Pharmaceutical Approach

Brain serotonin synthesis amplification

Evecxia seeks to leverage the therapeutic potential of serotonin synthesis amplification - building a more powerful endogenous brain serotonin system. Serotonin synthesis amplification is a unique mode of serotonin system modulation, distinct from targeting serotonin transporters (e.g., SSRIs/SNRIs) or receptors (e.g., psychedelics). Serotonin synthesis amplification is not utilized by any FDA/EMA-approved drugs; yet, convergent clinical trial evidence from the literature points to broad therapeutic potential across psychiatric and neurological disorders.

5-hydroxytryptophan (5-HTP) is the natural, rate-limiting precursor of serotonin

5-HTP is the natural endogenous immediate precursor of serotonin. In the body, 5-HTP is produced intracellularly from dietary tryptophan. 5-HTP synthesis is the rate-limiting step in serotonin synthesis. Endogenous 5-HTP levels are therefore low, as the 5-HTP is quickly converted to serotonin.


Serotonin, aka 5-hydroxytryptamine (5-HT), is a neurotransmitter in the brain. Serotonin released from the pre-synaptic nerve terminal into the extracellular synaptic space is the “active” serotonin, often referred to as extracellular serotonin. Extracellular serotonin binds to post-synaptic serotonin receptors, which elicits the serotonin neurotransmission. Hence, elevated extracellular serotonin equals stronger serotonin neurotransmission. In humans and primates, among several functions, serotonin neurotransmission promotes mood, sociability, and cognitive flexibility, and attenuates aggression and impulsivity.

Exogenous 5-HTP And Brain Serotonin

5-HTP can also be administered directly to the body. Such “exogenous” 5-HTP for human use is usually botanical, extracted from the seeds of the African shrub Griffonia Simplicifolia. EVX-101 and EVX-301 contain botanical 5-HTP. Numerous human and animal studies demonstrate that 5-HTP administered to the body, orally or intravenously, reaches the brain and is converted to serotonin by serotonergic neurons. At suffcient levels, exogenous 5-HTP will elevate extracellular serotonin and strengthen serotonin neurotransmission, as demonstrated by multiple biomarker and brain imaging studies. Thus,
exogenously administered 5-HTP can amplify brain serotonin levels and strengthen serotonin neurotransmission.

5-HTP Human Safety

5-HTP has a remarkably good human safety record. 5-HTP has been administered to thousands of human subjects in hundreds of studies since the 1950s. Many studies administered high (>1 gram/day) 5-HTP doses, often for long durations (months, years), and often with other drugs, including SSRI or SSRI-like drugs. 5-HTP has not been found to cause any severe side effects, human disease, or deaths.


Recently, Evecxia completed a Phase 1 SAD/MAD trial for EVX-101 and a Phase 1 SAD trial for EVX-301, both drug candidates administered to healthy volunteers concurrently treated with a first-line antidepressant (escitalopram, an SSRI). Both trials reported excellent safety profiles.

5-HTP Therapy For Human Diseases – Promise & Limitations

5-HTP has shown therapeutic potential in a wide spectrum of human disorders, most notably depression, but also in obesity, myoclonus, movement disorders, pain disorders, and some rare diseases. Despite these promising findings, no 5-HTP drug candidate has ever entered regulatory-grade clinical trials. No FDA- or EMA-approved drug product exists. Likely, this is because native 5-HTP is impractical as a drug treatment.


While 5-HTP appears to have good safety, the tolerability of native, immediate release, 5-HTP is often poor. 5-HTP is rapidly absorbed from the intestine. This can cause transient 5-HTP spikes and hence serotonin spikes and bothersome adverse events, manifest usually as nausea, vomiting, and diarrhea. Such CMax-effects are common for fast-absorbed compounds. Conversely, as native 5-HTP has a short half-life—2-3h in humans—blood 5-HTP levels drop off between administrations, necessitating three or more daily doses to maintain a just reasonably sustained serotonin amplifying effect. Further, native 5-HTP, when taken orally, is mostly degraded by the intestine. Hence, normally only a fraction of orally ingested 5-HTP reaches the blood stream and the brain. Thus, as a drug treatment, native 5-HTP is limited by the triple pharmacokinetic shortcomings of fast absorption, short half-life, and low bioavailability. Moreover, Evecxia discovered that 5-HTP has a narrow absorption window restricted to the upper intestine. A novel drug delivery technology that overcame the triple pharmacokinetic shortcomings of 5-HTP could, for the first time, realize the full therapeutic potential of 5-HTP and serotonin synthesis amplification, in depression, and in other mental and central nervous system disorders. EVX-101 is one such drug candidate.

Therapeutic Rationale

Sustained Amplification Of Brain Endogenous Serotonin By EVX-101

Dosing with native 5-HTP is associated with poor tolerability alternating with loss of pharmacological effect. These shortcomings, along with poor absorption, makes native 5-HTP a poor drug. The EVX pharmaceutical hypothesis posits that if the 5-HTP plasma spikes and valleys are eliminated or minimized, and 5-HTP's absorption enhanced, the ability of 5-HTP to amplify brain serotonin synthesis will be transformatively improved. Research by Evecxia’s founders Drs. Jacobsen and Caron confirmed this hypothesis in translational pre-clinical models.

