PE 22-28

1. Introduction

The pharmacological management of major depressive disorder (MDD) and associated cognitive neurodegenerations has, for the better part of a century, remained tethered to the monoaminergic hypothesis. This foundational framework posits that depressive symptomatology arises primarily from a deficiency in synaptic concentrations of serotonin (5-HT), norepinephrine (NE), and dopamine (DA). Consequently, the therapeutic landscape has been dominated by Tricyclic Antidepressants (TCAs), Monoamine Oxidase Inhibitors (MAOIs), and, most ubiquitously, Selective Serotonin Reuptake Inhibitors (SSRIs). While these agents have provided relief for millions, they are fundamentally limited by a temporal paradox: while synaptic monoamine levels are elevated within hours of administration, therapeutic remission often requires 3 to 6 weeks of continuous treatment. Up to one-third of patients are classified as non-responders, exhibiting resistance to multiple classes of monoaminergic interventions.

This latency suggests that the acute elevation of neurotransmitters is merely the proximal trigger for a more protracted cascade of neuroadaptive changes—specifically, the restoration of neuroplasticity and the upregulation of neurotrophic factors such as Brain-Derived Neurotrophic Factor (BDNF). The urgent clinical need for rapid-acting antidepressants has catalyzed the search for molecular targets that can bypass the slow desensitization of autoreceptors (e.g., 5-HT1A) and directly modulate neuronal excitability and plasticity.

In this context, the two-pore domain potassium channels (K2P) have emerged as a frontier of high-value targets. Among them, the TWIK-related potassium channel 1 (TREK-1), encoded by the KCNK2 gene, functions as a critical regulator of the resting membrane potential (RMP) in neurons. Genetic ablation of KCNK2 in murine models results in a depression-resistant phenotype that mimics the effects of chronic antidepressant treatment, but without the latency. This finding identified TREK-1 inhibition as a potential short-cut to antidepressant efficacy.

PE-22-28, a synthetic heptapeptide antagonist of TREK-1 is derived from the endogenous peptide Spadin—a fragment of the neurotensin receptor 3 (Sortilin). PE-22-28 represents the optimization of rational peptide design aimed at stabilizing neuronal membrane potential and enhancing neurogenesis. We will dissect the molecular evolution of this peptide, its specific pharmacological interactions, the robust preclinical evidence supporting its rapid-onset efficacy, and the systemic physiological implications of TREK-1 blockade, ranging from cardiac electrophysiology to smooth muscle dynamics.

2. Molecular Biology of the Target: The TREK-1 Channel

To fully appreciate the pharmacodynamics of PE-22-28, one must first possess a nuanced understanding of its target, the TREK-1 channel. Potassium channels constitute the most diverse class of ion channels, governing the resting potential and shaping the action potential of excitable cells. The K2P family, distinct from voltage-gated (Kv) or inward-rectifier (Kir) channels, is responsible for the background or leak potassium currents that maintain the negative resting potential of cells.

2.1 Structural Architecture and Polymodal Regulation

TREK-1 (K2P2.1) is a mechanosensitive channel characterized by a unique structural topology consisting of four transmembrane segments (M1–M4) and two pore-forming domains (P1 and P2) arranged in tandem. Functional channels assemble as dimers, creating a K+-selective pore that is constitutively open at resting voltages, thereby driving the membrane potential toward the potassium equilibrium potential (EK, typically ~ -90 mV) and reducing cellular excitability.6

What distinguishes TREK-1 from a simple leak channel is its sophisticated polymodal regulation. It functions as a molecular sensor, integrating various physical and chemical stimuli to tune neuronal excitability:

Mechanosensitivity: TREK-1 is activated by membrane stretch and cell swelling. This property is crucial for mechano-electric feedback in the heart and osmoregulation in the brain.
Lipid Regulation: The channel is potently activated by polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA) and docosahexaenoic acid (DHA), as well as by volatile anesthetics (e.g., chloroform, halothane). This lipid sensitivity suggests that the channel’s gating is intimately linked to the biophysical state of the membrane bilayer.
Thermal and pH Sensitivity: TREK-1 activity increases with temperature (acting as a heat sensor) and intracellular acidosis (pH < 7.0), providing a neuroprotective hyperpolarization during ischemic events where acidosis and heat are prevalent.
G-Protein Modulation: TREK-1 is inhibited by the activation of Gs and Gq protein-coupled receptors (GPCRs), which leads to phosphorylation of the channel’s C-terminal domain by Protein Kinase A (PKA) and Protein Kinase C (PKC). This action causes depolarization by closing this channel.

