Tianeptine: A Nootropic In A League Of Its Own

Tianeptine Sodium

Tianeptine was originally synthesized at the Servier Institute in France in the 1980’s while researchers were seeking novel mood-brightening drugs that promised to be more effective and safer than tricyclics. Tianeptine is now also considered to be an adaptogenic nootropic and antidepressant which is increasingly used clinically around the world, and it has drawn considerable attention for a variety of surprising reasons. Foremost, this nootropic challenges the conventional “monoamine hypothesis” of mood disorders.

It is abundantly clear that the antidepressant and nootropic function of tianeptine, combined with its phenomenal tolerance when used appropriately, can be understood by examination of its idiosyncratic neurobiological properties. The involvement of glutamate in the mechanism of action of is consistent with a well-developed preclinical literature demonstrating the key function of glutamate in the mechanism of altered neuroplasticity that underlies the symptoms of depression. However, this classical understanding of tianeptine only scratches the surface of the collective insights that recent research has yielded.

This Umbrella Labs review will take you through some of the latest evidence of tianeptine’s diverse mechanisms of action, which provide key insights into its sought-after antidepressant and nootropic functions. Parallel lines of evidence now demonstrate that the actions of tianeptine cannot be solely attributed to the glutamatergic system (ie. the classical understanding of tianeptine) and therefore new hypotheses into how tianeptine may be useful in the treatment of depressive disorders are emergent.

It has long been known that tianeptine exhibits mood-brightening activity in both animals [1]–[3] and humans [4], [5]. The neurochemical properties of tianeptine vary from those of other tricyclic and non-tricyclic antidepressants. While classic tricyclic antidepressants and selective serotonin uptake inhibitors (SSRIs) block serotonin (ie. 5-HT) reuptake, tianeptine is able to selectively enhance 5-HT uptake into the forebrain in early studies [6]. However, several succeeding studies interestingly indicated that tianeptine did not modify the efficacy of serotonin neuron transmission [7]–[9]. Tianeptine might also have additional properties, e.g. effects on various neuronal systems other than any observed serotonin-modulating effects in neurons.

The potent efficacy and agreeable tolerability of tianeptine are clearly demonstrated in depressed patients [10]. Intriguingly, the monoamine hypothesis cannot explain these properties. In fact, the study tianeptine itself has contributed greatly to our collective realization of the complexity of the molecular origin of depression, and to the complexity of central mechanisms triggered by antidepressants, both old and new. Their variable mechanisms of action clearly challenge the hypothesis of an immediate modulation of monoamine axes to support the mood-brightening actions. Rather, tianeptine triggers a cascade of cellular adaptations that ultimately will lead to the antidepressant efficacy.

Among those sustained adaptations, increased phosphorylation of glutamate receptors subtypes in circumscribed brain region appears particularly interesting [11], [12]. Glutamate is the major excitatory neurotransmitter in the brain controlling synaptic excitability and plasticity in most brain circuits, including limbic pathways. Glutamatergic mechanisms are crucial in virtually all key functions perturbed in depressed states [13]–[18]. In addition, glutamate is an essential participant in many forms of adaptive plasticity, including learning and memory. The actions of tianeptine on the glutamatergic system offer new insights into how this compound may be useful in the treatment of depressive disorders.

There are a number of experimental studies demonstrating robust efficiency of tianeptine in preclinical models evaluating mood-brightening [5], [19]–[22]. Further, tianeptine opposes not only the mood-affective, but also the cognitive and structural changes that characterize depressed states—at least in preclinical models of mood disorders based on chronic stress [23]. Moreover, in line with these observations, a compelling body of clinical data has demonstrated that the clinical efficacy of tianeptine in the treatment of depression is at least equivalent to those of selective serotonin reuptake inhibitors (SSRIs) [24]–[31].

Tianeptine provides rapid relief of depressive symptoms as the analysis of Montgomery-Asberg Depression Rating Scale (MADRS) individual items shows that decreased ability of concentration and inner tension are more rapidly improved in tianeptine-treated than in fluoxetine-treated (ie. Prozac) [32]. Tianeptine is effective in reducing symptoms of depression in mild to moderate-to-severe major depression, whereas it alleviates anxious symptoms associated with depression without the need for concurrent anti-anxiety therapy [33]–[36].

The excellent tolerability profile of tianeptine is also undergirded by the fact that the mood-brightener lacks the sedative, cardiovascular and undesirable side effects on attention and memory of tricyclics [19], and shows a low propensity to provoke sexual dysfunction and nausea as compared to SSRIs [37], [38].

More recently, however, tianeptine research has focused on its direct effects especially in hippocampal area on central neuroplasticity. Some additional intriguing results imply that tianeptine may have some beneficial effects on central nervous system disorders other than mood disorders, thus broadening the scope of interest into this remarkable compound. Thus, current efforts seek to explore the effects of tianeptine more broadly on neuroplasticity and its possible benefits and discuss how this information relates to combating diseases of the central nervous system other than depression in the light of current literature.

Tianeptine & Neuroplasticity

Tianeptine shows enormous promise in promoting neuroplasticity, which invariably involves structural changes in the brain. While there is no change in hippocampal volume in young patients with less depressive episodes [39], there is a marked decrease in volume in depressive patients with recurrent, hard-to-treat, unipolar or long-lasting depression which indicates that depression is associated with structural changes. Those changes include cell loss and atrophy in important regions like the hippocampus (ie. memory center), as well as with direct changes in the synaptic cell-to-cell activities of neurochemicals, like monoamines. Due to this evidence, many unrelated attempts have been made to explain the mechanism of depression using changes in neuroplasticity, and the neuroplasticity hypothesis of depression and mood disorders was proposed. Crucially, this also enabled the evidence for tianeptine’s role in promoting neuroplasticity to be understood in the context of mood-brightening.

