Nicotine Nicotine Nicotine. Often vilified for its association with smoking, it is surprisingly when people bring up its cognitive enhancing effects and other pleitropic benefits, but they exist nonetheless. What is the key to intelligent use? Understanding its interaction with the brain’s cholinergic system and finding the right balance of supplementation and lifestyle changes.

The Role of the Cholinergic System

The Cholinergic System – primarily centered around the neurotransmitter acetylcholine – is crucial for learning, memory, and attention. Enhancing this system involves increasing acetylcholine availability and optimising its receptor activity. Nicotine, is a potent stimulator (binds with a high affinity too, and activates) of the nicotinic cholinergic receptors, plays a central role in this process nAChRs in the brain AND throughout the body. Nicotine is basically a mimetic of acetylcholine, and by binding to these receptor it mimics the action of acetylcholine’s effects which releases neurotransmitters like dopamine, norepinephrine, and serotonin.

History: Research dating back to the 1960s shows nicotine’s positive effects on neurological function, particularly its ability to increase dopamine, serotonin, and norepinephrine in key regions like the hippocampus, frontal cortex, and cingulate cortex. Nicotine has long been a staple of many intellectuals’ lifestyles like Einstein, Freud, Darwin and many more.

Nicotine’s neuroprotective effects have even been linked to a lower incidence of Parkinson’s disease among smokers. 

But to harness nicotine’s cognitive benefits, it’s critical to respect its U-shaped dose-response curve: too little yields no benefits, while too much can cause anxiety, brain fog, and a general feeling of overstimulation.

Nicotine modulates the Default Mode Network (DMN) and the Central Executive Network (CEN), nicotine reduces rumination and enhances task-focused thought. This has potential therapeutic applications for conditions like depression and ADHD, where overactivity of the DMN is common. This particular line of investigation interested me due to my ADHD diagnosis, and all links to better treatment are welcomed by me. 

Considerations

The first consideration is dietary Choline: Choline is a precursor to acetylcholine and is essential for maintaining healthy brain function. Aim for at least 500 mg of choline daily, with higher amounts recommended for individuals with genetic methylation issues. Foods like eggs, liver, and soybeans are rich in choline. To test how much Choline you are consuming on a day-to-day basis log in your diet to Chronometer. Also supplemental forms like CDP choline and phosphatidylcholine offer optimal distribution in the body. The reason being ssing both hydrophilic (like CDP-Choline) and lipophilic (like Phosphatidylcholine) choline sources ensures better distribution. Hydrophilic forms more easily cross the blood-brain barrier so supply brain acetylcholine for sharper cognition, while lipophilic forms support long-term cell health by integrating into membranes.

Donepezil: Commonly prescribed for Alzheimer’s patients, Donepezil inhibits acetylcholinesterase, the enzyme that breaks down acetylcholine. A daily dose of 5-10 mg elevates baseline acetylcholine levels, creating a more responsive cholinergic system. Donepezil would be part of my limitless pill protocol, which I will publish soon. Also Donepezil is a sigma 1 agonist so could be a particularly useful add-on with certain ADHD/stimulant prescriptions.

The Nicotine+ Protocol

Nicotine: Use nicotine pouches/snus for controlled release, but Nicorette gum can also be utilised. Start with 2-4 mg and adjust based on your sensitivity. With nicotine it is particularly key you take a personalised, step-by-step approach, don’t follow an arbitrary rule. Try 1 or 2mg, if you feel good, try 3 or 4 mg, for those with a past smoking history, or those with certain genetic polymorphisms, or if you just don’t feel a improvement in focus  you could try higher. Adjust and take it step by step. 

Other Cholinergic supplements.

Uridine Monophosphate (300-600 mg): Boosts both cholinergic and dopaminergic signaling.

Alpha GPC (50-200 mg): Rapidly increases acetylcholine levels. 

Piracetam (400-800 mg): Improves cholinergic signaling and dopamine transmission. However it is often counterfeit due to its prescription status. Pharma-grade is key in this instance. 

Circadian Considerations

Acetylcholine levels naturally fluctuate, peaking during the day. Choline-rich foods and supplements are most effective when consumed in the morning. Additionally, taking days off from acute stimulants can help maintain sensitivity and prevent receptor desensitization.

Personalisation – Take it Step-By-Step

Individual responses to nicotine and supplements can vary significantly. Experimentation is key to finding your optimal dosages and combinations. Increased choline or Donepezil use may heighten sensitivity to nicotine, so adjust accordingly. Monitor for side effects like vivid dreams, which are a common sign of enhanced cholinergic activity.

References:

Lallai V, Grimes N, Fowler JP, Sequeira PA, Cartagena P, Limon A, Coutts M, Monuki ES, Bunney W, Demuro A, Fowler CD. Nicotine Acts on Cholinergic Signaling Mechanisms to Directly Modulate Choroid Plexus Function. eNeuro. 2019 Apr 23;6(2):ENEURO.0051-19.2019. doi: 10.1523/ENEURO.0051-19.2019. PMID: 31119189; PMCID: PMC6529591.

Gil SM, Metherate R. Enhanced Sensory-Cognitive Processing by Activation of Nicotinic Acetylcholine Receptors. Nicotine Tob Res. 2019 Feb 18;21(3):377-382. doi: 10.1093/ntr/nty134. PMID: 30137439; PMCID: PMC6379024.

Evidence of Altered Brain Responses to Nicotine in an Animal Model of Attention Deficit/Hyperactivity Disorder
Guillaume L Poirier, PhD, Wei Huang, PhD, Kelly Tam, BS, Joseph R DiFranza, MD, Jean A King, PhD

Wilcox CE, Claus ED, Calhoun VD, Rachakonda S, Littlewood RA, Mickey J, Arenella PB, Goodreau N, Hutchison KE. Default mode network deactivation to smoking cue relative to food cue predicts treatment outcome in nicotine use disorder. Addict Biol. 2018 Jan;23(1):412-424. doi: 10.1111/adb.12498. Epub 2017 Feb 23. PMID: 28231626; PMCID: PMC5874131.

Tanabe J, Nyberg E, Martin LF, Martin J, Cordes D, Kronberg E, Tregellas JR. Nicotine effects on default mode network during resting state. Psychopharmacology (Berl). 2011 Jul;216(2):287-95. doi: 10.1007/s00213-011-2221-8. Epub 2011 Feb 18. PMID: 21331518; PMCID: PMC3486925.

Lallai V, Grimes N, Fowler JP, Sequeira PA, Cartagena P, Limon A, Coutts M, Monuki ES, Bunney W, Demuro A, Fowler CD. Nicotine Acts on Cholinergic Signaling Mechanisms to Directly Modulate Choroid Plexus Function. eNeuro. 2019 Apr 23;6(2):ENEURO.0051-19.2019. doi: 10.1523/ENEURO.0051-19.2019. PMID: 31119189; PMCID: PMC6529591.

Paolini M, Keeser D, Rauchmann B-S, et al. Correlations Between the DMN and the Smoking Cessation Outcome of a Real-Time fMRI Neurofeedback Supported Exploratory Therapy Approach: Descriptive Statistics on Tobacco-Dependent Patients. Clinical EEG and Neuroscience. 2022;53(4):287-296. doi:10.1177/15500594211062703