Tianeptine was discovered and patented by the French Society of Medical Research in the 1960s. Currently, tianeptine is approved in France and manufactured and marketed by Laboratories Servier SA; it is also marketed in a number of other European countries under the trade name Coaxil as well as in Asia (including Singapore) and Latin America as Stablon and Tatinol but it is not available in Australia, Canada, New Zealand, the United Kingdom, or the United States.
A clinical trial comparing its efficacy and tolerability with amitriptyline in the treatment of irritable bowel syndrome 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 asthma. In August 1998, Dr. Fuad Lechin and colleagues at the Central University of Venezuela Institute of Experimental Medicine in Caracas published the results of a 52-week randomized controlled trial 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.
Known contraindications include the following:
Hypersensitivity to tianeptine or any of the tablet's excipients.
Compared to other tricyclic antidepressants it produces significantly fewer cardiovascular, anticholinergic (like dry mouth or constipation), sedative and appetite-stimulating effects. A recent review found that it was amongst the antidepressants most prone to causing hepatotoxicity (liver damage), although the evidence to support this concern was of limited quality. Unlike other tricyclic antidepressants, tianeptine does not affect heart function. μ-Opioid receptor agonists can sometimes induce euphoria, as does tianeptine, occasionally, at high doses, well above the normal therapeutic range. Tianeptine can also cause severe withdrawal symptoms after prolonged use at high doses which should prompt extreme caution.[better source needed]
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug interacts with the site.
Atypical μ-opioid receptor agonist
In 2014, tianeptine was found to be a μ-opioid receptor (MOR) full agonist using human proteins. It was also found to act as a full agonist of the δ-opioid receptor (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 had similar activity as a MOR agonist but with a much longer elimination half-life. Moreover, in mice, although tianeptine produced other opioid-like behavioral effects such as analgesia and reward, it did not result in tolerance or withdrawal. The authors suggested that tianeptine may be acting as a biased agonist 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 usage of dose usage 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 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 without impairing analgesia. In humans, however, tianapine was found to increase respiratory depression when administered in conjunction with the potent opioid remifentanil.
Glutamatergic, neurotrophic, and neuroplastic modulation
Research suggests that tianeptine produces its antidepressant effects through indirect alteration and inhibition of glutamate receptor activity (i.e., AMPA receptors and NMDA receptors) and release of BDNF, in turn affecting neural plasticity. Some researchers hypothesize that tianeptine has a protective effect against stress induced neuronal remodeling. There is also action on the NMDA and AMPA receptors. 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, many believe the efficacy of antidepressants is related to promotion of synaptic 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 enhancing BDNF expression, although these findings are based largely on preclinical studies.
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 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 inhibitorfluoxetine inhibited the effect of tianeptine on long-term potentiation 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 underlying the antidepressant effects of tianeptine.
Research indicates possible anticonvulsant (anti-seizure) and analgesic (painkilling) activity of tianeptine via downstream modulation of adenosineA1 receptors (as the effects could be experimentally blocked by antagonists of this receptor). Tianpetine is also weak histone deacetylase inhibitor and analogs with increased potency and selectivity are developed.
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 pharmacokinetical 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, the most closely related drug to have been widely studied, is a dopamine reuptake inhibitor with no significant effect on serotonin levels, nor opioid agonist activity. Tianeptinaline, analog of tianeptine, is a notable class I HDAC inhbitor.
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 and Belgium.Phase Iclinical trials 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.
The 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.
As a μ-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,
In 2003, Bahrain classified it a controlled substance due to increasing reports of misuse and recreational use.
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.[better source needed] Official DEA 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.
Tianeptine has been intravenously injected by drug users in Russia. This method of administration reportedly causes an opioid-like effect and is sometimes used in an attempt to lessen opioid withdrawal symptoms. Tianeptine tablets contain silica and do not dissolve completely. Often the solution is not filtered well thus particles in the injected fluid block capillaries, leading to thrombosis and then severe necrosis. 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 and barbiturates.
On 6 April 2018 Michigan became the first U.S. state to ban tianeptine sodium, classifying it as a schedule IIcontrolled substance. The scheduling of tianeptine sodium is effective 4 July 2018. The Centers 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. Alabama was set to ban it on March 15, 2021. Tennessee banned it on July 1, 2022.
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 it 9 in total). In this report, the amount of tianeptine used ranged from 50 mg/day to 10g/day orally.
On March 13, 2020, with a decree approved by the Minister of Health, Italy became the first European country to ban tianeptine considering it a Class I controlled substance.
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