Tianeptine was discovered and patented by the French Society of Medical Research in the 1960s. It was introduced for medical use inFrance in 1983.[18] Currently, tianeptine is approved in France and manufactured and marketed by LaboratoriesServier SA; it is also marketed in a number of other European countries under the trade name Coaxil as well as in Asia (includingSingapore) and Latin America as Stablon and Tatinol but it is not available inAustralia,Canada,New Zealand,Italy or theUnited Kingdom.[19][20] In the US, it is an unregulated drug sold under several names and some of these products have been found to be adulterated with otherrecreational drugs. It is commonly known by the nickname "gas station heroin".[21][22]
A clinical trial comparing its efficacy and tolerability with amitriptyline in the treatment ofirritable bowel syndrome showed that tianeptine was at least as effective as amitriptyline and produced fewer prominent adverse effects, such as dry mouth and constipation.[29]
Tianeptine has been reported to be very effective forasthma. In August 1998, Dr. Fuad Lechin and colleagues at theCentral University of Venezuela Institute of Experimental Medicine inCaracas published the results of a 52-weekrandomized controlled trial of asthmatic children; the children in the groups who received tianeptine had a sharp decrease in clinical rating and increased lung function.[30] Two years earlier, they had found a close, positive association between free serotonin inplasma and severity of asthma in symptomatic persons.[30] 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.[30] 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.[30]
Compared to othertricyclic antidepressants, it produces significantly fewer cardiovascular,anticholinergic (like dry mouth or constipation),sedative and appetite-stimulating effects.[14][19] Unlike other tricyclic antidepressants, tianeptine does not affect heart function.[36]
μ-Opioid receptor agonists can sometimes induceeuphoria, as does tianeptine, occasionally, at high doses, well above the normal therapeutic range (see§ Recreational use below). Tianeptine can also cause severe withdrawal symptoms after prolonged use at high doses which should prompt extreme caution.[37][38]
In 2014, tianeptine was found to be aμ-opioid receptor (MOR)full agonist using human proteins.[15] It was also found to act as a full agonist of theδ-opioid receptor (DOR), although with approximately 200-fold lower potency.[15] 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 primarymetabolite had similar activity as a MOR agonist but with a much longerelimination half-life.[42] Moreover, in mice, although tianeptine produced otheropioid-like behavioral effects such asanalgesia andreward, it did not result intolerance orwithdrawal.[42] The authors suggested that tianeptine may be acting as abiased agonist of the MOR and that this may be responsible for its atypical profile as a MOR agonist.[42] 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.[43][44] In addition to its therapeutic effects, activation of the MOR is likely to also be responsible for theabuse potential of tianeptine at high doses that are well above the normal therapeutic range and efficacy threshold.[citation needed]
In rats, when co-administered with morphine, tianeptine prevents morphine-inducedrespiratory depression without impairing analgesia.[45] In humans, however, tianeptine was found to increase respiratory depression when administered in conjunction with the potent opioidremifentanil.[46]
Glutamatergic, neurotrophic, and neuroplastic modulation
Research suggests that tianeptine produces its antidepressant effects through indirect alteration and inhibition ofglutamate receptor activity (i.e.,AMPA receptors andNMDA receptors) and release ofBDNFTooltip brain-derived neurotrophic factor, in turn affectingneural plasticity.[47][48][49][50][14][19] Some researchers hypothesize that tianeptine has a protective effect against stress inducedneuronal remodeling.[47][14] There is also action on theNMDA andAMPA receptors.[47][14] 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 asketamine, many believe the efficacy of antidepressants is related to promotion ofsynaptic plasticity. 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 enhancingBDNF expression, although these findings are based largely onpreclinical studies.[19]
Although tianeptine was originally found to have no effectin 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.[52] The (−)-enantiomer is more active in this sense than the (+)-enantiomer.[53] 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.[47] However, coadministration of tianeptine and theselective serotonin reuptake inhibitorfluoxetine inhibited the effect of tianeptine onlong-term potentiation inhippocampal CA1 area. This is considered an argument for the opposite effects of tianeptine and fluoxetine on serotonin uptake,[14] although it has been shown that fluoxetine can be partially substituted for tianeptine in animal studies.[54] In any case, the collective research suggests that direct modulation of the serotonin system is unlikely to be themechanism of action underlying the antidepressant effects of tianeptine.[51]
Tianeptine modestly enhances themesolimbic release ofdopamine[55] and potentiatesCNSD2 andD3 receptors.[56] Tianeptine has no affinity for thedopamine transporter or thedopamine receptors.[47]CREB-TF (CREB, cAMP response element-binding protein)[57] is a cellulartranscription factor. It binds to certainDNA sequences called cAMP response elements (CRE), thereby increasing or decreasing thetranscription of thegenes.[58] CREB has a well-documented role inneuronal plasticity andlong-term memory formation in the brain. Cocaine- and amphetamine-regulated transcript, also known asCART, is aneuropeptideprotein that in humans is encoded by theCARTPTgene.[59][60] CART appears to have roles in reward, feeding, stress,[61] and it has the functional properties of an endogenouspsychostimulant.[62] Taking into account that CART production is upregulated by CREB,[63] 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 possibleanticonvulsant (anti-seizure) andanalgesic (painkilling) activity of tianeptine via downstream modulation ofadenosineA1 receptors (as the effects could be experimentally blocked byantagonists of this receptor).[31] Tianpetine is also weakhistone deacetylase inhibitor and analogs with increased potency and selectivity are developed.[64]
Tianeptine has been shown to be a high-efficacy agonist ofPPAR-delta, a nuclear receptor.[65]
Thebioavailability of tianeptine is approximately 99%.[9][10] Itsplasma protein binding is about 95%.[10] Themetabolism of tianeptine ishepatic, viaβ-oxidation.[10] CYP enzymes are not involved, which limits the potential for drug-drug interactions.[10] Maximal concentration is reached in about an hour and theelimination half-life is 2.5 to 3 hours.[9][10] The elimination half-life has been found to be increased to 4 to 9 hours in theelderly.[11] Tianeptine is usually packaged as a sodium salt but can also be found as tianeptine sulfate, a slower-releasing formulation patented byJanssen in 2012.[66] 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.[67] The project was discontinued in late 2023 because of disappointing results inclinical trials.
