Pharmacodynamics<unk>  acts as a receptor agonist at most<unk> c acetylcholine receptors (nAChRs), except at two<unk> c receptor subunits (nAChRα9 and nAChRα10) where it acts as a receptor antagonist. Central nervous system Effect of<unk>  on dopaminergic neurons. By binding to<unk> c acetylcholine receptors in the brain,<unk>  elicits its psychoactive effects and increases the levels of several neurotransmitters in various brain structures – acting as a sort of "volume control".<unk>  has a higher affinity for<unk> c receptors in the brain than those in skeletal muscle, though at toxic doses it can induce contractions and respiratory paralysis.<unk> 's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.<unk>  is unusual in comparison to most drugs, as its profile changes from stimulant to sedative with increasing dosages, a phenomenon known as "Nesbitt's paradox" after the doctor who first described it in 1969. At very high doses it dampens neuronal activity.<unk>  induces both behavioral stimulation and anxiety in animals. Research into<unk> 's most predominant metabolite, cotinine, suggests that some of<unk> 's psychoactive effects are mediated by cotinine.<unk>  activates<unk> c receptors (particularly α4β2<unk> c receptors, but also α5 nAChRs) on neurons that innervate the ventral tegmental area and within the mesolimbic pathway where it appears to cause the release of dopamine. This<unk> -induced dopamine release occurs at least partially through activation of the cholinergic–dopaminergic reward link in the ventral tegmental area.<unk>  can modulate the firing rate of the ventral tegmental area neurons.<unk>  also appears to induce the release of endogenous opioids that activate opioid pathways in the reward system, since naltrexone – an opioid receptor antagonist – blocks<unk>  self-administration. These actions are largely responsible for the strongly reinforcing effects of<unk> , which often occur in the absence of euphoria; however, mild euphoria from<unk>  use can occur in some individuals. Chronic<unk>  use inhibits class I and II histone deacetylases in the striatum, where this effect plays a role in<unk>  addiction. Sympathetic nervous system Effect of<unk>  on chromaffin cells<unk>  also activates the sympathetic nervous system, acting via splanchnic nerves to the adrenal medulla, stimulating the release of epinephrine. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on<unk> c acetylcholine receptors, causing the release of epinephrine (and norepinephrine) into the bloodstream. Adrenal medulla By binding to ganglion type<unk> c receptors in the adrenal medulla,<unk>  increases flow of adrenaline (epinephrine), a stimulating hormone and neurotransmitter. By binding to the receptors, it causes cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and thus the release of epinephrine (and norepinephrine) into the bloodstream. The release of epinephrine (adrenaline) causes an increase in heart rate, blood pressure and respiration, as well as higher blood glucose levels. Pharmacokinetics Urinary metabolites of<unk> , quantified as average percentage of total urinary<unk> . As<unk>  enters the body, it is distributed quickly through the bloodstream and crosses the blood–brain barrier reaching the brain within 10–20 seconds after inhalation. The elimination half-life of<unk>  in the body is around two hours.<unk>  is primarily excreted in urine and urinary concentrations vary depending upon urine flow rate and urine pH. The amount of<unk>  absorbed by the body from smoking can depend on many factors, including the types of tobacco, whether the smoke is inhaled, and whether a filter is used. However, it has been found that the<unk>  yield of individual products has only a small effect (4.4%) on the blood concentration of<unk> , suggesting "the assumed health advantage of switching to lower-tar and lower-nicotine cigarettes may be largely offset by the tendency of smokers to compensate by increasing inhalation".<unk>  has a half-life of 1–2 hours. Cotinine is an active metabolite of<unk>  that remains in the blood with a half-life of 18–20 hours, making it easier to analyze.<unk>  is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6) and FMO3, which selectively metabolizes (S)-nicotine. A major metabolite is cotinine. Other primary metabolites include<unk>  N-oxide, nornicotine,<unk>  isomethonium ion, 2-hydroxynicotine and<unk>  glucuronide. Under some conditions, other substances may be formed such as myosmine. Glucuronidation and oxidative metabolism of<unk>  to cotinine are both inhibited by menthol, an additive to mentholated cigarettes, thus increasing the half-life of<unk>  in vivo. Metabolism<unk>  decreases hunger and food consumption. The majority of research shows that<unk>  reduces body weight, but some researchers have found that<unk>  may result in weight gain under specific types of eating habits in animal models.<unk>  effect on weight appears to result from<unk> 's stimulation of α3β4 nAChR receptors located in the POMC neurons in the arcuate nucleus and subsequently the melanocortin system, especially the melanocortin-4 receptors on second-order neurons in the paraventricular nucleus of the hypothalamus, thus modulating feeding inhibition. POMC neurons are a precursor of the melanocortin system, a critical regulator of body weight and peripheral tissue such as skin and hair.
Nicotine
Heroin
Cannabis 
Cannabis
Cocaine
Cocaine 
Benzyl alcohol
Methamphetamine