptine does not affect heart function. μ-Opioid receptor agonists can sometimes induce

euphoria Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and da ...

, as does tianeptine, occasionally, at high doses, well above the normal therapeutic range (see below). Tianeptine can also cause severe withdrawal symptoms after prolonged use at high doses which should prompt extreme caution.

By frequency

''Sources:'' ;Common (>1% frequency) * Headache (up to 18%) * Dizziness (up to 10%) * Insomnia/nightmares (up to 20%) * Drowsiness (up to 10%) * Dry mouth (up to 20%) * Constipation (up to 15%) * Nausea * Abdominal pain * Weight gain (~3%) * Agitation * Anxiety/irritability ;Uncommon (0.1–1% frequency) *

Bitter taste The gustatory system or sense of taste is the sensory system that is partially responsible for the perception of taste. Taste is the perception stimulated when a substance in the mouth reacts chemically with taste receptor cells located on tas ...

* Flatulence * Gastralgia * Blurred vision * Muscle aches * Premature ventricular contractions *

Micturition Urination is the release of urine from the bladder through the urethra in placental mammals, or through the cloaca in other vertebrates. It is the urinary system's form of excretion. It is also known medically as micturition, voiding, ures ...

disturbances *

Palpitations Palpitations occur when a person becomes aware of their heartbeat. The heartbeat may feel hard, fast, or uneven in their chest. Symptoms include a very fast or irregular heartbeat. Palpitations are a sensory symptom. They are often described as ...

Orthostatic hypotension Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when they are standing up ( orthostasis) or sitting down. Primary orthostatic hypotension is also often referred to as ne ...

* Hot flushes *

Tremor A tremor is an involuntary, somewhat rhythmic muscle contraction and relaxation involving neural oscillations, oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the h ...

;Rare (<0.1% frequency) *

Hepatitis Hepatitis is inflammation of the liver parenchyma, liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), Anorexia (symptom), poor appetite ...

Hypomania Hypomania (literally "under mania" or "less than mania") is a Psychiatry, psychiatric Abnormality (behavior), behavioral syndrome characterized essentially by an apparently non-contextual elevation of Mood (psychology), mood (i.e., euphoria) th ...

Euphoria Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and da ...

* ECG changes * Pruritus/allergic-type skin reactions * Protracted muscle aches * General fatigue

Pharmacology

Pharmacodynamics

Atypical μ-opioid receptor agonist

In 2014, tianeptine was found to be a

(MOR)

full agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agoni ...

using human proteins. It was also found to act as a full agonist of the

δ-opioid receptor The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi alpha subunit, Gi/G0 and has enkephalins as it ...

(DOR), although with approximately 200-fold lower potency. The same researchers subsequently found that the MOR is required for the acute and chronic antidepressant-like behavioral effects of tianeptine in mice and that its primary

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

had similar activity as a MOR agonist but with a much longer

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

. Moreover, in mice, although tianeptine produced other

opioid Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...

-like behavioral effects such as

analgesia Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professionals ...

and reward, it did not result in tolerance or withdrawal. The authors suggested that tianeptine may be acting as a

biased agonist Functional selectivity (or agonist trafficking, biased agonism, biased signaling, ligand bias, and differential engagement) is the ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand (often the end ...

of the MOR and that this may be responsible for its atypical profile as a MOR agonist. However, there are reports that suggest that withdrawal effects resembling those of other typical opioid drugs (including but not limited to depression, insomnia, and cold/flu-like symptoms) do manifest following prolonged use at dosages far beyond the medical range. In addition to its therapeutic effects, activation of the MOR is likely to also be responsible for the

abuse potential Substance misuse, also known as drug misuse or, in older vernacular, substance abuse, is the use of a drug in amounts or by methods that are harmful to the individual or others. It is a form of substance-related disorder, differing definitions ...

of tianeptine at high doses that are well above the normal therapeutic range and efficacy threshold. In rats, when co-administered with morphine, tianeptine prevents morphine-induced

respiratory depression Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide (hypercapni ...

without impairing analgesia. In humans, however, tianeptine was found to increase respiratory depression when administered in conjunction with the potent opioid

remifentanil Remifentanil, marketed under the brand name Ultiva is a potent, short-acting synthetic opioid analgesic drug. It is given to patients during surgery to relieve pain and as an adjunct to an anesthetic. Remifentanil is used for sedation as well a ...

