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Nootropics Tianeptine

Tianeptine Abuse, Safety and Withdrawal Syndrome

Tianeptine is a tricyclic antidepressant whose mechanism of action has been puzzling scientists for years. In fact, unlike most antidepressants, Tianeptine does not target monoamines (serotonin, norepinephrine, dopamine). It is, therefore, a very effective solution for individuals suffering from depression and anxiety, especially those who are afraid of the side effects of currently available antidepressants.

A few years ago, a new mechanism of action has been unveiled that is now thought to mediate the beneficial effects of Tianeptine on depression and cognition: mu-opioid receptor agonism. So what does this mean for Tianeptine users? Is it time to starting worrying about potential opiate-like addiction and withdrawal symptoms? Let’s find out.

1985-2009: Discovery & 5-HT theory

Tianeptine was discovered by French researchers Antoine Deslandes and Michael Spedding in the 1980s. We do not know exactly when that happened, but the first study that mentions “Tianeptine” was published in 1986.[1]

The animal studies carried in the late-90s to early 2000s showed that Tianeptine may be part of a new class of drugs named serotonin reuptake enhancers (SRE). In short, these drugs enhance serotonin uptake, instead of inhibiting it, thus reducing the overall amount of serotonin (5-HT) in the synapse. Serotonin reuptake enhancers, therefore, have the opposite mechanism of action of SSRIs drugs like Prozac and Zoloft.

Monoamines

It is important to point out that, until a couple of years ago, depression was thought to be the result of a depletion of monoamine neurotransmitters[2] [3], and, in particular, serotonin. This is known as the monoamine theory of depression.

However, when experimenting with pharmaceutical agents that are known to cause monoamine depletion, researchers have failed to generate (or worsen) depression in healthy subjects.[4] In addition, the MOA of drugs like Opipramol, — and Tianeptine itself —, is unrelated to monoamines, and they still have been found an antidepressant effect. Nowadays the monoamine theory is no longer the ruling paradigm in depression research, and depression is thought to be a consequence of several different neurotransmitters and brain changes.

So the theory that Tianeptine is an SRE may have been influenced by the technical limitations of the time, as well as the popular theory that antidepressant work by “fixing” a monoamine imbalance. But that was going to change with two new discoveries.

2010-2014: New findings

A study published in 2010[5], first mentioned the fact that Tianeptine’s antidepressant effects may have nothing to do with serotonin and other monoamines. The researchers thought, instead, that the antidepressant effects may be due to glutamateric modulation[6]. Tianeptine, in fact, has shown to be neuroprotective and to promote neurogenesis, as well as reduce the release of glutamate, a neurotransmitter that is thought to be implicated in schizophrenia, anxiety, depression, psychosis and bipolar disorder.[7]

However, the real surprise came four years later, when a study[8] showed that Tianeptine activates mu-opioid receptors[9], the same receptors targeted by frequently abused opioid drugs such as morphine, heroin and oxycodone.

Abuse of Tianeptine

Tianeptine is a relatively safe drug. However, like many pharmaceutical drugs, it can be used for purely recreational purposes.

Many heroin users in Russia, in fact, were abusing Coaxil (one of Tianeptine brand names), long before scientific research proved that it works as an opioid agonist. An article, published in the newspaper “Moscow Komsomolec” in 2008, first raised the alarm about Tianeptine abuse in Russia. This was the about the same time that Krokodil — a cheap homemade heroin substitute[10] that it is famously known to destroy body tissues[11] and cause death in a manner of weeks — hit Russia and neighboring countries, when the former USSR country started a major crackdown on heroin production and trafficking.

The drug market has changed completely in past few years in Moscow. “The time of synthetics has come!”-say drug users.

