NR (Nicotinamide Riboside) vs Pregnenolone

Mechanism

NR is converted to NMN by nicotinamide riboside kinases (NRK1/NRK2), then to NAD+ via the salvage pathway. Like NMN, elevated NAD+ activates sirtuins, PARPs, and CD38. NR has demonstrated ability to cross the blood-brain barrier and elevate brain NAD+ levels. It supports mitochondrial function, DNA repair, and circadian rhythm regulation through SIRT1-mediated deacetylation of BMAL1 and CLOCK proteins.

Standard Dosing

300-600mg daily

Timing

Morning with or without food.

Cycle Duration

ongoing

Side Effects

• Mild nausea
• Warmth/flushing (mild)
• GI upset
• Fatigue in some during initial days

Contraindications

• Active cancer (same theoretical NAD+ concern as NMN)
• Pregnancy/lactation
• Theoretical cancer concern shared with NMN

Best Stacking Partners

Mechanism

Pregnenolone is the 'master steroid' synthesized from cholesterol via CYP11A1 (side-chain cleavage enzyme) in adrenal glands, gonads, and brain. It serves as the biosynthetic precursor to all steroid hormones (progesterone, DHEA, cortisol, testosterone, estradiol, aldosterone). In the CNS, pregnenolone and its sulfated derivative (pregnenolone sulfate) function as potent neurosteroids: pregnenolone sulfate is a positive allosteric modulator of NMDA receptors enhancing glutamatergic neurotransmission, a negative modulator of GABA-A receptors (increasing neural excitability), and an activator of TRPM3 calcium channels. It also modulates sigma-1 receptors involved in neuroplasticity.

Standard Dosing

Research indicates 10-50 mg daily orally for neurosteroid and cognitive support. Clinical trials in schizophrenia used up to 500 mg/day.

Timing

Morning dosing preferred (aligns with diurnal cortisol rhythm). Sublingual may provide faster onset and better bioavailability. Take with or without food.

Cycle Duration

Ongoing with periodic reassessment. Cycle 5 days on / 2 days off, or 3-4 weeks on / 1 week off to prevent downstream hormone accumulation.

Side Effects

• Headache
• Irritability/mood changes
• Insomnia
• Acne (via androgenic metabolites)
• Heart palpitations
• Hair loss (if converting heavily down androgen pathway)
• Overstimulation
• Overstimulation and anxiety (from GABA-A antagonism at higher doses)
• Insomnia (if taken late in the day)
• Acne (from downstream androgen conversion)
• Irritability
• Hair growth or loss (from downstream hormonal changes)

Contraindications

• Hormone-sensitive cancers
• Seizure disorders (complex GABA modulation)
• Pregnancy
• PCOS
• Concurrent HRT without monitoring
• Use only with lab-guided supervision
• Hormone-sensitive cancers (breast, prostate, ovarian — due to downstream conversion)
• History of seizures (pregnenolone sulfate is pro-excitatory)
• Pregnancy and breastfeeding
• Bipolar disorder (may exacerbate manic episodes)

Best Stacking Partners