Glutamatergic, neurotrophic, and neuroplastic modulation

Research suggests that tianeptine produces its antidepressant effects through indirect alteration and inhibition of

glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...

receptor activity (i.e.,

AMPA receptor The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic receptor, ionotropic glutamate receptor (iGluR) and predominantly sodium ion channel that mediates fast excitator ...

s and

NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...

s) and release of , in turn affecting

neural plasticity Neuroplasticity, also known as neural plasticity or just plasticity, is the ability of neural networks in the brain to change through growth and reorganization. Neuroplasticity refers to the brain's ability to reorganize and rewire its neural ...

. Some researchers hypothesize that tianeptine has a protective effect against stress induced neuronal remodeling. There is also action on the

NMDA ''N''-methyl--aspartic acid, or ''N''-methyl--aspartate (NMDA), is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unl ...

and

s. In animal models, tianeptine inhibits the pathological stress-induced changes in glutamatergic neurotransmission in the amygdala and hippocampus. It may also facilitate signal transduction at the CA3 commissural associational synapse by altering the phosphorylation state of glutamate receptors. With the discovery of the rapid and novel antidepressant effects of drugs such as

ketamine Ketamine is a cyclohexanone-derived general anesthetic and NMDA receptor antagonist with analgesic and hallucinogenic properties, used medically for anesthesia, depression, and pain management. Ketamine exists as its S- (esketamine) a ...

, many believe the efficacy of antidepressants is related to promotion of

synaptic plasticity In neuroscience, synaptic plasticity is the ability of synapses to Chemical synapse#Synaptic strength, strengthen or weaken over time, in response to increases or decreases in their activity. Since memory, memories are postulated to be represent ...

. This may be achieved by regulating the excitatory amino acid systems that are responsible for changes in the strength of synaptic connections as well as enhancing

BDNF Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the cano ...

expression, although these findings are based largely on

preclinical In drug development, preclinical development (also termed preclinical studies or nonclinical studies) is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and dr ...

studies.

Serotonin reuptake enhancer

Tianeptine is no longer labelled a selective serotonin reuptake enhancer (SSRE) antidepressant. Tianeptine had been found to bind to the same

allosteric site In the fields of biochemistry and pharmacology an allosteric regulator (or allosteric modulator) is a substance that binds to a site on an enzyme or receptor distinct from the active site, resulting in a conformational change that alters the p ...

on the

serotonin transporter The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein t ...

(SERT) as conventional TCAs. However, whereas conventional TCAs inhibit

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

reuptake Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal (i.e., the pre-synaptic neuron at a synapse) or glial cell after it has performed its function of transmi ...

by the SERT, tianeptine appeared to enhance it. This seems to be because of the unique C3

amino In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...

heptanoic acid

side chain In organic chemistry and biochemistry, a side chain is a substituent, chemical group that is attached to a core part of the molecule called the "main chain" or backbone chain, backbone. The side chain is a hydrocarbon branching element of a mo ...

of tianeptine, which, in contrast to other TCAs, is thought to lock the SERT in a conformation that increases

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for and reuptake ( V_max) of serotonin. As such, tianeptine was thought to act a

positive allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that ...

of the SERT, or as a " serotonin reuptake enhancer". Although tianeptine was originally found to have no effect ''in vitro'' on monoamine reuptake, release, or receptor binding, upon acute and repeated administration, tianeptine decreased the extracellular levels of serotonin in rat brain without a decrease in serotonin release, leading to a theory of tianeptine enhancing serotonin reuptake. The (−)-

enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

is more active in this sense than the (+)-enantiomer. However, more recent studies found that long-term administration of tianeptine does not elicit any marked alterations (neither increases nor decreases) in extracellular levels of serotonin in rats. However, coadministration of tianeptine and the

selective serotonin reuptake inhibitor Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by blo ...

