Nicotine is a psychoactive chemical that acts on the nervous system, not a pathogen that triggers a classic immune response. Therefore, the concept of true immunity—a protective biological mechanism that prevents the substance from ever having an effect—does not apply. While outright immunity is not possible, some individuals possess significant natural resistance, and the body exhibits a powerful ability to adapt to its presence. This combination of innate resistance and acquired tolerance creates the perception of being unaffected, even though the chemical still alters the body’s chemistry.
How Nicotine Interacts with the Body
Nicotine is rapidly absorbed and crosses the blood-brain barrier, where it acts as a stimulant by targeting specific protein channels called nicotinic acetylcholine receptors (nAChRs). Nicotine mimics acetylcholine, binding to nAChRs, particularly the alpha-4 beta-2 (\(\alpha4\beta2\)) subtype, which is highly concentrated in brain regions associated with reward and motivation. Binding to these receptors triggers a cascade that leads to the release of several neurotransmitters, most notably dopamine, in the brain’s mesolimbic pathway. This dopamine surge creates immediate feelings of pleasure, mild euphoria, and increased alertness that reinforce the behavior.
Distinguishing Immunity from Tolerance and Resistance
The observed lack of effect in some individuals is explained by two distinct phenomena: tolerance and resistance. True immunity is a biological state where exposure to a foreign agent results in a protective, neutralizing response from the immune system, which is not how the body processes nicotine.
Tolerance is an acquired state where a higher concentration of the substance is required to achieve the initial effect. After nicotine binds to its receptors, they quickly enter a desensitized state, temporarily shutting down. With chronic use, the brain attempts to compensate for this constant desensitization by creating more nAChRs, a process known as upregulation. This physically alters the brain’s chemistry and drives the need for more nicotine.
Resistance, conversely, is typically an innate or genetic trait where a person naturally requires a higher dose to feel an effect, even on first exposure. This natural resistance is not due to a defense mechanism, but rather to inherited variations in the body’s machinery responsible for processing the chemical.
Genetic Variations in Nicotine Sensitivity
The most significant factor determining a person’s natural resistance is the variation in the gene that codes for the liver enzyme Cytochrome P450 2A6 (CYP2A6). This enzyme is responsible for metabolizing approximately 70–80% of nicotine into its inactive metabolite, cotinine. Genetic variations in the \(CYP2A6\) gene classify individuals as poor, intermediate, or extensive (fast) metabolizers.
Individuals who are fast metabolizers clear nicotine from their bloodstream quickly, meaning the chemical is active for a shorter duration before being broken down. To maintain the same rewarding effect, these people often need to use nicotine more frequently, which increases their risk for developing higher dependence later on. Conversely, poor metabolizers clear nicotine slowly, resulting in higher and longer-lasting concentrations in their system. This prolonged effect means they may require less frequent use and are less likely to become heavily dependent, as the higher concentrations can sometimes lead to mild toxicity.
Minor genetic variations in the structure of the nAChR protein subunits themselves, particularly \(\alpha5\), can also affect how efficiently nicotine binds to the receptor. These genetic differences influence the onset of addiction and the initial sensitivity to nicotine. However, these variations only change the dose required for an effect, not the fundamental mechanism of action.
The Development of Physical Dependence
The brain’s attempt to restore balance following repeated chemical stimulation ultimately leads to physical dependence. The process of nAChR upregulation, which creates an increased number of receptor sites on the neurons, is a key neuroadaptation in response to chronic exposure. When nicotine is present, these upregulated receptors are desensitized, but when the chemical is suddenly removed, they quickly resensitize. This sudden absence of nicotine leaves a population of now-active, over-abundant receptors that are no longer being stimulated, fundamentally altering the brain’s baseline function. The physiological imbalance created by these changes manifests as withdrawal symptoms, including irritability, intense craving, anxiety, and difficulty concentrating.