4 Uses of Tianeptine (Stablon) + Mechanisms & Side Effects

Tianeptine: Risk of Addiction and Abuse

4 Uses of Tianeptine (Stablon) + Mechanisms & Side Effects

Depression is a mental health condition that affects over 350 million people around the world. With so many people struggling with this disorder, it is important to have effective medical treatments that can partner with behavioral therapy.

Several types of antidepressant medications are prescribed to treat the condition, including MAO inhibitors, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs).

However, only a small percentage of people taking tricycling antidepressants, SSRIs, and other kinds of antidepressants achieve remission of depression symptoms, so it’s important that a variety of prescription approaches to treatment are available.

Antidepressant medications work in the brain differently, and tianeptine is one of those medications. This prescription antidepressant is prescribed under various brand names including Stablon, Tatinol, and Coaxil. Unfortunately, some other prescription drugs, tianeptine is abused, and it can cause serious side effects.

Tianeptine’s Positive and Negative Effects

Tianeptine was first synthesized by French researchers in 1981. This antidepressant is still widely available in Europe, but because the US patent expired, it is not prescribed in North America. The US and Belgium both began clinical research into the effectiveness of tianeptine in 2009 but abandoned research into the drug treatment in 2012.

Instead, psychiatrists in the United States typically prescribe SSRI medications to treat depression, with older classes of antidepressants tricyclics and MAO inhibitors following if SSRIs do not work.

However, because of rapidly growing illicit drug sales online, tianeptine can be purchased through various websites.

It is not specifically scheduled under US drug law, which makes tianeptine a potential substance of abuse.

Early research into tianeptine as an antidepressant suggested that this drug could be more effective than other classes of antidepressants, especially tricyclic drugs.

Tianeptine was investigated as a potential treatment for:

  • Major depression
  • Depression associated with bipolar disorder
  • Dysthymia
  • Adjustment disorder
  • Depression and anxiety associated with alcohol use disorder

Long-term treatment with tianeptine appeared to reduce the relapse of depression symptoms over time, although some study participants in other medical studies appeared to respond better to other antidepressants. Tianeptine worked as one potential medical treatment among many because some people may respond better than others.

Tianeptine appeared to have similar low-risk side effects as SSRIs, so it was not ly to cause:

  • Abuse or addiction
  • Weight gain
  • Cardiovascular damage
  • Problems with sleep
  • Trouble with thinking or memory
  • Changes to voluntary versus involuntary movement

Because of how the body processes tianeptine through the gut and liver, it has high bioavailability with a short half-life, so it is quickly eliminated.

This means the effects on the brain occur sooner; previous antidepressants took several weeks to become effective.

Because the body quickly eliminates the drug, people taking prescription tianeptine must stick to their scheduled doses, so a consistent level of the medication remains active in the body.

Un other antidepressants, tianeptine appears to work as a selective serotonin reuptake enhancer rather than an inhibitor. Breakthrough research in 2014 found that the drug works on some opioid receptors, though not the ones associated with intoxication. The action helps to improve mood by stimulating the release of neurotransmitters, which also soothes anxiety.

Tianeptine also increases how much serotonin the brain absorbs. Other classes of antidepressants block serotonin receptors from absorbing this important neurotransmitter, but absorbing it rapidly appears to have a depression-lifting effect, too.

Still, the 2014 study suggested that tianeptine’s effects on some opioid receptors may lead to intoxication if a large enough dose of the drug is abused.

The most common short-term effects reported in early medical studies included:

  • Headaches
  • Constipation
  • Stomach pain or cramps
  • Dizziness
  • Nausea
  • Changes to dreams or sleep patterns

The Potential to Abuse Tianeptine

Tianeptine abuse is still rare even in countries France that prescribe the medication. People who abuse multiple substances are more ly to also abuse tianeptine. Large enough doses of tianeptine can cause a high, though the drug appears to be abused mainly for its calming, anti-anxiety effects. It can be very hard to quit, leading to frequent relapses.

Taken in doses over 100 mg, tianeptine can cause euphoria similar to that caused by opioid drugs, including Vicodin, OxyContin, or heroin. The typical therapeutic dose, as prescribed in other countries, ranges from 25 mg to 30 mg, which allegedly does not produce any euphoric effect.

A 2009 study observed a small group of 24 volunteers who had abused opiate drugs in the past and who abused tianeptine at the time of the study. The overlap may involve compulsive behaviors involving pharmaceutical drugs prescription painkillers. Being prescribed tianeptine may have triggered the behavioral problem while attempting to address a mood disorder.

However, since tianeptine also triggers some opioid receptors in the brain, this group could have preferred tianeptine as a drug of abuse because of similar short-term effects as opioid drugs.

Study participants abused tianeptine alongside antihistamines to get high.

While the study did not describe the combination specifically, some people abuse antihistamines in combination with other central nervous system (CNS) depressants, alcohol, to enhance the feeling of lightheadedness and euphoria. It is ly that people abusing antihistamines and tianeptine together are seeking similar effects.

Another potential cause of tianeptine abuse may involve the reabsorption of serotonin while other mood-elevating neurotransmitters, dopamine, remain available in the brain.

The presence of dopamine may trigger the reward system, leading to elevated mood, which may become addictive.