Tianeptine has twoactive metabolites, MC5 (apentanoic acid derivative of the parent compound) and MC3 (apropionic acid derivative).[68][10] MC5 has a longer elimination half-life[42] 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, withEC50 at the mu-opioid receptor of 0.545 μM (vs 0.194 μM for tianeptine).[42] MC3 is a very weak mu-opioid agonist, with an EC50 of 16 μM.[42] Tianeptine isexcreted 65% in theurine and 15% infeces.[9][10]
In terms ofchemical structure, it is similar totricyclic antidepressants (TCAs), but it has significantly different pharmacology and important structural differences, so it is not usually grouped with them.
Although several related compounds are disclosed in the original patent,[69] no activity data are provided and it was unclear whether these share tianeptine's unique pharmacological effects. More recentstructure-activity relationship studies have since been conducted, providing some further insight on μ-opioid, δ-opioid, andpharmacokinetic activity.[70][71][72][73][74] 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, with up to 13x higher potency than tianeptine itself.[75][76][77]Amineptine, the most closely related drug to have been widely studied, is adopamine reuptake inhibitor with no significant effect on serotonin levels, nor opioid agonist activity.Tianeptinaline, analog of tianeptine, is a notable class I HDAC inhbitor.[64]
Under the code names JNJ-39823277 and TPI-1062, tianeptine was previously under development for the treatment of major depressive disorder in theUnited States andBelgium.[6]Phase Iclinical trials were completed in Belgium and the United States in May and June 2009, respectively.[6] For unclear reasons development of tianeptine was discontinued in both countries in January 2012.[6] In October 2023, Tonix Pharmaceuticals announced that it had discontinued its development of tianeptine as a monotherapy formajor depressive disorder after disappointing phase-2 clinical trial results.[78] An ongoing clinical trial, sponsored by theNew York Psychiatric Institute, is examining tianeptine's use intreatment-resistant depression.[79]
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.[17]
As aμ-opioid agonist, tianeptine in large doses has high abuse potential. In 2001,Singapore's Ministry of Health restricted tianeptine prescribing to psychiatrists due to its recreational potential.[80]
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 ofwithdrawal symptoms. The severity of the withdrawal is dependent on the daily dose, with high doses being extremely difficult to quit.[81][better source needed][82][83] An officialDEA statement[84] 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 toFrench Health Products Safety Agency, tianeptine's manufacturer Servier agreed to modify the drug's label, following problems with dependency.[85]
Tianeptine has been intravenously injected by drug users inRussia.[86][87] This method of administration reportedly causes anopioid-like effect and is sometimes used in an attempt to lessenopioid withdrawal symptoms.[86] Tianeptine tablets containsilica and do not dissolve completely. Often the solution is not filtered well thus particles in the injected fluid blockcapillaries, leading tothrombosis and then severenecrosis. Thus, in Russia tianeptine (sold under the brand name "Coaxil") is a schedule III controlled substance in the same list as the majority ofbenzodiazepines andbarbiturates.[88]
TheCenters for Disease Control and Prevention (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.[17] Sold retail as adietary supplement and touted as a mood-booster and an aid for concentration, it is colloquially known as "gas-station heroin".[21][22][89][90][91][92] 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.[22]
A literature review conducted in 2018 found 25 articles involving 65 patients with tianeptine abuse or dependence.[37] 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.
In 2003,Bahrain classified tianeptine a controlled substance due to increasing reports of misuse and recreational use.[93]
In Russia, tianeptine (sold under the brand name "Coaxil") is a schedule III controlled substance in the same list as the majority ofbenzodiazepines andbarbiturates.[88]
On 13 March 2020, with a decree approved by the Minister of Health,Italy became the first European country to outlaw tianeptine considering it a Class I controlled substance.[94]
In the US, tianeptine is not considered by theDrug Enforcement Administration as a controlled substance or analogue thereof.[95] However, its use in dietary supplements and food is unlawful.[96] TheFood and Drug Administration (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.[97]
On 6 April 2018, Michigan became the first US state to outlaw tianeptine sodium, classifying it as aschedule IIcontrolled substance.[98] The scheduling of tianeptine sodium is effective 4 July 2018.[99]
On 1 November 2019, Tianeptine became a Schedule II controlled dangerous substance as classified within the Uniform Controlled Dangerous Substances Act of the state of Oklahoma.
On 1 July 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 aschedule IIcontrolled substance.[102]
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