2.2 TREK-1 Distribution and the Depression Switch

The distribution of TREK-1 is widespread but regionally distinct. In the central nervous system (CNS), high expression levels are observed in the prefrontal cortex (PFC), hippocampus (particularly CA1, CA2, CA3, and dentate gyrus), and the dorsal raphe nucleus (DRN).

The DRN is the principal site of serotonergic (5-HT) cell bodies that project to the forebrain. Under basal conditions, TREK-1 channels in these neurons contribute to a hyperpolarized state, effectively acting as a brake on serotonin firing. The blockade of TREK-1 removes this brake, leading to depolarization, increased firing rates of 5-HT neurons, and enhanced release of serotonin in the PFC and hippocampus. This mechanism provides a direct physiological explanation for the antidepressant phenotype observed in TREK-1 knockout mice and forms the rationale for the development of TREK-1 antagonists like PE-22-28.

3. The Genesis of PE-22-28: From Sortilin to Synthetic Optimization

The discovery of PE-22-28 is a classic example of reverse pharmacology and rational drug design, stemming from the investigation of endogenous protein-protein interactions.

3.1 The Sortilin-TREK-1 Interactome

The parent molecule of PE-22-28 is Sortilin (Neurotensin Receptor 3/NTSR3), a type I membrane glycoprotein belonging to the Vps10p domain receptor family. Sortilin is a multifaceted trafficking receptor that sorts proteins to lysosomes and secretory pathways. Research demonstrated that Sortilin physically interacts with TREK-1, facilitating its trafficking to the plasma membrane.

During the maturation of Sortilin in the trans-Golgi network, a propeptide sequence is cleaved by furin convertases to generate the mature receptor. A specific fragment of this propeptide—comprising amino acid residues 17 through 28 (plus a specific conformational motif)—was identified as a natural ligand for TREK-1. This 17-amino acid peptide was named Spadin (Sortilin-derived Peptide with Antidepressant properties).

Spadin Sequence: Tyr-Ala-Pro-Leu-Pro-Arg-Trp-Ser-Gly-Pro-Ile-Gly-Val-Ser-Trp-Gly-Leu-Arg (YAPLPRWSGPIGVSWGLR).

3.2 The Limitations of Spadin

While Spadin proved to be a potent antidepressant in murine models, acting within 4 days compared to weeks for fluoxetine, it suffered from the pharmacokinetic liabilities inherent to natural peptides. Its in vivo stability was limited, with a duration of action extending only 6–7 hours post-administration due to rapid proteolytic degradation in the serum. As a viable therapeutic option, a longer half-life and greater stability were required.

3.3 Engineering Mini-Spadin: PE-22-28

To overcome these limitations, researchers at the Institute of Molecular and Cellular Pharmacology (Valbonne, France) conducted truncation and structure-activity relationship (SAR) studies. They systematically deleted amino acids from the N-terminus of Spadin to identify the minimum sequence required for TREK-1 inhibition.

They discovered that the C-terminal heptapeptide (7 amino acids) retained full biological activity. This synthetic analog was designated PE-22-28 (often referred to as Mini-Spadin).

PE-22-28 Characteristics:

Sequence: Gly-Val-Ser-Trp-Gly-Leu-Arg (GVSWGLR).
Molecular Formula: C35H54N12O9S (varies slightly with salt form).
Molecular Weight: ~773.89 Da to 802.94 Da.
Affinity: PE-22-28 inhibits TREK-1 with an IC50 of ~0.12 nM, compared to 40–60 nM for native Spadin.
Selectivity: PE-22-28 is highly selective for TREK-1. It does not inhibit related K2P channels such as TREK-2, TRAAK, TRESK, or TASK-1, nor does it affect the voltage-gated hERG channel (crucial for cardiac safety profiles).
Stability: The peptide demonstrates significantly enhanced stability in vivo, with antidepressant efficacy persisting for over 24 hours after a single intraperitoneal injection.

Further modifications, such as the substitution of the N-terminal Glycine with Alanine (G/A-PE 22-28), were also explored and showed similar potency, but the native GVSWGLR sequence remains the primary candidate in research contexts.