Other addictive substances trigger the release of dopamine, too, so there may be a similar pattern with tianeptine.

Increasingly, tianeptine is being abused as a nootropic, or a drug that enhances cognition, memory, or learning. Because of how the drug binds to receptors in the brain, it can cause muscle relaxation, relieve anxiety, and elevate mood. This combination may make the person feel as though they can think better because they are not worried, in pain, or depressed.

A 2011 French assessment of tianeptine abuse indicated that some people do misuse or abuse the medication, leading to doctor-shopping behaviors to get multiple prescriptions.

The investigation found that, among French prescriptions, tianeptine was the most abused antidepressant, with benzodiazepines being the only other psychiatric medications that were abused at higher rates, using doctor-shopping indicators (DSIs).

A 2011 French assessment of tianeptine abuse indicated that some people do misuse or abuse the medication.

It’s Never Too Late to Get Help

Tianeptine Withdrawal

While earlier studies reported no withdrawal symptoms from suddenly quitting tianeptine, later studies suggest that rebound symptoms of underlying depression and anxiety could be part of the withdrawal experience, which may trigger cravings for the drug, leading to cycles of abuse.

Signs of tianeptine withdrawal may include:

  • Low mood
  • Anhedonia, or not feeling pleasure in anything
  • Numbness
  • Other depression symptoms
  • High physical energy
  • Inability to sleep, insomnia, and other sleep disorders
  • Excitability
  • Worry
  • Other signs of anxiety

People who abuse tianeptine and attempt to quit without the help of a doctor or therapist may experience these withdrawal symptoms and feel they need tianeptine to feel normal. This can cause a relapse back into abuse of the drug.

One case report of severe tianeptine withdrawal suggests that these symptoms may occur if one abuses a lot of tianeptine, then tries to quit suddenly:

  • Agitation
  • Physical aggression
  • Paranoid delusions

These indicate withdrawal psychosis, which should be rare with tianeptine but is a potential risk. The drug may also have gastrointestinal side effects, diarrhea, which are similar to withdrawal symptoms associated with opioids.

Overdose on Tianeptine Is Rare but Possible

Tianeptine is not widely associated with overdose, but because the drug acts on some opioid receptors, there are some case reports of respiratory depression associated with too much tianeptine.

Slowed, irregular, shallow, and stopped breathing are all usually associated with opioid abuse and overdose; this effect can lead to death if it is not treated by emergency medical professionals.

Tianeptine overdose is also associated with cardiovascular damage, so changes to heart rate can lead to a heart attack or death.

In one case report, an individual suffering a tianeptine overdose was given naloxone in the ER. Naloxone is a drug most often associated with temporarily stopping opioid overdoses, but the drug appeared to work for this instance of tianeptine overdose, too.

Professional Help

Since purchasing drugs over the Internet is getting easier and easier, there may be a rise in tianeptine abuse in the US soon. Any form of prescription drug abuse requires treatment. Addiction specialists can help with the detox process, which may involve using a drug buprenorphine to taper off high doses of tianeptine, opioids, and similar drugs.

Professional help to change compulsive behaviors around drugs is important, too, which is why rehabilitation programs offer individual and group therapy. The combination of medically supervised detox and evidence-based therapy in rehabilitation programs create a solid foundation to overcome addiction to any substance.

Source: https://sdtreatmentcenter.com/tianeptine/

TIANEPTINE: Uses, Side Effects, Interactions and Warnings

4 Uses of Tianeptine (Stablon) + Mechanisms & Side Effects
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References:

Awad, R., Arnason, J. T., Trudeau, V., Bergeron, C., Budzinski, J. W., Foster, B. C., and Merali, Z. Phytochemical and biological analysis of skullcap (Scutellaria lateriflora L.): a medicinal plant with anxiolytic properties. Phytomedicine. 2003;10(8):640-649. View abstract.

Bakota EL, Samms WC, Gray TR, Oleske DA, Hines MO. Case Reports of Fatalities Involving Tianeptine in the United States. J Anal Toxicol. 2018;42(7):503-509. View abstract.

Bence C, Bonord A, Rebillard C, et al. Neonatal Abstinence Syndrome Following Tianeptine Dependence During Pregnancy. Pediatrics. 2016;137(1). View abstract.

Dempsey SK, Poklis JL, Sweat K, Cumpston K, Wolf CE. Acute Toxicity From Intravenous Use of the Tricyclic Antidepressant Tianeptine. J Anal Toxicol. 2017;41(6):547-550. View abstract.

El Zahran T, Schier J, Glidden E, et al. Characteristics of Tianeptine Exposures Reported to the National Poison Data System – United States, 2000-2017. MMWR Morb Mortal Wkly Rep. 2018;67(30):815-818. View abstract.

Goodnough R, Li K, Fouladkou F, et al. Notes from the Field: Toxic Leukoencephalopathy Associated with Tianeptine Misuse – California, 2017. MMWR Morb Mortal Wkly Rep. 2018;67(27):769-770. View abstract.

Grasela TH, Fiedler-Kelly JB, Salvadori C, Marey C, Jochemsen R. Development of a population pharmacokinetic database for tianeptine. Eur J Clin Pharmacol. 1993;45(2):173-9. View abstract.