Everything was clear before: heroin, cannabis, “clubbing” pills. Today the main drugs are so-called pharmaceutical drugs: drugs that cannot be sold without a prescription, but nevertheless they are sold in big quantities through dishonest pharmacists. The most widely-spread and most dangerous one is antidepressant Coaxil. Its affordable and life-threatening if injected intravenously. […]

-If you watch the process of making coaxil substance by drug users you will see quite clearly why. They crush the pills and dissolve them in water, very often it is tap water. Then they get a disperse substance and it’s particles cause damage to a vessel and build a thrombus (clot) inside it. The thrombus starts growing rapidly. The thrombus itself is a very good environment for various microorganisms and that provokes purulent complications. If a drug user by chance injects coaxil into an artery –then that develops thrombus not only in a big vessel, but even in small ones, called arterioles. In these cases gangrene starts very quickly. As a rule complications come in the first six months of using the drug, sometimes even sooner. Very often “neophytes of coaxil” slip up at first injection. The most careful and accurate can last maximum for a year.

As a consequence, Tianeptine is now a controlled substance in Russia and France.

Tianeptine is not the only drug of the tricyclic family of antidepressants that has been banned. Amineptine – a drug closely related to Tianeptine – was banned years ago due to liver damage and frequent abuse and addiction among patients who were prescribed it as a depression treatment. I would like to point out that, unlike Tianeptine, Amineptine is also a dopamine reuptake inhibitor, so it may have a higher recreational value compared to Tianeptine.

Safety of Tianeptine

Tianeptine is safe at the recommended dose (12.5 mg three times a day) and users may benefit from the neurogenic, neuroprotective and antidepressant properties of the drug without having to worry about addiction and withdrawal symptoms.

That said, Tianeptine is not the kind of nootropic that you take every day and “forget about it.” It is still a very potent compound, with multiple molecular targets, and I can easily imagine how some people — particularly those with a history of drug abuse — may be tempted to binge on it, in an attempt to emulate the effects of prescription painkillers.

It is, therefore, a good idea to cycle it with other antidepressant nootropics, like Coluracetam or NSI-189. Tianeptine has instant mood elevating properties, and some users report tolerance to the positive effects after repeated administration, so it may be a good idea to use Tianeptine as needed instead of taking it daily for extended periods of time.

Withdrawal Symptoms

Tianeptine withdrawal is characterized by high level of anxiety and excitability[12] akin to withdrawal from opioids. The severity of the symptoms is directly influenced by the dosage used and the length of time that the drug has been taken.

A Reddit user reported full-blown withdrawal syndrome akin to opiate withdrawal when using Tianeptine at an incredible dose of 250 mg to 1 gram (!) of Tianeptine sodium a day. You can find more details about his experience here. However, as said before, it’s no wonder that the user had those symptoms when talking about that sort of amount of drug in their bodies. In my experience, Kratom is an overall better opioid replacement as far as safety and risk of addiction.

If you are going to use Tianeptine long-term, we suggest Tianeptine Sulfate or Free Acid. The slightly longer duration of effect of these compounds means a lower risk of addiction and withdrawals (though it has not been scientifically tested).

Conclusion

In the end, I feel that Tianeptine is an incredible drug, one that can be truly life-changing for those who suffer from depression and anxiety. I discourage anyone from trying Tianeptine if they are just looking for a “legal high”.

It would be a shame if the drug were banned because a few subjects exploiting the legal status of this amazing substance in search of a poor man’s high.

That’s all for now — for any question or doubts leave us a comment; and if you have enjoyed the article consider following our Facebook and Twitter age.

References   [ + ]

Categories
Cognitive Health Memantine Nootropics Recovery

Can Nootropics Help With Drug Abuse and Addiction?

In recent years, evidence has compiled suggesting a common pathologic mechanism underlying addictive behaviours of several substances. Dysregulation of glutamatergic neurotransmission within the prefrontal cortex (PFC) and nucleus accumbens (NA) appears to predispose to a higher tendency towards drug-seeking behaviour.

Thus far, this mechanism has been associated with the addiction potential of cocaine, heroin, nicotine, cannabis, & alcohol, with possible implications for other substances and even non-drug-related compulsive habits such as pathological gambling. Discovery of this shared pathology has led to the investigation of the potential application of existing agents, such as Memantine and n-acetylcysteine.

Could nootropics targeting elements in this key glutamatergic circuit reduce symptoms and complications of substance use disorders?

Glutamate Spillover

«Glutamate spillover» refers to the pathologic cascade in brain chemistry that occurs with chronic abuse of certain substances that results in reinforcement of the behaviour[1].