4. Pharmacodynamics and Mechanisms of Action

The mechanism by which PE-22-28 exerts its effects is distinct from all currently approved classes of antidepressants. It does not inhibit monoamine reuptake, nor does it inhibit monoamine oxidase enzymes. Instead, it acts as a state-dependent allosteric antagonist of an ion channel.

4.1 Allosteric Inhibition of TREK-1

Electrophysiological patch-clamp studies in HEK-293 cells and COS-7 cells expressing human TREK-1 (hTREK-1) reveal that PE-22-28 does not act as a simple pore blocker like barium (Ba2+) or tetraethylammonium (TEA). Pore blockers typically physically occlude the ion conduction pathway. Instead, PE-22-28 appears to bind to an extracellular domain of the channel, locking it in a closed conformation or desensitizing it to activating stimuli.

Research indicates that Spadin and PE-22-28 specifically antagonize the activation of TREK-1 by arachidonic acid (AA). In the absence of channel activation (basal state), the inhibitory effect is less pronounced, but when the channel is stimulated by lipids or stretch, the peptide effectively clamps the channel shut. This property is significant because it suggests the peptide may selectively target neurons that are active or under stress, potentially reducing off-target effects in quiescent tissue.

4.2 The Neurotrophic Cascade: CREB and BDNF

The immediate consequence of TREK-1 inhibition is membrane depolarization. In the serotonergic neurons of the DRN, this lowers the rheobase (the current required to trigger an action potential), thereby increasing the firing rate. This enhanced serotonergic tone propagates to the hippocampus, initiating a specific intracellular signaling cascade:

GPCR Activation: Increased 5-HT levels activate postsynaptic 5-HT receptors (likely Gs-coupled subtypes like 5-HT4 or 5-HT7).
cAMP-PKA Pathway: Receptor activation leads to an increase in cyclic AMP (cAMP) and the activation of Protein Kinase A (PKA).
CREB Phosphorylation: PKA phosphorylates the cAMP Response Element Binding protein (CREB) at Serine-133.
Transcription: Phosphorylated CREB (pCREB) translocates to the nucleus and binds to CRE sites on DNA, driving the transcription of immediate early genes and Brain-Derived Neurotrophic Factor (BDNF).

This pathway is the final common pathway for most antidepressants, but PE-22-28 engages it rapidly. Within 4 days of treatment, PE-22-28 treatment results in elevated BDNF mRNA and protein levels in the hippocampus.

4.3 Comparison with SSRIs

The contrast with SSRIs is stark. Fluoxetine blocks the serotonin transporter (SERT) immediately, but this leads to a surge in synaptic 5-HT that activates inhibitory 5-HT1A autoreceptors on the cell bodies of the DRN. This negative feedback loop suppresses neuronal firing. It takes weeks for these autoreceptors to desensitize and internalize before firing rates recover and therapeutic effects manifest. PE-22-28, by directly blocking the K+ leak, depolarizes the soma of the 5-HT neuron, overriding the inhibitory input from autoreceptors and increasing firing immediately.

Feature	SSRIs (e.g., Fluoxetine)	PE-22-28 (TREK-1 Inhibitor)
Primary Target	Serotonin Transporter (SERT)	TREK-1 K2P Channel
Initial Effect on 5-HT Firing	Suppression (via 5-HT1A autoreceptors)	Stimulation (Direct depolarization)
Onset of Action	Delayed (3-6 weeks)	Rapid (4 days in mice)
Mechanism	Reuptake Inhibition	Background K+ Current Blockade
Neurogenesis	Yes (Delayed)	Yes (Rapid)

5. Preclinical Efficacy: Evidence from Mammalian Models

The therapeutic potential of PE-22-28 is supported by a robust body of preclinical evidence in rodent models. These studies serve as the primary basis for our understanding of its effects on living organisms.