Guelfi JD, Dulcire C, Le Moine P, Tafani A. Clinical safety and efficacy of tianeptine in 1,858 depressed patients treated in general practice. Neuropsychobiology. 1992;25(3):140-8. View abstract.

Gupta S, Wallace R, Sloshower J. Online Sales of Unscheduled Pharmaceutical Agents: A Case Report of Tianeptine Use in the United States. J Addict Med. 2017;11(5):411-412. View abstract.

Jeon HJ, Woo JM, Lee SH, et al. Improvement in subjective and objective neurocognitive functions in patients with major depressive disorder: a 12-week, multicenter, randomized trial of tianeptine versus escitalopram, the CAMPION study. J Clin Psychopharmacol. 2014;34(2):218-25. View abstract.

Kasper S, Olié JP. A meta-analysis of randomized controlled trials of tianeptine versus SSRI in the short-term treatment of depression. Eur Psychiatry. 2002;17 Suppl 3:331-40. View abstract.

Lauhan R, Hsu A, Alam A, Beizai K. Tianeptine Abuse and Dependence: Case Report and Literature Review. Psychosomatics. 2018;59(6):547-553. View abstract.

Le Bricquir Y, Larrey D, Blanc P, Pageaux GP, Michel H. Tianeptine–an instance of drug-induced hepatotoxicity predicted by prospective experimental studies. J Hepatol. 1994;21(5):771-3. View abstract.

Lechin F, van der Dijs B, Hernández G, Orozco B, Rodríguez S, Baez S. Acute effects of tianeptine on circulating neurotransmitters and cardiovascular parameters. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30(2):214-22. View abstract.

Lechin F, van der Dijs B, Lechin AE. Treatment of bronchial asthma with tianeptine. Methods Find Exp Clin Pharmacol. 2004;26(9):697-701. View abstract.

Lechin F, van der Dijs B, Orozco B, et al. The serotonin uptake-enhancing drug tianeptine suppresses asthmatic symptoms in children: a double-blind, crossover, placebo-controlled study. J Clin Pharmacol. 1998;38(10):918-25. View abstract.

Lucaj S, Leo RJ. Tianeptine Sodium: A Nootropic With Potentially Lethal Consequences. Prim Care Companion CNS Disord. 2018;20(4). View abstract.

Marraffa JM, Stork CM, Hoffman RS, Su MK. Poison control center experience with tianeptine: an unregulated pharmaceutical product with potential for abuse. Clin Toxicol (Phila). 2018;56(11):1155-1158. View abstract.

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. View abstract.

Royer RJ, Albin H, Barrucand D, Salvadori-Failler C, Kamoun A. Pharmacokinetic and metabolic parameters of tianeptine in healthy volunteers and in populations with risk factors. Clin Neuropharmacol. 1988;11 Suppl 2:S90-6. View abstract.

Salvadori C, Ward C, Defrance R, Hopkins R. The pharmacokinetics of the antidepressant tianeptine and its main metabolite in healthy humans–influence of alcohol co-administration. Fundam Clin Pharmacol. 1990;4(1):115-25. View abstract.

Samuels BA, Nautiyal KM, Kruegel AC, et al. The Behavioral Effects of the Antidepressant Tianeptine Require the Mu-Opioid Receptor. Neuropsychopharmacology. 2017;42(10):2052-2063. View abstract.

Sohn W, Lee OY, Kwon JG, et al. Tianeptine vs amitriptyline for the treatment of irritable bowel syndrome with diarrhea: a multicenter, open-label, non-inferiority, randomized controlled study. Neurogastroenterol Motil. 2012;24(9):860-e398. View abstract.

Summary of Product Characteristics Stablo: Tianeptine. 2008. Available at: https://www.servier.com.ve/sites/default/files/spc-pil/spc-stablon.pdf

Vadachkoria D, Gabunia L, Gambashidze K, Pkhaladze N, Kuridze N. Addictive potential of Tianeptine – the threatening reality. Georgian Med News. 2009;(174):92-4. View abstract.

Voican CS, Corruble E, Naveau S, Perlemuter G. Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry. 2014;171(4):404-15. View abstract.

Wolfson P, Hoffmann DL. An investigation into the efficacy of Scutellaria lateriflora in healthy volunteers. Altern Ther Health Med 2003;9:74-8. View abstract.

Zini R, Morin D, Salvadori C, Tillement JP. The influence of various drugs on the binding of tianeptine to human plasma proteins. Int J Clin Pharmacol Ther Toxicol. 1991;29(2):64-6. View abstract.

Source: https://www.webmd.com/vitamins-supplements/ingredientmono-1587-tianeptine.aspx?activeIngredientId=1587&activeIngredientName=tianeptine

Tianeptine combination for partial or non‐response to selective serotonin re‐uptake inhibitor monotherapy

4 Uses of Tianeptine (Stablon) + Mechanisms & Side Effects

Volume 67, Issue 4 First published: 20 May 2013 https://doi.org/10.1111/pcn.12042

The goal of this study was to assess the efficacy and tolerability of tianeptine in combination with selective serotonin re‐uptake inhibitor (SSRI) in partial responders or non‐responders to SSRI monotherapy.