The neuroplasticity hypothesis explains depression via adaptogenic changes in the brain and remodeling in some critical areas, like the hippocampus, by means of these physical changes rather than the levels of neurotransmitters released into the synaptic cell-to-cell spaces, or their metabolism and their effects on neurotransmitter receptors. This remodeling occurs due to a change in brain neuroplasticity. Besides monoamines like noradrenaline and 5-HT (ie. serotonin), changes in the amounts of several excitatory neurotransmitters, like glutamate, are also associated with remodeling-related functional impairment. Remember that that glutamate signaling was among the first routes proposed for tianeptine’s mechanism of action. Antidepressant treatment primarily reverses this remodeling, in addition to stabilizing the impaired monoaminergic balance.

During chronic antidepressant treatment, a normalized state of neuronal structure and synapses is maintained due to the neuroprotective effect [40]. Some physical changes may appear in the whole neuron or partially due to neuroplasticity, like the dendrite. In addition, new neuron formation, changes in neurons’ resistance to negative factors, e.g. chronic severe stress and an increase or decrease in synaptic activity, may appear. Changes in the central nervous system associated with neuroplastic responses are seen.

Learning and memory are considered to be canonical manifestations of neuroplasticity response, so examining the relationship between stress and long-term potentiation, and the effects of mood-brighteners on acquisition and recall of new information, is well supported. Intriguingly, when tianeptine is administered several hours after stress exposure, it overcomes the block of hippocampal long-term potentiation induction by induced stress at a dose level that did not affect LTP in non-stressed participants [41]. This finding is consistent with other studies showing that tianeptine can reverse stress-contingent anxiety when administered after the stress [42]. Taken together, the improvement in memory function by tianeptine may represent the partial restoration of normal functional neuroplasticity within hippocampal and cortical neuron networks induced by tianeptine via acceleration of neural adaptive mechanisms.

Tianeptine & Cognitive Enhancement

Cognitive deficits, such as an impairment of attention, memory and problem-solving, have often been reported in patients with mood disorders [43]. Cognitive deficits and memory impairments in patients with mood disorders may arise via disruption of the hypothalamic–pituitary–adrenal axis through hippocampal brain volume loss and changes in the amygdala. The degree of hippocampal shrinkage reported in certain preclinical models may partly underlie some of cognitive deficits that accompany major mood disorders. Conversely, any prevention or restoration of these morphological changes in the hippocampus should occur in parallel to cognitive enhancing effects. Accordingly, tianeptine has particularly favorable effects on cognitive functions and the positive effect of tianeptine may be mediated through its upregulation of neurogenesis. 

Mechanistically, tianeptine is able to prevent and reverse stress-induced glucocorticoid-mediated neuron remodeling in CA3 pyramidal neurons in the hippocampus region of the brain [44], [45].  Moreover, tianeptine can mitigate stress-induced increases in dendritic neuron dysfunction and improper branching in the amygdala [46]. Tianeptine blocks the unwanted dendritic remodeling caused by stress or glucocorticoids, blocks stress-induced impairments of spatial memory performance [47], [48], and even prevents the deleterious effects of chronic alcohol exposure [49].

Tianeptine for Anxiety Reduction

There is considerable evidence for adaptogenic anxiety reduction by tianeptine. When administered acutely, tianeptine counteracts the anxiety-inducing effect of benzodiazepine and alcohol withdrawal in the social interaction test, whereas no effects are observed in the stress-induced hyperthermia or social interaction test [50], [51]. More recent data also provide some convergence on the potential efficacy of tianeptine in terms of its action on the amygdala (ie. fear center of the brain). One research group demonstrated that chronic use of tianeptine prevented stress-induced potentiation of aggressive conflicts, such that there was an interaction between chronic stress and tianeptine treatment over the course of the entire study.

Tianeptine also significantly reduced the incidence of aggressive conflicts in stressed and unstressed animals during periods when aggression is high. Moreover, another group reported that chronic tianeptine given for 21 days before training can reduce fear-conditioning (ie. a strong form of emotional learning) as much as chronic SSRI treatments [52]. Intriguingly, in this context tianeptine did not show anxiety-inducing effects after acute administration, yet acute SSRI treatment did.

Tianeptine Sodium vs Tianeptine Sulfate

Among the preeminent questions for those who wish to study the effects of tianeptine is the divergence in subjective effects between two forms of tianeptine: sodium vs sulfate. There are important biochemical considerations that underlie the predictable differences in how patients respond to each formulation. 

For use as a nootropic, the tianeptine sulfate formulation has distinct advantages. First, it is more bioavailable and possess a longer half-life. However, tianeptine sulfate is not water soluble and thus must be consumed with dietary fat in order to promote absorption.

For use as an acute mood-brightener, the tianeptine sodium formulation possesses stronger short-term potency in euphoric potentiation. However, this is not altogether beneficial if long-term use is desired, as more rapid tolerance develops at high doses in this context [53]. Tianeptine sodium is also water soluble and thus compatible with mixing into beverages for added convenience. 


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