inhibited the effect of tianeptine on

long-term potentiation In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neuron ...

in hippocampal CA1 area. This is considered an argument for the opposite effects of tianeptine and fluoxetine on serotonin uptake, although it has been shown that fluoxetine can be partially substituted for tianeptine in animal studies. In any case, the collective research suggests that direct modulation of the serotonin system is unlikely to be the

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...

underlying the antidepressant effects of tianeptine.

Other actions

Tianeptine modestly enhances the mesolimbic release of

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

and potentiates CNS D₂ and D₃ receptors. Tianeptine has no affinity for the

dopamine transporter The dopamine transporter (DAT, also sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in humans by the ''SLC6A3'' gene (also known as ''DAT1''), that pumps the neurotransmitter dopamine out of the synaptic cleft ba ...

or the

dopamine receptor Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through diff ...

CREB CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first des ...

-TF (CREB, cAMP response element-binding protein) is a cellular

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...

. It binds to certain

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

s. CREB has a well-documented role in neuronal plasticity and

long-term memory Long-term memory (LTM) is the stage of the Atkinson–Shiffrin memory model in which informative knowledge is held indefinitely. It is defined in contrast to sensory memory, the initial stage, and short-term or working memory, the second stage ...

formation in the brain. Cocaine- and amphetamine-regulated transcript, also known as

CART A cart or dray (Australia and New Zealand) is a vehicle designed for transport, using two wheels and normally pulled by draught animals such as horses, donkeys, mules and oxen, or even smaller animals such as goats or large dogs. A handcart ...

, is a

neuropeptide Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''CARTPT''

. CART appears to have roles in reward, feeding, stress, and it has the functional properties of an endogenous

psychostimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition ...

. Taking into account that CART production is upregulated by CREB, it could be hypothesized that due to tianeptine's central role in BDNF and neuronal plasticity, this CREB may be the transcription cascade through which this drug enhances mesolimbic release of dopamine. Research indicates possible

(anti-seizure) and

(painkilling) activity of tianeptine via downstream modulation of

adenosine Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9- glycosidic bond. Adenosine is one of the four nucleoside build ...

A₁ receptors (as the effects could be experimentally blocked by

antagonists An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. Tianpetine is also weak

histone deacetylase Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on both histone and non-histone proteins. HDACs allow histones to wrap the DNA more tightly. This is important becaus ...

inhibitor and analogs with increased potency and selectivity are developed. Tianeptine has been shown to be a high-efficacy agonist of PPAR-delta, a nuclear receptor, possibly carcinogenic.

Pharmacokinetics

The

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

of tianeptine is approximately 99%. Its

plasma protein binding Plasma protein binding refers to the degree to which medications attach to blood proteins within the blood plasma. A drug's efficacy may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse o ...

is about 95%. The

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

of tianeptine is

hepatic The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

, via

β-oxidation In biochemistry and metabolism, beta oxidation (also β-oxidation) is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA. Acetyl-CoA enters ...

. CYP enzymes are not involved, which limits the potential for drug-drug interactions. Maximal concentration is reached in about an hour and the

is 2.5 to 3 hours. The elimination half-life has been found to be increased to 4 to 9 hours in the

elderly Old age is the range of ages for people nearing and surpassing life expectancy. People who are of old age are also referred to as: old people, elderly, elders, senior citizens, seniors or older adults. Old age is not a definite biological sta ...