In this prospective, open‐label, 6‐week study, 150 patients with major depressive disorder who had previously not responded or partially responded to SSRI monotherapy were recruited. Tianeptine was given in combination with an SSRI for 6 weeks.

Significant improvements were observed in the mean scores of the Hamilton Depression Rating Scale (HDRS), Montgomery–Åsberg Depression Rating Scale (MADRS), and Clinical Global Impression–Severity (CGI‐S). The change in the mean HDRS, MADRS, and CGI‐S scores was significant from week 1.

The response rates were 64.7% (HDRS) and 68.7% (MADRS), and the remission rates were 34.0% (HDRS) and 42.0% (MADRS) at week 6. Thirty‐six patients (24.0%) reported adverse events that were determined by the investigator to be related to one of the study drugs.

The tianeptine and SSRI combination was generally well‐tolerated.

A combination strategy with tianeptine may be an effective and well‐tolerated tool for patients who have failed to adequately respond to SSRI monotherapy.

DESPITE THE ADVANCES in pharmacologic agents used for the treatment of depression in the last several decades, a large percentage of patients with major depressive disorder (MDD) fail to respond to treatment with antidepressants.

It is estimated that approximately 50% of the patients who receive first‐time treatment for MDD respond adequately to antidepressants, and as many as 30% of those treated for MDD do not benefit from a series of treatment trials.

1, 2 In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the relative efficacy and tolerability of various treatments for adult outpatients with non‐psychotic MDD was evaluated, and only 28–33% of patients achieved remission to open‐label monotherapy with citalopram.

3 Moreover, remission should be the goal of treatment because failure to achieve remission is associated with greater relapse rate, poorer functional outcome, and a worsening of long‐term prognosis. Full and persistent remission, however, is uncommon in acute depression trials.

4 In managing partial or non‐response to antidepressant treatment, various alternatives have been proposed,5-7 such as optimization of the posologic regimen, switching of the antidepressant or the addition of a new drug, which may be another antidepressant or a medication belonging to a different class, such as lithium, buspirone, pindolol, or thyroid hormone.

Despite these data, there is no consensus on the treatment of treatment‐resistant depression (TRD).

8 Hence, the choice of one or another of these alternatives depends on anecdotal experience and clinician knowledge.

9, 10 Although the number of published studies that have focused on combination treatment has increased markedly, the efficacy of combination treatment has not been established controlled trials.11, 12

Tianeptine is an antidepressant in clinical use that has drawn much attention because the effects of this compound argue against traditional monoaminergic hypotheses of depression. Tianeptine enhances the synaptic uptake of serotonin with minimal effects on norepinephrine and dopamine uptake.

13, 14 Tianeptine monotherapy has antidepressant and anxiolytic activities and good tolerability.

15-17 The involvement of glutamate in the mechanism of action of tianeptine is consistent with a well‐developed pre‐clinical literature demonstrating the key role of glutamate in the altered neuroplasticity that underlies the symptoms of depression.

18 But there have been no reports focusing on the combination of tianeptine with selective serotonin re‐uptake inhibitors (SSRI). Therefore, the aim of the present study was to assess the efficacy and tolerability of tianeptine as a combination strategy in patients who had not responded or partially responded to treatment with SSRI over a 6‐week period.

This was an open‐label, prospective, multicenter, 6‐week study that included 150 patients diagnosed with MDD according to DSM‐IV‐TR criteria who did not respond or partially responded to SSRI monotherapy. The study was conducted at 11 centers in Korea. Partial or non‐response was defined as a decrease in the score on the 17‐item Hamilton Depression Rating Scale (HDRS) to

Source: https://onlinelibrary.wiley.com/doi/full/10.1111/pcn.12042

Tox and Hound – Not For Human Consumption

4 Uses of Tianeptine (Stablon) + Mechanisms & Side Effects

by Dan Rusyniak

At my poison center we have seen an increasing number of a calls related to a drug I had never heard of – Tianeptine. Tianewhat? Yes, I thought the same. Although I had not heard of it, this is a drug that has been around since the 1970’s.

Synthesized in the 60’s by the French Society of Medical Research, it was approved in France and other European countries under the brand names of Stablon™ and Coaxil™.

It has never been approved in the US – woohoo FDA! It was a prescribed for the treatment of depression and anxiety, which makes sense since it has a similar tricyclic backbone to other well-known antidepressants (Figure modified from Wikipedia – woohoo structures!) But there was something weird about this antidepressant, it didn’t seem to work the others.

What was different? For one, it seemed to work a lot faster than most antidepressants. Patients reported improved symptoms within days instead of weeks. Another big difference is that it didn’t seem to work by blocking monoamine reuptake transporters. So, no SSRI or SNRI effects.

But patients d it nonetheless. It seemed to help with depression, reduced anxiety, improved PTSD symptoms, and relieved irritable bowel symptoms (that should have been a red flag right there. . .) Scientists were perplexed as to how this drug worked.

There was some evidence that it affected glutamate neurotransmission, and some that it worked on adenosine receptors. Or, maybe it worked through dopamine or by doing the opposite of SSRIs – enhancing the reuptake of serotonin?1,2 Nobody really seemed to know why this drug had antidepressant effects.

