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 [1].

GSK3 has been implicated in various diseases such as diabetes, inflammation, cancer, Alzheimer’s and bipolar disorder [2].

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 [3].

Benefits of GSK3B Inhibition

1) Alzheimer’s

GSK3B inhibition may reduce the formation of amyloid plaques, a hallmark of Alzheimer’s [4].

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 [5].

Increased GSK3 has been reported in type II diabetics and obese animal models [2].

Inhibitors of GSK3 have been demonstrated to have anti-diabetic effects in test tubes and animal models [6].

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 [5].

Increased hypothalamic GSK3β signaling contributes to deleterious effects of leptin deficiency and exacerbates high-fat diet-induced weight gain and glucose intolerance [7].

Inhibitors of GSK3B activity improve insulin response and maintain proper glucose levels [8].

In muscle, GSK3b inhibits glycogen synthesis [2].

3) Cancer

Inhibitors of GSK3B activity could be useful in prostate, glioblastoma, neuroblastoma, pancreatic, and colorectal cancer [8].

GSK3B promotes ovarian cancer cell proliferation and chemotherapy resistance [8].

Inhibitors of GSK3B could be useful in prostate cancer therapy [8].

Pancreatic cancer cells contain a pool of active GSK3B, and inhibition of GSK3B leads to decreased cancer cell proliferation and survival [8].

Colon cancer cells from patients have higher levels of GSK3B expression than their normal counterparts [8].

4) Mood: Depression and Anxiety

Increased GSK3B activity has been reported as a state marker of major affective episodes in patients with depression and bipolar disorder.

Elderly depressed patients had significantly higher GSK3B activity. Higher GSK3B activity was observed in patients with severe depressive episodes and with cognitive impairment [9].

Inhibitors of GSK3b (in forebrain) are important for reducing anxiety and depression by way of serotonin pathway effects [10].

5) Inflammation and Pain

Inhibitors of GSK3β have been shown to be beneficial in many neuroinflammatory disease models including Alzheimer’s disease, multiple sclerosis and AIDS dementia complex [11].

GSK3-β induces TLR-mediated excessive inflammatory responses in the gut [12].

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 [12].

Inhibitors of GSK3b stop neuroinflammation and pain [11].

Inhibition of GSK3β in cells leads to suppression of Toll-like receptor (TLR)-initiated proinflammatory cytokines from NfkB.

Inhibiting GSK3b is capable of decreasing TNF, IL-6, IL-1b and IL-12/IL-23 and IL-17 [13].

GSK3b increases NfkB [14].

Inhibition of GSK3b is involved in the resistance to oxidative stress [15].

6) Sociability and Resilience

Suppression of GSK3β in the brain (forebrain) increases sociability, which would mean that it can be useful for autism [10].

GSK3 inhibition (hippocampus and striatum) increases resilience to defeat and decreases responsiveness to psychostimulants [10].

7) Nootropic Effects

Studies have found increased platelet GSK3B activity in patients with mild cognitive impairment and Alzheimer’s disease [16].

GSK3 is critical for brain development and neuroplasticity, which appear to be interrelated and to mediate age-associated neurological diseases [17].

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 [17].

GSK3 is proposed to be a therapeutic target for the restoration of synaptic functioning and cognition [17].

GSK3β inhibition stimulates the regeneration of myelin-forming cells and remyelination following chemically induced demyelination [18].

GSK3b inhibition stimulates axon regeneration in injured cortical connections [19].

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 [19].

Glycogen synthase kinase-3 inhibitors reverse deficits in long-term potentiation and cognition in fragile X mice [20].

Inhibition of GSK3β in cells leads to the promotion of CREB-dependent gene activation [13], which can improve cognitive function.

8) Addiction

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 [21].

9) Circadian Rhythms

GSK3 activity status is regulated by the circadian clock and GSK3 feeds back to regulate the molecular clock amplitude in the Suprachiasmatic Nucleus [22].

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 [22].

Chronic activation of GSK3 impaired rhythmicity of BMAL1. Furthermore, chronic inhibition of GSK3 enhanced the amplitude and shortened the period of PER2 rhythms in SCN cultures [22].

GSK3b increases Rev-Erb-a while helping to break down ARNTL/BMAL1, CLOCK, and PER2 [23].

Top GSK3 beta Inhibitors


Lithium is the most popular GSK3B inhibitor. It works by competing with magnesium inside cells, which is needed to activate GSK3 [24, 25].

  • Lithium (potent, IC50=1-2mM, but actual inhibition is more in-vivo) [26, 24]
  • Zinc (potent, IC50 = 15 μM) [26]
  • Copper (potent) [2627]




  • SSRIs [36]
  • Ketamine [37]
  • Trichostatin [30+]
  • Valproic Acid [30]
  • Antipsychotics
  • Intranasal insulin (normalized high GSK3b in diabetic animals) [38]

Natural pathways:


  • Beryllium (potent, 1000X more than lithium) [42, 26]
  • Mercury (potent) [26]
  • Tungstate [26]

What Increases GSK3b?

Genetics and GSK3B

Genetic variants of GSK3B are associated with biomarkers for Alzheimer’s disease and cognitive function [45].

Check out the GSK3b gene on SelfDecode.

The most important SNPs in GSK3B are:

Want Better Ways to Improve Your Mood?

If you’re interested in natural and targeted ways of improving your mood, we recommend checking out SelfDecode’s Mood DNA Wellness Report. It gives genetic-based diet, lifestyle and supplement tips that can help improve your mood. The recommendations are personalized based on your genes.

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