McClure EA, Gipson CD, Malcolm RJ, Kalivas PW, Gray KM. Potential role of N-acetylcysteine in the management of substance use disorders. CNS Drugs. 2014 02;28(2):95-106.

Prolonged exposure to substances of abuse leads to several maladaptive changes in the glutamatergic PFC-NA pathway, specifically:

  • Downregulation of glial glutamate transporter-1 (GLT1) expression in the nucleus accumbens. By removing glutamate from the extrasynaptic space, GLT1 prevents inappropriate excitatory stimulation due to an accumulation of the excitatory neurotransmitter.
  • Decreased ability of presynaptic metabotropic glutamate receptor 2 (mGluR2) to inhibit glutamate release. In normal physiology, mGluR2 autoreceptors manage a feedback loop where increased extracellular glutamate levels trigger a reduction in the presynaptic release of glutamate. This auto-regulatory mechanism also serves to prevent an extracellular accumulation of glutamate.

When glutamate spillover within the non-synaptic extracellular space does occur as a result of the combination of these processes, the following sequelae are may manifest:

  • Stimulation of postsynaptic mGluR5, AMPA and NMDA receptors.
  • Upregulation of AMPA and NMDA receptors (increased synaptic plasticity).
  • Stimulation of extrasynaptic glutamate receptors may also occur.

Increased excitatory tone due to these two processes culminates in impaired inhibition with regard to drug-seeking behaviour as well as increased risk of relapse. Furthermore, persistently elevated glutamatergic tone may lead to neurotoxicity secondary to excessive Ca2+ ion influx. This pathology has also been associated in neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s disease.

n-acetylcysteine

n-acetylcysteine (NAC) is a cysteine precursor that has a long history of use for indications ranging from bronchopulmonary disorders to paracetamol overdose. It produces many beneficial effects through a variety of mechanisms ranging from supporting antioxidant processes to suppressing over-reactive immune responses to inhibiting apoptosis. NAC’s glutamatergic modulation, however, is of key interest in managing substance use disorders[2].

Brown RM, Kupchik YM, Kalivas PW. The story of glutamate in drug addiction & of n-acetylcysteine as a potential pharmacotherapy. JAMA Psychiatry. 2013 09;70(9):895-7.

NAC is converted to L-cysteine in vivo, which enhances the activity of the cysteine/glutamate exchange transporter positioned near the pre-synaptic terminal. This increases the concentration of extracellular glutamate, resulting in increased tonic activation of pre-synaptic mGluR2 autoreceptors. This causes a subsequent decrease in glutamate release. NAC also increases expression of GLT1 and the cysteine/glutamate exchange transporter, promoting the removal of glutamate from the extrasynaptic space and ‹putting it back› in the pre-synaptic area. These effects in concert have been shown to mitigate the complications from glutamate spillover, & have been tested in several small trials with promising results.

  • When administered in patients with a history of cocaine addiction, NAC was shown to decrease self-reported cocaine use within the 28 days of treatment (mean 8.1 days out of 28 days before treatment & 1.1 days during treatment, p = 0.001)[3], desire to use cocaine (F = 5.07; df = 1,13; p = 0.05), & response to cocaine cues (F = 4.79, df = 1,13, p = 0.05)[4]. A magnetic resonance spectroscopy study confirmed elevated glutamate levels in the dorsal anterior cingulate cortex of cocaine users when compared against non-users (t(7) = 3.08, p = 0.02), and also showed a reduction 1 hour after a single 2.4 g dose of NAC[5].
  • With regard to cannabis, 2.4 g/day NAC decreased craving in one 4-week open label study of 24 patients[6]; in a double-blind placebo-controlled trial, subjects given 2.4 g/day NAC in addition to counselling were 2.4 times more likely to test negative on urinalysis (95%CI 1.1 to 5.2) but there was no difference in number of reported days of cannabis use[7].

The dosage for managing consequences of substance use disorders in trials ranged from 1.2 to 2.4 g by mouth daily. Benefits on neurochemistry may occur with single doses although significant alterations in behaviour may take days to weeks. The pharmacodynamic effect also depends upon the history of substance use and individual predisposition to addictive behaviour.