Then in 2014, researchers looking for the mechanism of the drugs action screened it for binding and activity at a variety of different receptors. What they found was that tianeptine was a mu agonist3; an effect that might actually be behind its antidepressant effect.

4 That’s right, tianeptine worked as an agonist at the same receptor in the brain as heroin, fentanyl, and oxycodone. No wonder patients d it.

While there had been a few reports of tianeptine abuse prior to 2014, it was after the publication that it was a mu agonist that cases really started to mount; yes drug dealers read the scientific literature.5,6 In 2016, a 27-yo-male overdosed on tianeptine with predictable mu opioid effects: small pupils, slow respirations, and coma (AJRCCM 2016).

Equally predictable, he woke up after 0.4 mg naloxone (he required another dose a few hours later). In 2017, a 36-year-old in Virginia injected tianeptine with similar results.7 I mentioned at the start that we have seen an increasing number of cases. All of these were similar to the case reports.

Patients using tianeptine as a drug of abuse present with a classic opioid toxidrome. And my poison center is not alone. Since 2014 there has been a dramatic increase in calls to poison centers regarding tianeptine.8,9 Tianeptine abusers who abruptly stop can also develop a withdrawal syndrome similar to opioid abstainers.

10 And, sadly, tianeptine abuse also seems to carry the same neonatal risks as opioids – there is a reported case of neonatal abstinence syndrome from tianeptine.11

What about the other TCA effects? Do patients who overdose on this get a prolonged QRS and QTc, do they seize, do they get anticholinergic? Those are great questions. I am so glad you asked. The short answer is NO, this has not been reported.

Although it shares a TCA structure, this drug appears not to have the sodium channel blocking effects (wide QRS), potassium channel blocking effects (prolonged QTc), anticholinergic effects, or proconvulsant effects.

It should be said with caution, however, that there are very few cases of overdose in the literature to date. It is possible that these effects could occur in larger doses.

Lastly, if this drug is not approved for use in the US, then how are people getting it? Are they flying to Europe to buy it? Don’t be silly, that is what the Internet is for. Yes, you can buy this stuff in large quantities on the internet. Just Google it.

For instance, you can get 10 grams (10,000 mg) of pure tianeptine for $85 by clicking a button on your computer (and no, I am not providing a link . . . shame on you!) The antidepressant dose is 12.5 mg twice daily. Most people seem to abuse it at doses of up to ~100mg (check out Reddit for more experiences).

So, for $85 you can get 100 doses. That is a really cheap high. And that scares the heck me.

What does this mean for all of you? Just that, as the opioid crisis continues, and people are looking for alternatives, we are ly to see an increasing number of overdoses from this drug. Treatment is the same as any opioid overdose. It responds to naloxone, but can require more than one dose.

So along with asking about IV use, prescription drugs and alternative agents with your opioid patients, make sure you ask about “tia” (its street name) or online nootropics. What is a nootropic? It’s just a stupid name for a drug that should not be sold on the Internet, but is.

Why is it legal to sell this stuff on the Internet? Because the companies that sell it make sure to state that the drug is not for human consumption. This circumvents the 1986 Federal Controlled Substance Analogue Enforcement Act and why Internet tianeptine is labeled “not human consumption”.

12 If only we would listen, then we wouldn’t need tianeptine to feel better again.

Wrong Way sign by NeONBRAND

Brink C, Harvey B, Brand L. Tianeptine: a novel atypical antidepressant that may provide new insights into the biomolecular basis of depression. Recent Pat CNS Drug Discov. 2006;1(1):29-41. [PubMed] Uzbay T. Tianeptine: potential influences on neuroplasticity and novel pharmacological effects. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(4):915-924. [PubMed] Gassaway M, Rives M, Kruegel A, Javitch J, Sames D. The atypical antidepressant and neurorestorative agent tianeptine is a μ-opioid receptor agonist. Transl Psychiatry. 2014;4:e411. [PubMed] Samuels B, Nautiyal K, Kruegel A, et al. The Behavioral Effects of the Antidepressant Tianeptine Require the Mu-Opioid Receptor. Neuropsychopharmacology. 2017;42(10):2052-2063. [PubMed] Leterme L, Singlan Y, Auclair V, Le B, Frimas V. [Misuse of tianeptine: five cases of abuse]. Ann Med Interne (Paris). 2003;154 Spec No 2:S58-63. [PubMed] Kisa C, Bulbul D, Aydemir C, Goka E. Is it possible to be dependent to Tianeptine, an antidepressant? A case report. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(3):776-778. [PubMed] Dempsey S, Poklis J, Sweat K, Cumpston K, Wolf C. Acute Toxicity From Intravenous Use of the Tricyclic Antidepressant Tianeptine. J Anal Toxicol. 2017;41(6):547-550. [PubMed] El Z, Schier J, Glidden E, et al. Characteristics of Tianeptine Exposures Reported to the National Poison Data System – United States, 2000-2017. MMWR Morb Mortal Wkly Rep. 2018;67(30):815-818. [PubMed] Marraffa J, Stork C, Hoffman R, Su M. Poison control center experience with tianeptine: an unregulated pharmaceutical product with potential for abuse. Clin Toxicol (Phila). May 2018:1-4. [PubMed] Vadachkoria D, Gabunia L, Gambashidze K, Pkhaladze N, Kuridze N. Addictive potential of Tianeptine – the threatening reality. Georgian Med News. 2009;(174):92-94. [PubMed] Bence C, Bonord A, Rebillard C, et al. Neonatal Abstinence Syndrome Following Tianeptine Dependence During Pregnancy. Pediatrics. 2016;137(1). [PubMed] Musselman M, Hampton J. “Not for human consumption”: a review of emerging designer drugs. Pharmacotherapy. 2014;34(7):745-757. [PubMed]