. Tianeptine is usually packaged as a sodium salt but can also be found as tianeptine sulfate, a slower-releasing formulation patented by Janssen in 2012. In 2022 Tonix Pharmaceuticals received permission from the US FDA to conduct phase II clinical trials on tianeptine hemioxalate extended-release tablets designed for once-daily use. The project was discontinued in late 2023 because of disappointing results in

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s. Tianeptine has two

active metabolite An active metabolite, or pharmacologically active metabolite is a biologically active metabolite of a xenobiotic substance, such as a drug or environmental chemical. Active metabolites may produce therapeutic effects, as well as harmful effects. ...

s, MC5 (a

pentanoic acid Valeric acid or pentanoic acid is a straight-chain alkyl carboxylic acid with the chemical formula . Like other low-molecular-weight carboxylic acids, it has an unpleasant odor. It is found in the perennial flowering plant '' Valeriana officin ...

derivative of the parent compound) and MC3 (a

propionic acid Propionic acid (, from the Greek language, Greek words πρῶτος : ''prōtos'', meaning "first", and πίων : ''píōn'', meaning "fat"; also known as propanoic acid) is a naturally occurring carboxylic acid with chemical formula . It is a ...

derivative). MC5 has a longer elimination half-life of approximately 7.6 hours, and takes about a week to reach steady-state concentration under daily-dosing. MC5 is a mu-opioid agonist but not delta-opioid agonist, with

EC50 ] Half maximal effective concentration (EC50) is a measure of the concentration of a drug, antibody or toxicant which induces a stimulus–response model, biological response halfway between the baseline and maximum after a specified exposure tim ...

at the mu-opioid receptor of 0.545 μM (vs 0.194 μM for tianeptine). MC3 is a very weak mu-opioid agonist, with an EC50 of 16 μM. Tianeptine is excretion, excreted 65% in the

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

and 15% in

feces Feces (also known as faeces American and British English spelling differences#ae and oe, or fæces; : faex) are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the ...

Chemistry

In terms of

chemical structure A chemical structure of a molecule is a spatial arrangement of its atoms and their chemical bonds. Its determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target m ...

, it is similar to

tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains ...

(TCAs), but it has significantly different pharmacology and important structural differences, so it is not usually grouped with them.

Analogues

Although several related compounds are disclosed in the original patent, no activity data are provided and it was unclear whether these share tianeptine's unique pharmacological effects. More recent structure-activity relationship studies have since been conducted, providing some further insight on μ-opioid, δ-opioid, and

pharmacokinetic Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific subs ...

activity. Derivatives where the aromatic chlorine substituent is replaced by bromine, iodine or methylthio, and/or the heptanoic acid tail is varied in length or replaced with other groups such as 3-methoxypropyl, show similar or increased opioid receptor activity relative to tianeptine itself.

Amineptine Amineptine, formerly sold under the brand name Survector among others, is an atypical antidepressant of the tricyclic antidepressant (TCA) family. It acts as a selective and mixed dopamine reuptake inhibitor and releasing agent, and to a le ...

, the most closely related drug to have been widely studied, is a

dopamine reuptake inhibitor A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dop ...

with no significant effect on serotonin levels, nor opioid agonist activity. Tianeptinaline, analog of tianeptine, is a notable class I HDAC inhbitor.

History

Tianeptine was introduced for medical use in

under the brand name Stablon in 1983.

Society and culture

Approval and brand names

Brand names include: * Coaxil ( BG, CR, CZ, EE, HU, LT, LV, PL, RO, RU, SK UA) * Salymbra ( EE) * Stablon ( AR, AT, BR, FR, HK, IN, ID, MY, MX, PK, PT, SG, SK, TH, TT, TR, VE) * Tatinol ( CN) * Tianeurax ( DE) * Tynept ( IN) * Zinosal ( ES) * Tianesal ( PL)

Development

Under the code names JNJ-39823277 and TPI-1062, tianeptine was previously under development for the treatment of major depressive disorder in the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

and

Belgium Belgium, officially the Kingdom of Belgium, is a country in Northwestern Europe. Situated in a coastal lowland region known as the Low Countries, it is bordered by the Netherlands to the north, Germany to the east, Luxembourg to the southeas ...