Mechanism Of Action Of EVX-101 Vs First-Line Antidepressants

First-line antidepressant are the selective serotonin reuptake inhibitors (SSRIs) and the serotonin norepinephrine reuptake inhibitors (SNRIs). First-line antidepressants treat depression, as well as anxiety disorders, by elevating extracellular serotonin in the frontal cortex, which activates post-synaptic serotonin receptors, enhances serotonin neurotransmission in the frontal cortex, and causes the antidepressant effect. First-line antidepressants work predominantly by blocking the serotonin reuptake transporter, one of several regulators of extracellular serotonin. However, human frontal cortex levels of serotonin transporters are low. In human brain imaging studies SSRIs elevate extracellular serotonin modesty and inconsistently across subjects, and with a delay. The first-line antidepressants’ inherently limited pharmacology may contribute to the generally modest, inconsistent, and delayed therapeutic effect of first-line antidepressants.


In contrast, EVX-101 amplifies endogenous serotonin synthesis and levels, independently of the serotonin transporter, thereby amplifying dynamic serotonin neurotransmission.

Adjunctive EVX-101 Synergizes With First-Line Antidepressants To Enhance The Serotonergic Therapeutic Mechanism

"Adjunctive" means adding-on a second treatment to an already ongoing treatment to augment clinical efficacy. Adjunctive drug therapy is common in Psychiatry. Evecxia’s pre-clinical research demonstrated that adjunctive 5-HTP sustained-release (5-HTP SR, modeling EVX-101) interacts synergistically with ongoing SSRI treatment to elevate extracellular serotonin and amplify serotonin neurotransmission beyond the effect of SSRI monotherapy. This antidepressant augmentation-like pharmacological effect in animals of 5-HTP SR was not associated with any apparent adverse events.


Evecxia’s pre-clinical data aligns with several clinical pilot studies conducted over the years with native 5-HTP. These studies reported that (i) adjunctive native 5-HTP can elevate brain extracellular serotonin beyond the first-line antidepressant effect, based on neuroendocrine biomarkers, and (ii) that adjunctive native 5-HTP can augment antidepressant efficacy in depressed patients, albeit often with bothersome CMax-related adverse events, and a requirement for multiple daily doses to maintain exposure.


Further, in a Phase 1 trial in healthy volunteers conducted by Evecxia, EVX-101 administered adjunctively to a first-line antidepressant demonstrated neuroendocrine biomarker evidence of extracellular serotonin elevation beyond the effect of the first-line antidepressant, which, everything equal, could equate augmented antidepressant efficacy in patients.

The Serotonin Synapse




Serotonin Transporter

Serotonin Receptor


Serotonin is continuously released extracellularly into the synaptic cleft. Extracellular serotonin activates post-synaptic receptors that mediates serotonin neurotransmission. Pre-synaptic serotonin transporters work as a break on serotonin neurotransmission, by pumping extracellular serotonin back into the pre-synaptic neuron terminal.

SSRI treated

Blocking the serotonin transporter with an SSRI is intended to elevate extracellular serotonin. SSRI treatment depends on baseline serotonin release, which limits how much and how reliably an SSRI (or SNRI) can enhance serotonin neurotranmission.

Adjunctive EVX-101 to SSRI treatment

Adjunctive EVX-101 amplifies neuronal serotonin production and release, thereby synergizing with SSRI (or SNRI) treatment in elevating extracellular serotonin and strengthening serotonin neurotransmission.

Technology Rationale

Overcoming 5-HTP’s Limitation As A Therapeutic

Native 5-HTP has 3 shortcomings as a therapeutic:

  1. Fast absorption associated with side effects and poor tolerability.
  2. Short half-life, necessitating multiple daily doses.
  3. Poor absorption, necessitating large doses.

In addition, 5-HTP has a narrow absorption window restricted to the upper intestine. Evecxia is employing proven drug delivery technologies and combinations with other compounds to remedy the short-comings of 5 HTP as a therapeutic.

Overcoming 5-HTP’s Fast Absorption And Short Half-Life

Evecxia is developing drug delivery technologies that secures sustained 5-HTP plasma levels and consequently sustained brain serotonin amplification. These technologies optimize the therapeutic effect of 5-HTP and minimize side effects.

Overcoming 5-HTP’s Narrow Absorption Window

In humans 5-HTP is substantially absorbed only by the upper intestine, and not by the colon. This narrow absorption window occludes using conventional drug delivery technologies to achieve sustained delivery of 5-HTP. Evecxia employs novel proprietary embodiments of validated technologies, to either deliver 5-HTP over a prolonged period to the upper intestine [EVX-101], or to deliver 5-HTP parenterally, bypassing the intestine [EVX-301]. These approaches enable for the first time to achieve sustained drug delivery of 5-HTP in humans.

Overcoming 5-HTP’s Poor Absorption With Low-Dose Carbidopa

Carbidopa is a drug that inhibits aromatic L-amino acid decarboxylase, the enzyme that converts 5-HTP to serotonin, thus protecting 5-HTP against first-pass metabolism. Evecxia has discovered that extremely small doses of carbidopa can many-fold enhance 5-HTP’s absorption from the intestine. Carbidopa has previously been reported to enhance 5-HTP’s absorption, but in orders of magnitude higher doses. This unexpected pharmacological phenomenon requires that 5-HTP and carbidopa are delivered in close spatial and temporal juxtaposition to the site of 5-HTP absorption, the upper intestine. The low-dose carbidopa approach is used in EVX-101.


In another approach, 5-HTP is delivered via a constant IV infusion. This provides complete dose control, to optimize the rate of brain serotonin amplification, and to personalize the dose to the needs of the individual patient. This approach is used in EVX-301.