Tox & Hound. Tox and Hound – Not For Human Consumption. EMCrit Blog. Published on February 4, 2019. Accessed on March 15th 2020. Available at [https://emcrit.org/toxhound/not-for-human-consumption/ ].

Financial Disclosures

Unless otherwise noted at the top of the post, the speaker(s) and related parties have no relevant financial disclosures.

Source: https://emcrit.org/toxhound/not-for-human-consumption/

Acute Toxicity From Intravenous Use of the Tricyclic Antidepressant Tianeptine

4 Uses of Tianeptine (Stablon) + Mechanisms & Side Effects

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Tianeptine (7-[([3-chloro-6,11]-dihydro-6-methyldibenzo[c,f][1,2]thiazepin-11-yl) amino] heptanoic acid S, S dioxide) is a tricyclic compound prescribed as an antidepressant in European countries, but is not currently approved for use in the United States. There are few published case reports of tianeptine intoxication. Presented is the first case of acute toxicity associated with the intravenous use of tianeptine. A 36-year-old male intentionally injected tianeptine powder intravenously to “help him see into the future”. He became unresponsive and a bystander called emergency medical services. Upon arrival to the Emergency Department, excessive constriction of the pupils, sedation, and a respiratory rate of 6 respirations per minute (rpm) were noted. Blood and urine were collected ~2 h post admission. The patient's serum ethanol concentration was 133 mg/dL. His toxicity was successfully reversed with two doses of naloxone 0.4 mg IV. He was started on a naloxone infusion at 0.2 mg/h and discharged 13 h after admittance awake, alert and oriented. The patient's urine sample screened negative for common drugs of abuse and total tricyclic antidepressants. A high performance liquid chromatography tandem mass spectrometry method was developed and validated to quantify tianeptine in urine. The calibration range was 1–100 ng/mL with linear regression correlation (r2) of 0.9996 or greater. The limit of quantitation was administratively set at 1 ng/mL. The bias of the assay was determined to be within ±20% of the target value for each quality control specimen. The intra-day and inter-day precision did not exceed 15% coefficient of variation for each quality control specimen. Matrix effects, absolute recovery, carryover and specificity were also evaluated. The patient's tianeptine urine concentration was determined to be 2 ng/mL.

Tianeptine (7-[([3-chloro-6,11]-dihydro-6-methyldibenzo[c,f][1,2]thiazepin-11-yl) amino] heptanoic acid S, S dioxide) (Figure 1) is a tricyclic compound prescribed as an antidepressant in European countries, but is not currently approved for use in the United States (1).

It is currently being sold on certain websites in the United States as a nootropic or smart drug/cognitive enhancer. Tianeptine has a similar anxiolytic efficacy profile to other tricyclic antidepressants (TCAs), but it has differing mechanisms of action.

Instead of blocking the reuptake of serotonin or norepinephrine and thereby enhancing synaptic concentrations of these neurotransmitters, tianeptine's mechanism of action remains elusive (2).

Originally thought to be a serotonin reuptake enhancer, newer studies suggest that tianeptine's possible dual activation of the mu and delta opioid receptors is the initial molecular event responsible for tianeptine's modulation of the glutamatergic system (2, 3).

The activation of these receptors are also thought to be responsible for causing many of the known acute and chronic effects of this compound, including its antidepressant/anxiety actions (2, 3).

Tianeptine also differs from most TCAs in that it is not primarily metabolized by the hepatic cytochrome p450 system, indicating less lihood of drug–drug interactions (4). The major metabolic pathway is β-oxidation and the principal metabolites are propanoic acid sidechain (MC3, inactive metabolite) and pentanoic acid sidechain (MC5, active metabolite).

Less than 3% of the dose is excreted unchanged in urine and MC5 half-life is 7.2 h. (4–6). Previously published methods for the detection of tianeptine use high performance liquid chromatography with UV or fluorescence detection, and one case used liquid chromatography with photodiode array mass spectrometry detection (1, 7, 8). There are limited published case reports of tianeptine intoxication. A case study is presented of an acute toxicity associated with the intravenous use and the identification and quantitation of tianeptine in urine using a high performance liquid chromatography tandem mass spectrometry (HPLC–MS-MS) method.

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Case History

A 36-year-old male intentionally injected tianeptine powder dissolved in water intravenously to “help him see into the future”. He became unresponsive and a bystander called emergency medical services.

He was administered naloxone 1 mg IV due to suspected heroin use by medical personal and was transported to the Emergency Department (ED) around midnight. Upon arrival to the ED, excessive constriction of the pupils, sedation and a respiratory rate of 6 respirations per minute (rpm) were noted.

