Varenicline

(1S,12R)-5,8,14-triazatetracyclo[10.3.1.02,11.04,9]hexadeca-2,4,6,8,10-pentaene

Overview

Varenicline belongs to Nicotinics.

Key safety note: Varenicline's most common adverse effect is nausea (around 30% of users, usually mild and rarely causing discontinuation), along with vivid or abnormal dreams, insomnia, headache and constipation.[2]
Effects
Subjective effects vary. What a substance feels like depends on dose, individual physiology, mindset, and setting. The points below describe commonly reported effects, not guaranteed, uniform, or desirable outcomes.
  • Reduced craving for and withdrawal from nicotine, and a blunted reward from cigarettes smoked during treatment.
  • Commonly: nausea (usually mild), vivid or unusual dreams, insomnia and headache.
  • Not euphoric or reinforcing itself: little recreational appeal or abuse potential.
Dosing & duration
Harm-reduction note: These are commonly cited reference ranges, not a recommendation or a “safe” dose. Potency, purity, body chemistry, tolerance, and drug combinations vary widely. Start low, go slow, wait for full effects before redosing, and never assume an unknown product matches these figures. Missing data is not evidence of safety.

Oral tablets, prescribed by a clinician. A standard one-week titration precedes the maintenance dose. Figures are therapeutic (prescribing) context, not a recreational guide.. Varenicline is started at a low dose and titrated up over the first week to limit nausea, then continued at the maintenance dose for about 12 weeks (with a possible further 12 weeks to maintain abstinence). The dose is reduced in significant renal impairment. Taking it with food and a full glass of water reduces nausea.

Dose ranges

Days 1–3

0.5 mg once daily

Days 4–7

0.5 mg twice daily

Day 8 onward (maintenance)

1 mg twice daily for ~12 weeks

Duration

onset

Steady state in ~4 days, quit date typically ~1 week into treatment

total

12-week course (extendable to 24 weeks)

after effects

Chemical & Physical Properties
FormulaC13H13N3
Molar mass211.26 g/mol
StateSolid (usually the tartrate salt, white non-hygroscopic crystalline powder)
Melting point≈232 °C (tartrate salt)
Boiling pointNot reported
DensityNot reported
Vapor pressureNot reported
pKaNot reported
LogP0.9 (computed, free base)
SolubilityTartrate salt: freely soluble in water
Refractive indexNot reported
Identifiers & Synonyms
CAS249296-44-4
CAS (enantiomer)
PubChem CID5310966
InChIKeyJQSHBVHOMNKWFT-DTORHVGOSA-N
InChIInChI=1S/C13H13N3/c1-2-16-13-5-11-9-3-8(6-14-7-9)10(11)4-12(13)15-1/h1-2,4-5,8-9,14H,3,6-7H2/t8-,9+
SMILESC1[C@@H]2CNC[C@H]1C3=CC4=NC=CN=C4C=C23

Synonyms

  • Chantix
  • Champix
Pharmacodynamics & Biochemistry

Varenicline (Chantix, Champix) is a smoking-cessation drug and the prototypical high-affinity partial agonist at the α4β2 nicotinic acetylcholine receptor: the subtype that mediates nicotine's rewarding effects. Developed from the natural alkaloid cytisine, it binds α4β2 with subnanomolar affinity and activates it only partially (about 45% of nicotine's maximal effect). At other nicotinic subtypes it behaves differently: a full agonist at α7 and an agonist at α3β4 and α6-containing receptors. This partial agonism is the basis of its dual action. On its own, varenicline produces a modest, sustained release of dopamine in the nucleus accumbens: enough to blunt craving and nicotine-withdrawal symptoms, but much less than nicotine would. At the same time, by occupying the α4β2 receptor it competitively blocks inhaled nicotine from binding, so a cigarette smoked during treatment delivers little added reward. Reducing both the withdrawal 'stick' and the smoking 'reward' is why it is among the most effective single-agent cessation aids (more effective than bupropion or nicotine-replacement therapy in head-to-head trials). Varenicline is a single defined stereoisomer (not a racemate). It is barely metabolised, most of a dose is excreted unchanged by the kidneys via the OCT2 transporter, which gives it a long (~24 h) half-life supporting once- or twice-daily dosing and very few cytochrome-P450 drug interactions.

Biological targets

  • alpha4beta2 nAChR

Binding & functional measurements

TargetMeasurementSpecies
nicotinic acetylcholine receptor α4 subunitpKi 10.4Human
nicotinic acetylcholine receptor α3 subunitpKi 7.4Human
Pharmacokinetics
BioavailabilityHigh oral absorption, unaffected by food
Tmax≈3–4 h
Half-life≈24 h
VdNot reported
Protein bindingNot reported
MetabolismMinimal: no significant CYP metabolism
ExcretionRenal (~92% excreted unchanged, via the OCT2 transporter)
Toxicology & Safety
Harm-reduction note: Toxicity and risk depend on dose, route, purity, combinations, setting, and individual health factors. Missing harms should never be interpreted as evidence of safety.

Not reported

Varenicline's most common adverse effect is nausea (around 30% of users, usually mild and rarely causing discontinuation), along with vivid or abnormal dreams, insomnia, headache and constipation. Its safety history is notable for two warnings that were later downgraded. In 2009 the FDA added a boxed warning for serious neuropsychiatric events (mood changes, agitation, suicidal thoughts). The large randomised EAGLES trial and later analyses found no increase in neuropsychiatric risk versus placebo or other cessation aids, and the boxed warning was removed in 2016, though patients are still advised to stop and seek help if they notice changes in mood or behaviour. A 2011 signal of a small increased cardiovascular risk was likewise not confirmed by subsequent meta-analyses. Separately, in 2021 Pfizer recalled Chantix because some batches contained N-nitroso-varenicline (a nitrosamine) above acceptable limits: a manufacturing-impurity issue, not an inherent drug effect. Varenicline is not a controlled substance and has little or no abuse potential, but caution applies in significant renal impairment (dose reduction), in pregnancy, and when combined with alcohol (reports of altered or heightened intoxication).[2]

Legal Status
Legal note: Legal status can change over time and may vary by country, region, formulation, analogue status, prescription context, and enforcement practice. Always confirm with current official sources before relying on this section.
Interactions & Contraindications

Drug interactions

CYP1A2 substrate drugs (clozapine, olanzapine, theophylline) Stopping smoking raises blood levels of CYP1A2 substrates (theophylline, clozapine, olanzapine), because tobacco smoke induces that enzyme, so those doses may need review on quitting.[2]
Alcohol Reports of increased intoxication, unusual behaviour or aggression (FDA warning): moderate intake until individual tolerance is known.[2]

Contraindications

Known hypersensitivity to the drug hypersensitivity to varenicline.[2]
Kidney or liver impairment severe renal impairment (reduce the dose).[2]
Personal or family history of psychosis, schizophrenia or bipolar disorder history of serious psychiatric illness (monitor mood and behaviour).[2]
Pregnancy or breastfeeding limited data.[2]
Current or prior seizure disorder history of seizures (caution).[2]
Usage & Context
  • A first-line prescription aid for smoking cessation, taken as a 12-week course (extendable) starting shortly before or around a chosen quit date. More effective than bupropion or nicotine-replacement therapy in head-to-head trials.
  • Also approved (as the Tyrvaya nasal spray) for dry-eye disease, exploiting nicotinic stimulation of tear production: a separate indication from the oral cessation tablets.
  • On the WHO Model List of Essential Medicines. Available as a generic.
Sources & Evidence

Further Information