NAC is significantly protein-bound (80%). It is metabolised in the liver via non-CYP450 pathways. NAC and its metabolites are primarily eliminated in the urine, with a half-life of 5.6 hours in adults[8].

NAC is generally well-tolerated. Nausea, vomiting, rash, and fever have been reported.

Memantine

Memantine (Namenda®) is an uncompetitive NMDA receptor antagonist most commonly used in the management of moderate-to-severe Alzheimer’s disease. In addition to its glutamatergic modulation, memantine also acts as an agonist at the D2 and nicotinic acetylcholinergic receptors (nAChR). Memantine binds and inhibits NMDA receptors with low-to-moderate affinity, most effectively in states of excess glutamatergic activity (such as in substance use disorder). By blocking NMDA receptors, memantine decreases glutamatergic tone[9].

Clapp P, Bhave SV, Hoffman PL. How adaptation of the brain to alcohol leads to dependence: a pharmacological perspective. Alcohol Res Health. 2008;31(4):310-39.
Neurochemical effects of alcohol intoxication in various contexts.

Upregulation of NMDA receptors has been observed with chronic alcohol consumption. Abrupt discontinuation of alcohol removes GABAergic suppression, resulting in the characteristic acute sequelae of alcohol withdrawal (symptoms of excitotoxicity): seizures, hallucinations, tachycardia, and shock. By inhibiting these receptors, memantine may theoretically attenuate symptoms of alcohol withdrawal.

  • In one RCT of 18 moderate alcohol drinkers (10-30 drinks/week), 30 mg/day memantine significantly decreased alcohol craving before alcohol consumption in comparison to 15 mg/day and placebo[10]. Another placebo-controlled RCT with 10-40 mg/day showed no difference[11].
  • A subsequent study of 38 patients utilising 20-40 mg/day memantine showed dose-dependent reductions in cue-induced craving[12].
  • In another RCT of 127 male patients undergoing alcohol withdrawal, administration of 10 mg memantine three times a day decreased apparent withdrawal symptom severity, dysphoria, and need for diazepam[13].
  • Administration of 60 mg significantly alleviated subjectively-rated symptoms of naloxone-induced opioid withdrawal in 8 heroin-dependent patients[14].
  • In a study of 67 heroin-dependent subjects, 10-30 mg/day memantine significantly reduced heroin craving, depression, and state & trait anxiety compared to placebo after 3 weeks of use. A separate treatment arm using amitriptyline 75 mg/day achieved similar results but with a higher incidence of side effects and a higher dropout rate[15].
  • Clinical data on application in cocaine[16],[17] and nicotine abuse[18] is less promising.

The dosage for mitigating substance use disorders in trials ranged from 5 to 60 mg, with 30 mg by mouth once daily showing the best effects for alcohol abuse and 30 to 60 mg by mouth once daily shown to be most effective in limited trials for opioid dependence. Safety is best characterised at doses up to 30 mg, as this dosage is used in Alzheimer’s disease. Memantine is typically initiated at 5 mg daily then titrated by 5 mg per week up to the goal dose (30 to 60 mg depending upon the indication).

Memantine undergoes favourable non-hepatic metabolism; its metabolites are minimally active. Individuals with a history of kidney disease should consult a doctor or pharmacist before use, as memantine undergoes significant renal elimination (74% is excreted in the urine). The half-life of memantine ranges from 60-80 hours.

The most common side effects noted at therapeutic doses higher than 7 mg/day are dizziness, headache, confusion, anxiety; increased blood pressure; cough; & constipation[19].

Summary

  • Disrupted regulation of glutamatergic pathways in the prefrontal cortex-nucleus accumbent pathway has been implicated as an underlying pathology among several substance use disorders, including cocaine, alcohol, and opioid dependence.
  • Therapies such as n-acetylcysteine (NAC) and memantine have demonstrated efficacy in attenuating the symptoms of some of these disorders in small trials.