His toxicity was successfully reversed with two doses of naloxone 0.4 mg IV and he was placed on a naloxone infusion at 0.2 mg/h. Blood and urine were collected ~2 h post admission.

Initial vital signs included an electrocardiogram that gave a QRS 104 ms with QT of 461 ms. Initial serum laboratory results were sodium 140 mEq/L, potassium 3.4 mEq/L, bicarbonate 23 mg/dL, chloride 101 mEq/L, glucose 190 mg/dL, anion gap 16, AST 51 IU/L, ALT 69 IU/L. The patient's serum ethanol concentration was also determined to be 133 mg/dL.

The patient remained stable on the naloxone infusion, and was titrated off and discontinued 9 h after his arrival. He was observed for another 4 h, and at the time of discharge, he was alert, awake and oriented. Vital signs were blood pressure 94/43 mm Hg, heart rate 72 bpm, respiratory rate 12 rpm, pulse oximetry 98% on room air and temperature 36.5°C.

A urine specimen was sent to the Virginia Commonwealth University Health System FIRM laboratory for analysis of drugs of abuse and tianeptine. Serum was not forwarded to the FIRM laboratory for additional testing. The patient's urine sample screened negative for common drugs of abuse and total TCAs. The urine creatinine was determined to be 0.

11 mg/dL.

Reagents

The primary reference materials for tianeptine and its internal standard (ISTD) protriptyline were purchased from Cayman Chemical Company (Ann Arbor, MI) and Cerilliant Corporation (Round Rock, TX), respectively.

Protriptyline was chosen as the ISTD as it is used in the FIRM laboratory's TCA assay and in a published method for the detection of tianeptine in post-mortem samples (1).

Ammonium formate, acetonitrile, methanol and water were purchased from Fisher Scientific (Hanover Park, IL). Clean Screen FAStTM solid phase extraction (SPE) columns were purchased from United Chemical Technologies (Bristol, PA).

In-house ultrapure air was supplied to the UCT Positive Pressure Manifold. In-house certified drug-free urine provided the matrix for all prepared calibrators, and quality control (QC) specimens.

Sample preparation

Appropriate volumes of the tianeptine working solution prepared in methanol were added to urine to obtain a seven point calibration curve with a range of 1–100 ng/mL.

The following QC urine specimens were prepared and analyzed with the test specimen: limit of quantification quality control (LOQ), target concentration of 1 ng/mL; low control (LQC), target concentration of 3 ng/mL; medium control (MQC), target concentration of 30 ng/mL; and a high control (HQC), target concentration of 75 ng/mL.

A drug-free control (negative control) that did not contain tianeptine but did contain the ISTD, protriptyline, and a double negative control that did not contain tianeptine or ISTD were also run with each sample batch. All QC samples were stored at −20°C until analysis.

Specimen extraction

Tianeptine was isolated from urine by use of Clean Screen FAStTM SPE columns.

Briefly, to 200 μL aliquots of calibrators, QC specimens or patient samples, 20 μL of 100 ng/mL working solution in methanol of the ISTD for a total of 10 ng was added followed by the addition of 200 μL of 50:50 acetonitrile:distilled water. Samples were mixed using a vortex mixer.

The samples were transferred to Clean Screen FAStTM SPE columns and rapidly aspirated into auto-sampler vials with air in an UCT Positive Pressure Manifold. Vials were then capped and placed on the HPLC–MS-MS for analysis.

Instrumental analysis

The HPLC–MS-MS analysis of tianeptine was performed on a Waters Xevo TQD LC–MS-MS attached to an Acquity HPLC® System controlled by MassLynx software (Milford, MA). Chromatographic separation (Figure 2) was performed on an Allure Biphenyl 5 μm 100 × 2.5 mm2 column (Restek, Bellefonte, PA). The column temperature was 40°C and 10 µL was the sample injection volume.

The mobile phase consisted of A: water and 20 mM ammonium formate and B: methanol and 20 mM ammonium formate. The following gradient was used: 0.00–1.5 min at 95% A and 5% B, 1.5–3 min at 60% A and 40% B, 3–3.5 min at 100% B and then return to 95% A and 5% B at 3.6 min. The flow rate was 0.6 mL/min. The source temperature was set at 150°C with a capillary voltage of 3.00 kV.

The desolvation temperature was set at 600°C with a gas flow rate of 650 L/h. The cone flow rate was set at 100 L/h. The acquisition mode used was multiple reaction monitoring. The retention times (min), cone voltage (V), transition ions (m/z) and corresponding collection energies (eV) for the compounds can be found in Table I. The total run time for the analytical method was 4.0 min.

HPLC–MS-MS acquisition parameters

Analyte . RT (min) . Cone (V) . Transition ions (m/z) . CE (eV) . 
Tianetpine 2.95 40 437 > 292 15 
437 > 228 39 
Protriptyline 2.86 28 264 > 191 43 
264 > 154 19 

The analytical method was evaluated over five analytical runs on 5 separate days. For each day the linear regression correlation coefficients (r2) for the tianeptine calibration curve were 0.9996 or better.

The LOQ and the lower limit of detection (LOD) were administratively set at a concentration of 1 ng/mL. The LOD had a response at least ten times the signal to noise ratio of the response to drug-free pooled urine.

