GSK3b inhibition is one of my favorite pathways for enhancement.
What is GSK3B?
GSK3B (Glycogen synthase kinase 3 beta) is an enzyme associated with energy metabolism, neuronal cell development, and body pattern formation .
Glycogen synthase kinase 3 (GSK-3) acts as an essential “brake” on many growth-signaling pathways including Wnt and insulin. GSK-3 has high activity in resting tissues and is inhibited upon cellular stimulation .
Benefits of GSK3B Inhibition
GSK3B inhibition may reduce the formation of amyloid plaques, a hallmark of Alzheimer’s .
2) Obesity and Type 2 Diabetes
Glycogen synthase kinase-3 (GSK-3) has important roles in the regulation of glycogen synthesis, protein synthesis, gene transcription, and cell differentiation in various cell types .
Inhibitors of GSK3 have been demonstrated to have anti-diabetic effects in test tubes and animal models .
Overexpression and overactivity of GSK-3 in the muscle of rodent models of obesity and type 2 diabetic humans are associated with an impaired ability of insulin to activate glucose disposal and glycogen synthase .
In muscle, GSK3b inhibits glycogen synthesis .
GSK3B promotes ovarian cancer cell proliferation and chemotherapy resistance .
Pancreatic cancer cells contain a pool of active GSK3B, and inhibition of GSK3B leads to decreased cancer cell proliferation and survival .
Colon cancer cells from patients have higher levels of GSK3B expression than their normal counterparts .
4) Mood: Depression and Anxiety
Elderly depressed patients had significantly higher GSK3B activity. Higher GSK3B activity was observed in patients with severe depressive episodes and with cognitive impairment .
5) Inflammation and Pain
GSK3-β induces TLR-mediated excessive inflammatory responses in the gut .
Blockade of GSK3-β attenuates excessive proinflammatory TLR-mediated immune responses. GSK3-β inhibition, therefore, constitutes a promising therapeutic option for selectively reducing exaggerated intestinal immune reactions toward the luminal flora in inflammatory bowel disease .
Inhibitors of GSK3b stop neuroinflammation and pain .
Inhibition of GSK3β in cells leads to suppression of Toll-like receptor (TLR)-initiated proinflammatory cytokines from NfkB.
GSK3b increases NfkB .
6) Sociability and Resilience
GSK3 inhibition (hippocampus and striatum) increases resilience to defeat and decreases responsiveness to psychostimulants .
7) Nootropic Effects
GSK3 is critical for brain development and neuroplasticity, which appear to be interrelated and to mediate age-associated neurological diseases .
Specifically, GSK3 plays a pivotal role in controlling neuronal progenitor proliferation and establishment of neuronal polarity during development, and neuronal GSK3 function affects neuroplasticity throughout the lifespan .
GSK3 is proposed to be a therapeutic target for the restoration of synaptic functioning and cognition .
GSK3β inhibition stimulates the regeneration of myelin-forming cells and remyelination following chemically induced demyelination .
GSK3b inhibition stimulates axon regeneration in injured cortical connections .
Damaged axons in the adult central nervous system normally do not regenerate after lesion, largely because of the presence of growth inhibitory molecules at the scar .
Glycogen synthase kinase-3 inhibitors reverse deficits in long-term potentiation and cognition in fragile X mice .
Mice injected with cocaine (20 mg/kg, i.p) showed an increase in the activity of GSK3β in the caudate putamen.
GSK3b inhibitors produced significant dose-dependent reductions in cocaine-induced activity .
GSK3 activity status is regulated by the circadian clock and GSK3 feeds back to regulate the molecular clock amplitude in the Suprachiasmatic Nucleus .
Glycogen synthase kinase 3 (GSK3) interacts with at least 5 core clock proteins and shows daily variation itself. Significant circadian rhythmicity of phosphorylated GSK3 (α and β) was observed in the SCN .
GSK3b increases Rev-Erb-a while helping to break down ARNTL/BMAL1, CLOCK, and PER2 .
Top GSK3 beta Inhibitors
- Lithium (potent, IC50=1-2mM, but actual inhibition is more in-vivo) [26, 24]
- Zinc (potent, IC50 = 15 μM) 
- Copper (potent) [26, 27]
- Curcumin (very potent, IC50=66nM) 
- Butyrate [30+]
- Quercetin (potent, IC50=2.0 μM) 
- Luteolin (potent, IC50=1.5 μM) 
- Apigenin (potent, IC50=1.9 μM) 
- Cinnamon 
- Angelica Sinensis 
- Berberine 
- Resveratrol 
- SSRIs 
- Ketamine 
- Trichostatin [30+]
- Valproic Acid 
- Intranasal insulin (normalized high GSK3b in diabetic animals) 
What Increases GSK3b?
Genetics and GSK3B
The most important SNPs in GSK3B are:
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