References   [ + ]

1. McClure EA, Gipson CD, Malcolm RJ, Kalivas PW, Gray KM. Potential role of n-acetylcysteine in the management of substance use disorders. CNS Drugs. 2014 02;28(2):95-106.
2. Brown RM, Kupchik YM, Kalivas PW. The story of glutamate in drug addiction & of n-acetylcysteine as a potential pharmacotherapy. JAMA Psychiatry. 2013 09;70(9):895-7.
3. Mardikian PN, LaRowe SD, Hedden S, Kalivas PW, Malcolm RJ. An open-label trial of n-acetylcysteine for the treatment of cocaine dependence: a pilot study. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:389-94.
4. LaRowe SD, Myrick H, Hedden S, Mardikian P, Saladin M, McRae A, et al. Is cocaine desire reduced by n-acetylcysteine? Am J Psychiatry. 2007;164:1115-7.
5. Schmaal L, Veltman DJ, Nederveen A,van den Brink W, Goudriaan AE. n-acetylcysteine normalizes glutamate levels in cocaine- dependent patients: a randomized crossover magnetic resonance spectroscopy study. Neuropsychopharmacology. 2012;37:2143-52.
6. Gray KM, Watson NL, Carpenter MJ, LaRowe SD. n-acetylcysteine (NAC) in young marijuana users: an open-label pilot study. Am J Addict. 2010;19:187-9.
7. Gray KM, Carpenter MJ, Baker NL, DeSantis SM, Kryway E, Hartwell KJ, et al. A double-blind randomized controlled trial of n-acetylcysteine in cannabis-dependent adolescents. Am J Psychiatry. 2012;169:805-12.
8. Medscape® 5.1.2, (electronic version). Reuters Health Information, New York, New York.
9. Zdanys K, Tampi RR. A systematic review of off-label uses of memantine for psychiatric disorders. Prog Neuro-Psychopharmacol Biol Psychiatry. 2008 8/1;32(6):1362-74.
10. Bisaga A, Evans SM. Acute effects of memantine in combination with alcohol in moderate drinkers. Psychopharmacology 2004;172:16–24.
11. Evans SM, Levin FR, Brooks DJ, Garawi F. A pilot double-blind treatment trial of memantine for alcohol dependence. Alcoholism: Clin Exp Res 2007;31(5):775–82.
12. Krupitsky EM, Neznanova O, Masalov D, Burakov AM, Didenko T, Romanova T, et al. Effect of memantine on cue-induced alcohol craving in recovering alcohol-dependent patients. Am J Psychiatry 2007a;164(3):519–23.
13. Krupitsky EM, Rudenko AA, Burakov AM, Slavina TY, Grinenko AA, Pittman B, et al. Antiglutamatergic strategies for ethanol detoxification: comparison with placebo & diazepam. Alcoholism: Clin Exp Res 2007b;31(4):604–11.
14. Bisaga A, Comer SD, Ward AS, Popik P, Kleber HD, Fischman MW. The NMDA antagonist memantine attenuates the expression of opioid physical dependence in humans. Psychopharmacology 2001(157):1–10.
15. Krupitsky EM, Masalov DV, Burakov AM, Didenko TY, Romanova TN, Bespalov AY, et al. A pilot study of memantine effects on protracted withdrawal (syndrome of anhedonia) in heroin addicts. Addict Disord Treat 2002;1(4):143–6.
16. Collins ED, Vosburg SK, Ward AS, Haney M, Foltin RW. Memantine increases cardiovascular but not behavioral effects of cocaine in methadone-maintained humans. Pharmacol Biochem Behav 2006;83(1):47–55.
17. Collins ED, Ward AS, McDowell DM, Foltin RW, Fischman MW. The effects of memantine on the subjective, reinforcing, & cardiovascular effects of cocaine in humans. Behav Pharmacol 1998;9(7):587–98.
18. Thuerauf N, Lunkenheimer J, Lunkenheimer B, Sperling W, Bleich S, Schlabeck M, et al. Memantine fails to facilitate partial cigarette deprivation in smokers—no role of memantine in the treatment of nicotine dependency? J Neural Transm 2007;114:351–7.
19. Micromedex® 1.0 (Healthcare Series), (electronic version). Truven Health Analytics, Greenwood Village, Colorado, U.S.A. Available at: http://www.micromedexsolutions.com/