. Phase I

s were completed in Belgium and the United States in May and June 2009, respectively. For unclear reasons development of tianeptine was discontinued in both countries in January 2012. In October 2023, Tonix Pharmaceuticals announced that it had discontinued its development of tianeptine as a monotherapy for

after disappointing phase-2 clinical trial results. An ongoing clinical trial, sponsored by the New York Psychiatric Institute, is examining tianeptine's use in

treatment-resistant depression Treatment-resistant depression (TRD) is often defined as major depressive disorder in which an affected person does not respond adequately to at least two different antidepressant medications at an adequate dose and for an adequate duration. Inad ...

. U.S. National Poison Data System data on tianeptine showed a nationwide increase in tianeptine exposure calls and calls related to abuse and misuse during 2014–2017.

Recreational use

As a μ-opioid agonist, tianeptine in large doses has high abuse potential. In 2001,

's Ministry of Health restricted tianeptine prescribing to psychiatrists due to its recreational potential. Between 1989 and 2004, in France 141 cases of recreational use were identified, correlating to an incidence of 1 to 3 cases per 1000 persons treated with tianeptine and 45 between 2006 and 2011. According to Servier, stopping of treatment with tianeptine is difficult, due to the possibility of withdrawal symptoms in a person. The severity of the withdrawal is dependent on the daily dose, with high doses being extremely difficult to quit. An official

DEA The Drug Enforcement Administration (DEA) is a United States federal law enforcement agency under the U.S. Department of Justice tasked with combating illicit drug trafficking and distribution within the U.S. It is the lead agency for domes ...

statement states that the withdrawal symptoms in humans typically result in: agitation, nausea, vomiting, tachycardia, hypertension, diarrhea, tremor, and diaphoresis, similar to other opioid drugs. In 2007, according to French Health Products Safety Agency, tianeptine's manufacturer Servier agreed to modify the drug's label, following problems with dependency. Tianeptine has been intravenously injected by drug users in

Russia Russia, or the Russian Federation, is a country spanning Eastern Europe and North Asia. It is the list of countries and dependencies by area, largest country in the world, and extends across Time in Russia, eleven time zones, sharing Borders ...

. This method of administration reportedly causes an

-like effect and is sometimes used in an attempt to lessen opioid withdrawal symptoms. Tianeptine tablets contain

silica Silicon dioxide, also known as silica, is an oxide of silicon with the chemical formula , commonly found in nature as quartz. In many parts of the world, silica is the major constituent of sand. Silica is one of the most complex and abundant f ...

and do not dissolve completely. Often the solution is not filtered well thus particles in the injected fluid block

capillaries A capillary is a small blood vessel, from 5 to 10 micrometres in diameter, and is part of the microcirculation system. Capillaries are microvessels and the smallest blood vessels in the body. They are composed of only the tunica intima (the in ...

, leading to

thrombosis Thrombosis () is the formation of a Thrombus, blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thrombocytes) and fib ...

and then severe

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. The term "necrosis" came about in the mid-19th century and is commonly attributed to German pathologist Rudolf Virchow, who i ...

. Thus, in Russia tianeptine (sold under the brand name "Coaxil") is a schedule III controlled substance in the same list as the majority of

benzodiazepines Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat co ...

and

barbiturates Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as ...

. The

Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the National public health institutes, national public health agency of the United States. It is a Federal agencies of the United States, United States federal agency under the United S ...

(CDC) has expressed concern that tianeptine may be an "emerging public health risk", citing an increase in exposure-related calls to poison control centers in the United States. Sold retail as a

dietary supplement A dietary supplement is a manufactured product intended to supplement a person's diet by taking a pill (pharmacy), pill, capsule (pharmacy), capsule, tablet (pharmacy), tablet, powder, or liquid. A supplement can provide nutrients eithe ...

and touted as a mood-booster and an aid for concentration, it is colloquially known as "gas-station heroin". In the US, it is an unregulated drug sold under several product names and has been found to be adulterated with synthetic cannabinoid receptor agonists (SCRAs) or other drugs. A literature review conducted in 2018 found 25 articles involving 65 patients with tianeptine abuse or dependence. Limited data showed that a majority of patients were male and that age ranged from 19 to 67. Routes of intake included oral, intravenous, and insufflation entry. In the 15 cases of overdose, 8 combined ingestion with at least one other substance, of which 3 resulted in death. Six additional deaths are reported involving tianeptine (making 9 in total). In this report, the amount of tianeptine used ranged from 50 mg/day to 10 g/day orally.