QC specimens were extracted and analyzed in triplicate for each analytical run and were used to determine the bias and precision.

The bias of the assay for the LOQ (1 ng/mL) ranged from 4 to 13%, at the LQC (3 ng/mL) from −15 to 9%, at the MQC (30 ng/mL) from −15 to 10%, and at the HQC (75 ng/mL) from 2 to −15%. The intra-day precision for the four QC specimens ranged between −2 and 9% with a coefficient of variation of

Source: https://academic.oup.com/jat/article/41/6/547/3852120

Tianeptine: Why has it not been classified as a narcotic in Spain? | Revista de Psiquiatría y Salud Mental (English Edition)

4 Uses of Tianeptine (Stablon) + Mechanisms & Side Effects

Tianeptine is a tricyclic antidepressant marketed in France since 1988 that has recently entered the Spanish market as a generic medicine.

1 It is a drug that is chemically similar to another amphetamine-type stimulant and antidepressant–amineptine, which was withdrawn from commercialisation in Spain (1999) and in other countries due to its addictive properties and adverse hepatic and cutaneous effects.

The structural similarity of tianeptine to amineptine and the cases of abuse and addiction reported for it have given rise to many doubts about its safety profile.2,3

In 2012, France's National Agency for Medicines and Health Products Safety (ANSM is the acronym in French), at the request of the Narcotic Drugs and Psychotropic Substances Committee, decided to re-evaluate the benefit–risk ratio of Stablon® (the brand name of tianeptine in France).

When that committee analysed the cases detected, the results permitted them to conclude that, in effect, there was a risk of abuse and addiction associated with its use.

4 The overall assessment of efficacy and safety led the French agency to decide that the benefit–risk ratio of tianeptine was favourable, but limited.

With respect to its benefits for health, the agency's conclusions were: “Given the available information, bearing in mind the therapeutic alternatives existing and the drug dependence problems identified, Stablon® does not present any benefit for the public health system”.4

As a consequence, tianeptine has been classified as a narcotic drug in France.

Since 3 September 2012,5 this antidepressant has been subject to the same prescription and supply restrictions as any other narcotic substance in List i, with a maximum length of prescription of 28 days.

Before that, it had been withdrawn from marketing in Georgia and included in the list of psychotropic substances in Russia, Ukraine and Armenia. Tianeptine is not authorised in several Anglo-Saxon countries.

At present, the safety of tianeptine is still a concern. The well-known journal Prescrire has repeatedly denounced that its benefit–risk ratio is unfavourable.

6 Previously, the conclusion reached by the re-evaluation the ANSM performed had been noted and the reason that the French authorities had allowed this drug to continue to be funded had been questioned.

7 Tianeptine is included in the list of drugs to avoid that this journal publishes every year.

8 Up till now, the European Pharmacovigilance Risk Assessment Committee has not carried out an assessment of tianeptine, but the data recorded in EudraVigilance (a European database of reports on presumed adverse reactions) confirm that there is a risk of abuse and addiction associated with its use. Up to October 2015, of the 563 cases reported, 125 included abuse and 27, addiction.9

In spite of these antecedents, to date no restrictions in the prescription or supply of tianeptine (Zinosal®) have been established in Spain.

Given that it is a generic medicinal product, the applicable regulation for obtaining its authorisation is much simpler and only requires bioequivalence studies against the reference compound.

It is not known whether the Spanish Agency of Medicines and Medical Devices has assessed the safety of this drug and whether it has taken the measures adopted in other countries into consideration.

In similar situations, when the evidence of efficacy and safety of a new drug is questionable, its promoters have used information of little scientific reliability to back up their sales strategies.

Among these are: (1) citing action mechanisms–described for laboratory animals–that distinguish the substance promoted from its competitors, but that are perhaps irrelevant for the indication sought and that sometimes do not distinguish it from the placebo; (2) using ambiguous terms that seem neuroscientific–such as “neuroplasticity” and “regulation of glutamatergic transmission”–to justify its sales without specifying either how or on which of the hundred of elements that comprise such processes the substance being promoted acts, nor what relevance such an action (if it exists) has on the disorder in human beings; and (3) directly extrapolating the effects observed on experimental animals submitted to stress to therapeutic effects in complex human syndromes.

It is the reader who must decide if these strategies are applicable to the molecule in question the information provided and, consequently, the one who must decide upon the credibility of the information. Of course, this is a logical process that should precede any modification of clinical practice.

In short, tianeptine is a drug new to Spain, but it is one that has raised numerous issues elsewhere for years. Compared to other antidepressants, it does not present any advantages with respect to either efficacy or convenience (administration 3 times a day).

In addition, its cost exceeds that of selective serotonin reuptake inhibitors considered to be first line treatments for depression.

The justifiable uncertainties about its safety reinforce the idea that aspects as crucial as its funding or its classification as a narcotic substance have to be put to consideration again.

The authors declare that this article has been written in agreement with the accepted standards on transparency with regard to the publication of scientific articles.10

Source: https://www.elsevier.es/en-revista-revista-psiquiatria-salud-mental-486-articulo-tianeptine-why-has-it-not-S2173505016300206

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