5.1 Depression and Behavioral Despair

The efficacy of PE-22-28 has been evaluated using validated behavioral assays that model depressive states:

Forced Swim Test (FST): In this paradigm, mice are placed in a cylinder of water. Immobility reflects a state of behavioral despair or giving up. Mice treated with PE-22-28 showed a statistically significant reduction in immobility time (approx. 30–50% reduction). Crucially, this effect was observed after acute or short-term (4-day) administration, whereas fluoxetine required chronic dosing (14+ days) to achieve comparable efficacy.
Novelty Suppressed Feeding Test (NSFT): This test creates a conflict between the drive to eat and the fear of a novel environment. It is sensitive to chronic, but usually not acute, antidepressant treatment. Remarkably, a 4-day regimen of PE-22-28 significantly reduced the latency to eat, indicating a rapid anxiolytic and antidepressant effect.
Learned Helplessness: While less explicitly detailed in the snippets for PE-22-28 specifically, the parent peptide Spadin showed efficacy in reversing learned helplessness, a model with high face validity for depression.

5.2 Neurogenesis and Synaptic Plasticity

Depression is increasingly viewed as a disorder of neuroplasticity, characterized by atrophy in the hippocampus and PFC.

Neurogenesis: Using BrdU (Bromodeoxyuridine) labeling to tag dividing cells, researchers found that PE-22-28 treatment significantly increased the number of progenitor cells in the subgranular zone of the dentate gyrus. This neurogenic response—approximately a doubling of BrdU+ cells—was evident after only 4 days. This finding challenges the dogma that neurogenesis is a slow, weeks-long process.
Synaptogenesis: Treatment with PE-22-28 increased the expression of synaptic markers, including PSD-95 (postsynaptic density protein 95) and synapsin. This indicates that the peptide not only stimulates the birth of new neurons but facilitates their maturation and integration into functional synaptic networks. The preservation of PSD-95 is critical, as its loss is associated with cognitive decline and depressive behaviors.

5.3 Neuroprotection and Stroke Recovery

While K2P channels are generally considered neuroprotective mechanisms (opening during stress to hyperpolarize and silence neurons), the specific blockade of TREK-1 by PE-22-28 has shown paradoxical neuroprotective benefits in ischemia models.

Ischemia/Reperfusion: In rodent models of stroke, PE-22-28 administration reduced the volume of the infarct (dead tissue) and improved neurological scores.
Mechanism: This counter-intuitive finding is likely explained by the robust upregulation of BDNF and activation of survival pathways (PI3K/Akt and MAPK/ERK) induced by the peptide. These neurotrophic signals may outweigh the loss of hyperpolarization-induced metabolic savings. Additionally, PE-22-28 has been shown to protect β-cells (pancreatic cells) and reduce apoptotic signals, suggesting a broad anti-apoptotic potential.

6. Systemic Physiology and Theoretical Safety Profile

While the CNS effects of PE-22-28 are promising, TREK-1 channels are not restricted to the brain. They are ubiquitously expressed in the heart, smooth muscle (gut, bladder, uterus), and sensory neurons. A deep dive analysis must critically evaluate the potential systemic consequences of blocking these channels.

6.1 The Cardiac Paradox: Arrhythmia vs. Protection

The presence of TREK-1 in the heart, particularly in the ventricular endocardium, raises significant safety questions. TREK-1 contributes to the repolarization reserve of cardiac myocytes and is involved in mechano-electric feedback (the heart’s electrical response to stretch).

Pro-Arrhythmic Risk: Theoretically, inhibiting a potassium channel that aids in repolarization could prolong the action potential duration (APD) and the QT interval on an electrocardiogram (ECG). QT prolongation is a precursor to Torsades de Pointes, a potentially fatal ventricular arrhythmia. Genetic studies have identified TREK-1 mutations (e.g., I267T) that render the channel dysfunctional or permeable to sodium, leading to right ventricular outflow tract (RVOT) tachycardia. TREK-1 knockout mice exhibit prolonged QT intervals.
Preclinical Safety Data: Despite these theoretical risks, studies on Spadin and PE-22-28 have reported a lack of cardiac toxicity in healthy mice. Researchers argue that because TREK-1 is a background channel, its contribution to repolarization is minor compared to the voltage-gated channels IKr (hERG) and IKs. Therefore, in a healthy heart, TREK-1 blockade may be well-tolerated.
The Compromised Heart Warning: The risk profile likely changes in pathological hearts. In conditions of ischemia, hypertrophy, or heart failure, the repolarization reserve is diminished. The loss of TREK-1 (via PE-22-28 blockade) could be the straw that breaks the camel’s back, unmasking arrhythmias. Patients with pre-existing cardiac conditions must view this as a significant potential contraindication.

6.2 Smooth Muscle Dynamics: Bladder and Gut

TREK-1 regulates the resting membrane potential of smooth muscle cells, generally promoting relaxation.

