Discovered and patented by the French Society of Medical Research in the 1960s, Tianeptine has been an approved medication in France for decades and is marketed in a number of other European and Asian countries. It is not, however, currently available in the US and most countries in Europe.
Now, this may change: ATAI platform company Kures, Inc has initiated a program to study tianeptine analogs as atypical antidepressants.
An unusual antidepressant
Tianeptine is an unusual and interesting antidepressant from a pharmacological perspective. Tianeptine is a μ-opioid receptor (MOR) full agonist and full δ-opioid receptor (DOR) (with approximately 200-fold lower potency than MOR); researchers hypothesize that this MOR activity is required for the acute and chronic antidepressant effects of Tianeptine in mice. Additionally, Tianeptine’s primary metabolite also exhibits MOR activity, but with a much longer half-life.
While MOR activity also likely raises the abuse potential of Tianeptine, Tianeptine use at therapeutic doses does not seem to lead to the tolerance or withdrawal symptoms seen upon cessation of use of other opioids. When using doses that exceed the medically accepted range, however, there have been reports of respiratory depression, insomnia, and flu-like symptoms.
Effective antidepressant, anxiolytic, and analgesic (maybe)
Encouragingly, though Tianeptine shows comparable efficacy to common antidepressants like fluoxetine, its use is associated with significantly fewer side effects, including diminished cardiovascular, cognitive, psychomotor, and metabolic disturbances. Common side effects do include:
- Nausea
- Constipation
- Abdominal pain
- Headache
- Dizziness
- Changes in dreaming
Tianeptine shows evidence of efficacy in anxiety and substance use disorder.
We need to learn more
Yet, despite three decades of clinical investigation and demonstrated therapeutic efficacy across numerous indications, the mechanisms behind Tianeptine’s effects have eluded obvious explanations. And in a therapeutic space that has seen limited pharmacological innovation, an explanation of the mechanism of action of this compound is important, as it has the potential to lead to insights on the pathophysiology of depression itself as well as provide new therapeutic avenues.
Apart from the MOR activity mentioned above, some research also suggests that tianeptine indirectly modulates glutamate receptor activity and stimulates the release of brain-derived neurotrophic growth factor {BDNF), thereby enhancing neuroplasticity. Others hypothesize that Tianeptine exerts a protective effect against neuronal remodeling and acts on both the NMDA and AMPA receptors (associated with synaptic plasticity). A number of studies have also focused on Tianeptine’s modulation of the serotonin system, though collective research now largely dismisses this as the mechanism underlying tianeptine’s antidepressant effects.
Conclusion
The Kures team at ATAI is now focused on further elucidating the mechanisms underlying Tianeptine’s effects, with particular emphasis on the differentiation of Tianeptine’s effects on the MOR relative to standard opioids, to ensure that analogs are both effective and safe.
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