Nicotine

Nicotine is a tertiary alkaloid occurring naturally in tobacco (Nicotiana tabacum). Therapeutically it is delivered as patches, lozenges, gum, nasal sprays or pouches to reduce withdrawal during smoking cessation. Recreationally it is inhaled in cigarette smoke or vaporised in e‑cigarettes.

Clinical indications include relief of withdrawal symptoms and promotion of long‑term abstinence from combusted tobacco. Efficacy depends on both dose delivery and individual pharmacokinetics.

Mechanistically nicotine binds heteropentameric neuronal nicotinic acetylcholine receptors (nAChRs), producing inward cation currents that depolarise mesolimbic dopaminergic neurons. Reinforcement involves dopamine release in nucleus accumbens, while tolerance and withdrawal reflect receptor desensitisation and up‑regulation.

CHRNA5 encodes the α5 subunit that modulates Ca²⁺ permeability and desensitisation kinetics of high‑affinity nAChRs. The missense variant rs16969968 (Asp398Asn) alters channel conductance and intracellular signalling. Functional studies show reduced receptor current yet amplified reward signalling in knock‑in mice, suggesting a complex gain‑of‑function at the circuit level.

CYP2A6 encodes the hepatic cytochrome P450 isoform that C‑oxidises ~80 % of nicotine to cotinine. Null alleles (for example *4 whole‑gene deletion) or reduced‑function alleles (for example *9, *12) slow clearance, increase systemic exposure, and lower daily cigarette consumption. Conversely, rapid metaboliser genotypes are associated with heavier smoking and reduced quit rates.

COMT encodes catechol‑O‑methyl‑transferase responsible for methylation of catecholamines. Val158Met (rs4680) halves enzymatic activity, raising cortical dopamine tone. This increases subjective reward from nicotine and can attenuate withdrawal.

Variation in these genes therefore influences pharmacodynamics (CHRNA5, COMT) and pharmacokinetics (CYP2A6), providing a mechanistic basis for genotype‑guided counselling.

CHRNA5 rs16969968. Large genome‑wide association meta‑analyses show that each risk (A) allele increases cigarettes‑per‑day by roughly one stick and reduces cessation success by 10 – 15 % Romero Villela 2024. Controlled laboratory studies confirm higher puff volumes and plasma cotinine in A‑allele carriers Smith 2024.

CYP2A6. The nicotine metabolite ratio (NMR = 3‑hydroxy‑cotinine : cotinine) quantitatively reflects CYP2A6 activity. A pan‑ancestry model predicted by 275 tagging variants explains ~70 % of NMR variance McMahan 2022. Slow metabolisers (lowest NMR quartile) demonstrate higher steady‑state nicotine, fewer cigarettes per day and superior patch efficacy, whereas normal metabolisers benefit more from varenicline Adey 2024.

COMT Val158Met. Human laboratory work shows larger heart‑rate and subjective reward responses to intravenous nicotine in Met carriers, alongside smaller deficits in working memory during abstinence Ray 2013. A 2022 systematic review reports that Met homozygosity predicts higher quit rates with nicotine replacement, although findings are heterogeneous McKinney 2022.

CHRNA5 rs16969968

• Effect – Risk allele augments mesolimbic dopamine response despite reduced channel conductance.
• Implication – Higher craving intensity, heavier smoking, delayed cessation.
• Side effects – No specific somatic toxicity, but dependence severity is clinically significant.

CYP2A6 Loss‑of‑Function Haplotypes

• Effect – Slow systemic clearance and elevated nicotine area‑under‑curve.
• Implication – Reduced withdrawal severity, lower cigarette consumption, but increased nausea with fixed‑dose patches.
• Side effects – Dose dependent dizziness or tachycardia if replacement dose is not adjusted.

COMT Val158Met

• Effect – Met allele raises cortical dopamine after nicotine.
• Implication – Greater subjective reinforcement yet milder withdrawal, with potential for sex‑specific effects.
• Side effects – No direct toxicity, but increased dependence risk especially in adolescent onset users.

Indeterminate / Not Available

• Effect: Unknown
• Implication: No specific guidance – follow standard dosing with clinical monitoring

The rs16969968 A allele is present in approximately 37 % of Europeans, 5 % of South Asians and is <1 % in most East Asian and African cohorts Zhou 2024. In contrast, the loss‑of‑function CYP2A6*4 deletion allele reaches 15 – 24 % in Japanese but is below 2 % in European populations Xu 2015. COMT Met frequency is roughly 50 % in Northern Europeans, 25 % in East Asians and 20 % in Sub‑Saharan Africans KNMP 2025. These disparities contribute to observed ethnic differences in nicotine dependence severity and response to nicotine replacement therapy.

• Romero Villela PN et al. Drug Alcohol Depend 2024. Link
• Smith JD et al. Nicot Tob Res 2024. Link
• McMahan AC et al. BMC Genomics 2022. Link
• Adey EM et al. Tob Prev Cessat 2024. Link
• Ray R et al. Pharmacogenomics J 2013. Link
• McKinney YY et al. Curr Addict Rep 2022. Link
• Zhou K et al. BMC Psychiatry 2024. Link
• Xu C et al. Exp Cell Res 2015. Link
• Royal Dutch Pharmacists Association (KNMP) COMT guideline 2025. Link