Urinary Bladder: TREK-1 is the primary K2P channel in the bladder detrusor muscle. In TREK-1 knockout mice, bladders are hypertrophic and exhibit non-voiding contractions (overactivity). Pharmacological blockade of TREK-1 in human bladder strips prevents relaxation and triggers spontaneous contractions.
Implication: Systemic use of PE-22-28 could theoretically induce symptoms of Overactive Bladder (OAB), urinary urgency, or frequency.
Gastrointestinal Tract: In the ileum and colon, TREK-1 helps maintain muscle relaxation. Blockade could lead to increased contractility. While this might theoretically aid in hypomotility disorders, it poses a risk of cramping, hypermotility, or exacerbation of Irritable Bowel Syndrome (IBS) subtypes characterized by cramping. Some research suggests TREK-1 activators are the therapeutic goal for IBS to induce relaxation, reinforcing that an inhibitor like PE-22-28 would be contraindicated in such conditions.

6.3 Pain Perception and Nociception

TREK-1 is expressed in small-diameter sensory neurons of the Dorsal Root Ganglia (DRG) and is involved in polymodal pain perception (thermal and mechanical).

Hyperalgesia Risk: Activation of TREK-1 typically dampens neuronal firing, reducing pain sensation. TREK-1 knockout mice are more sensitive to thermal and mechanical stimuli (hyperalgesia and allodynia).
Clinical Relevance: Systemic inhibition of TREK-1 by PE-22-28 could theoretically lower the pain threshold, making subjects more sensitive to painful stimuli. This contrasts with peptides like Selank, which inhibits enkephalin degradation and produces analgesic effects. Users with chronic pain conditions (e.g., fibromyalgia, neuropathy) should approach PE-22-28 with extreme caution.

7. Human Applications and Anecdotal Evidence

Despite robust animal data, PE-22-28 has not completed Phase II/III clinical trials for depression in Western regulatory frameworks. The human studies often cited in literature from off-label use typically refer to in vitro studies using human tissue lines (HEK-293 cells) or are extrapolations from Russian literature on related peptides. An active community of integrative medicine practitioners utilizes PE-22-28, providing a repository of anecdotal data.

7.1 Anecdotal Logs and Dosage

Reports from peptide clinics describe a user experience that largely aligns with the preclinical profile, though with notable variations.

Subjective Effects: Users frequently report a lifting of mood and a reduction in brain fog within 3 to 5 days of initiation. This aligns with the rapid-onset data from murine models. Unlike psychostimulants (e.g., amphetamines), users describe the effect as clean or stabilizing rather than euphoric. It is often distinguished from Selank (which is described as more sedating/anxiolytic) and Semax (which is described as more stimulating/focus-orientated).

Dosing Protocols:

Standard Dose: 50 mcg to 100 mcg per day.
Route: Subcutaneous injection is the standard. Intranasal sprays are available but suffer from variable absorption and lack of pharmacokinetic data specific to PE-22-28 compared to Semax/Selank.
Cycling: Users often cycle the peptide (e.g., 2 weeks on, 2 weeks off) to mitigate theoretical receptor desensitization, although preclinical data suggests a lack of tolerance.
Side Effects: Self-reports are generally mild, with headaches and fatigue being the most common complaints. Significantly, there is a lack of widespread reports regarding urinary urgency or palpitations, suggesting that at the low doses used (micrograms), the systemic affinity for peripheral TREK-1 might be lower than for CNS targets, or that physiological redundancy (e.g., other K+ channels) masks these effects in healthy individuals.

7.2 Stacking with Selank and Semax

PE-22-28 is frequently stacked with Selank and Semax, two other Russian-origin peptides. This practice is based on complementary mechanisms:

Selank: Modulates GABAergic systems and inhibits enkephalin degradation (Anxiolytic).
Semax: Increases BDNF and modulates dopaminergic systems (Cognitive/Focus).
PE-22-28: Disinhibits serotonergic firing via TREK-1 (Antidepressant/Mood).

Users theorize that this triad covers the three major axes of neurochemistry: GABA (calm), Dopamine (focus), and Serotonin (mood). There is no clinical data on the safety of this combination, and the risk of serotonin syndrome or over-stimulation should not be ruled out.