Legality

In 2003,

Bahrain Bahrain, officially the Kingdom of Bahrain, is an island country in West Asia. Situated on the Persian Gulf, it comprises a small archipelago of 50 natural islands and an additional 33 artificial islands, centered on Bahrain Island, which mak ...

classified tianeptine a controlled substance due to increasing reports of misuse and recreational use. In Russia, tianeptine (sold under the brand name "Coaxil") is a schedule III controlled substance in the same list as the majority of

and

. On March 13, 2020, with a decree approved by the Minister of Health,

became the first European country to outlaw tianeptine considering it a Class I controlled substance.

United States

In the US, tianeptine is not considered by the

Drug Enforcement Administration The Drug Enforcement Administration (DEA) is a Federal law enforcement in the United States, United States federal law enforcement agency under the U.S. Department of Justice tasked with combating illicit Illegal drug trade, drug trafficking a ...

as a controlled substance or analogue thereof. However, its use in dietary supplements and food is unlawful. The

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) has issued warnings, as recently as January 2024, about the dangers of recreational tianeptine use and the risks posed by adulterated dietary supplements containing undeclared tianeptine. On 6 April 2018, Michigan became the first US state to outlaw tianeptine sodium, classifying it as a schedule II

controlled substance A controlled substance is generally a drug or chemical whose manufacture, possession and use is regulated by a government, such as illicitly used drugs or prescription medications that are designated by law. Some treaties, notably the Sing ...

. The scheduling of tianeptine sodium is effective 4 July 2018. On March 15, 2021, Alabama outlawed tianeptine, initially classifying it as a schedule II

. It was later reclassified as a schedule I

in November 14th, 2021. On July 1, 2022, Tennessee outlawed tianeptine and adds "any salt, sulfate, free acid, or other preparation of tianeptine, and any salt, sulfate, free acid, compound, derivative, precursor, or preparation thereof that is substantially chemically equivalent or identical with tianeptine", classifying it as a schedule II

. On December 22, 2022, Ohio outlawed tianeptine, classifying it as a schedule I

with

Ohio Governor The governor of Ohio is the head of government of Ohio and the commander-in-chief of the U.S. state's Ohio National Guard, military forces. The officeholder has a duty to enforce state laws, the power to either approve or veto bill (proposed law ...

Mike DeWine Richard Michael DeWine ( ; born January 5, 1947) is an American politician and attorney serving as the 70th List of governors of Ohio, governor of Ohio since 2019. A member of the Republican Party (United States), Republican Party, he served a ...

referencing the widespread availability of the chemical there as "gas-station heroin". On March 23, 2023, Kentucky outlawed tianeptine, classifying it as a schedule I substance by an order of the

Governor of Kentucky The governor of the Commonwealth of Kentucky is the head of government of the Commonwealth (U.S. state), Commonwealth of Kentucky. Sixty-two men and one woman have served as governor of Kentucky. The governor's term is four years in length; sinc ...

. On September 20, 2023, Florida outlawed tianeptine, classifying it as a schedule I substance by an administrative edict issued by the

Florida Attorney General The Florida attorney general is an elected Florida Cabinet, cabinet official in the U.S. state of Florida. The attorney general serves as the chief legal officer of the state, and is head of the Florida Department of Legal Affairs. The office is ...

References

External links

Tianeptine – David Pearce – The Good Drug Guide
{{Tricyclics Secondary amines Anxiolytics Chloroarenes Euphoriants Laboratoires Servier Mu-opioid receptor agonists Synthetic opioids Tricyclic antidepressants Sultams Sulfur heterocycles Nitrogen heterocycles Drugs with unknown mechanisms of action