7.3 Comparative Pharmacology

Feature	PE-22-28	Selank	Semax
Parent Molecule	Spadin (Sortilin)	Tuftsin (IgG)	ACTH (4-10)
Mechanism	TREK-1 Antagonist	GABA Modulation, Enkephalinase Inhibitor	Melanocortin/BDNF Agonist
Primary Effect	Antidepressant, Neurogenesis	Anxiolytic, Immunomodulator	Nootropic, Neuroprotection (Stroke)
Onset	Rapid (Days)	Rapid (Minutes)	Rapid (Hours)
Key Safety Concern	Cardiac/Smooth Muscle Excitability	Mild Sedation	Overstimulation

8. Clinical Translation: Benefits, Concerns, and Contraindications

Based on the synthesis of preclinical data and theoretical physiology, the following profile for human application can be constructed.

8.1 Potential Benefits

Rapid Antidepressant Action: Ideal for patients requiring immediate relief, potentially bridging the gap until SSRIs take effect.
Cognitive Restoration: Reversal of stress-induced cognitive deficits via hippocampal neurogenesis.
Treatment-Resistant Depression: Offers a mechanism completely distinct from monoaminergic drugs, potentially aiding non-responders.
Stroke Recovery: Potential to reduce infarct size and improve motor outcomes if administered in the acute window.

8.2 Concerns and Risks

Cardiovascular Instability: The most significant concern. Blockade of TREK-1 could prolong the QT interval. In patients with silent channelopathies or those taking QT-prolonging drugs (e.g., certain antibiotics, antipsychotics), PE-22-28 could precipitate arrhythmias.
Visceral Hyper-excitability: Potential for bladder spasms, urinary urgency, or gastrointestinal cramping due to smooth muscle depolarization.
Hyperalgesia: Potential lowering of pain thresholds.
Seizure Threshold: While PE-22-28 is claimed to be neuroprotective, widespread neuronal depolarization carries an intrinsic theoretical risk of lowering seizure thresholds, particularly in epileptics. One study noted Spadin-treated mice were more resistant to seizures, highlighting the complexity of K2P physiology.

8.3 Potential Contraindications

Given the physiological distribution of TREK-1, the following populations should theoretically avoid PE-22-28 until safety is proven:

Cardiac Patients: History of Long QT syndrome, arrhythmias, or recent myocardial infarction.
Epilepsy: Patients with a history of seizures.
Urological Conditions: Patients with Overactive Bladder (OAB) or Interstitial Cystitis.
Gastrointestinal Disorders: Patients with IBS-C or cramping disorders.
Pregnancy: Complete lack of teratogenic data.

9. Conclusion

PE-22-28 represents a significant leap forward in neuropsychopharmacology. By identifying the TREK-1 channel as a depression switch and engineering a stable peptide to toggle it, science has potentially unlocked a faster, more direct path to antidepressant efficacy than the monoaminergic strategies of the past 50 years. The capacity to induce neurogenesis within days rather than weeks offers profound hope for the treatment of depressive disorders and cognitive decline.

The very mechanism that grants PE-22-28 its power—the systemic blockade of a fundamental background potassium channel—is also the source of its potential liability. TREK-1 is not merely a mood regulator; it is a guardian of cellular quiescence in the heart, bladder, and sensory nerves. While preclinical mammalian studies suggest a wide therapeutic window with no side effects, the translational gap to human physiology is fraught with unknowns, particularly regarding cardiac repolarization and smooth muscle function.

For the medical community, PE-22-28 is a high-priority candidate for rigorous clinical trials. For the individual users, it represents a promising but experimental tool that demands a high degree of caution, particularly regarding cardiovascular health.

Summary Data Table

Parameter	PE-22-28 Data	Clinical Implication
Target	TREK-1 (K2P2.1)	Direct modulation of excitability; distinct from SSRIs.
IC50	~0.12 nM	Highly potent; microgram dosing sufficient.
Half-Life	>24 hours (Effect duration)	Once-daily dosing is feasible.
CNS Effect	5-HT firing ↑, BDNF ↑, Neurogenesis ↑	Rapid antidepressant and cognitive enhancing effects.
Cardiac Risk	Theoretical QT prolongation	Major caution for those with heart conditions.
Smooth Muscle	Depolarization / Contraction	Risk of bladder urgency or gut cramping.
Status	Preclinical / Research Chemical	Not FDA approved; use is off-label/experimental.