History and Metabolic Context

History and Definition of Nicotine toxicity:

Nicotine toxicity is a broad term used to cover a host of metabolic actions and systemic actions arising from elevated levels of nicotine within the body. Nicotine itself is an alkaloid compound found naturally within tobacco plants as a pesticide agent, specifically pertaining to plants of the Solanacacae (nightshade)[1] Family, and is indigenous to the Americas. In order to understand the history behind the current relatively common mechanisms of nicotine exposure in humans, one needs to first review the history of tobacco containing products. Prior to European arrival in the Americas, Nicotina Tabacum had been sought out and utilized by local religious practitioners and shamans for roles within ceremonies where it was consumed for its ability to induce altered states of consciousness. Additionally, the pain-killing effects of nicotine prompted light medicinal uses as a sedative. Due in part to the limited nature of Native American practices with tobacco products in the context of ceremonial settings, and the lack of recreational use, instances of chemical dependence appear to have been rarer than in later exposed populations. Upon exposure to the European populace in the early 1500’s, it rapidly grew in popularity due to its supposed medical uses passed along secondhand from New World traders, and supported by mainland European physicians. Additionally, the highly-addictive nature of nicotine found many victims whom were unaware of its trends towards chemical dependence in a more rapid fashion that that of other drugs at the time, such as alcohol. As plantation level quantities arose to meet demand, Eurasia was flooded with exposure to the potent new drug and tobacco rapidly became a common portion of European and south Asian culture. As individuals took to growing their own tobacco plants in southern Europe and south Asia, tobacco permeated the common culture for its potent stimulant qualities. For a period of time in the prior to the Civil War, tobacco excise tax was responsible for a full third of the United States internal revenue sources.

Fig 1: Nicotina Tabacum, flowering (Google images)
Fig 1: Nicotina Tabacum, flowering (Google images)

In a tobacco enveloped world, the identification of chronic health risks (particularly cancer) would take time before becoming a publicly noted concern, with major public knowledge about the risk of smoking only coming to the forefront in the middle of the 20th century.  As nicotine itself is not conclusively linked to having carcinogenic properties, it has been perceived as safer than other  compounds found within cigarettes, and has as such been less regulated then the carcinogenics and additives targeted by regulatory organizations.

With the rise of smoking cessation products on the market offering supplemental forms of nicotine combined with the emergence of electronic nicotine delivery systems (ENDS) over the past decade, possible sources of nicotine in more concentrated and less popularly understood forms have risen on the marketplace. As a result, incidences of accidental nicotine poisoning have risen, with the mechanism of delivery being the major changing factor.

Figure 2: The progressive rise of acute nicotine toxicity incidents from 2012-2014, as measured in incidents per month. (Chatham-Stevens 2014)
Figure 2: The progressive rise of acute nicotine toxicity incidents from 2012-2014, as measured in incidents per month. (Chatham-Stevens 2014)


Symptoms and of acute Nicotine toxicity:

Acting as a CNS stimulant, nicotine toxicity primarily is expressed clinically via hypertension, tachycardia, and bodily tremors (Schep, 2009). In late stages and high quantities of nicotine poisoning, slowed symptoms of the body including low blood pressure, slow heart rhythms, and difficulty breathing present themselves. These symptoms can be primarily attributed to its mechanism of action upon Nicotinic-type acetylcholingeric receptors (nAChR’s), which are responsible for proper muscle signaling.

nAChR’s are neuron receptor proteins which regulate and signal for muscle contraction within the body in response to chemical stimuli. Usually triggered by acetylcholine, nAChR’s are also found to have favorable binding interactions with nicotine, leading to opening of it’s non-selective cation channel. With the increased allowance in cation transfer, positively charged entities such as Sodium and Potassium are more freely able to cross and depolarize the plasma membrane of the cell. The resulting depolarization stimulates neurons to fire action potentials, being the mechanism by which the stimulant effects are most felt.

Figure 3: A modeling image showing the 5 domains of nAChR bound to nicotine molecules, highlighted in yellow. (Celie 2004)
Figure 3: A modeling image showing the 5 domains of nAChR bound to nicotine molecules, highlighted in yellow. (Celie 2004)

Like most natural systems, prolonged exposure to a stimulus can lead to decreased response to that stimulus in later iterations. In the context of nAChR’s, an abundance of nicotine binding to sites in place of acetylcholine can lead to poor mediation of gated cation channels, which in turn corresponds to a lack of action potentials. With this corresponding decrease in the number of action potentials within the musculoskeletal system, impairment of respiratory and cardiac muscles is followed by lethargy and systemic effects up to and including comas. These symptoms tend to be more serious than those of low-level nicotine use, as the drug moves from having primarily stimulatory effects upon the body to impairing wide-ranging effects of acetylcholine mediated processes.

Figure 4: A close up image of a nicotine molecule in binding configuration with the nAChR alpha subunit complex. (Vos, 2015)
Figure 4: A close up image of a nicotine molecule (highlighted yellow)  in binding configuration with the nAChR Alpha subunit complex. (Self 2015)

Nicotine containing products maintain a unique place in the world of recreational drugs, as those which are inhalable (cigarettes, pipes) allow for determination by the user of the effect they wish to feel. Lower quantities of nicotine inhalation lightly act upon the acetylcholine receptors, and preferentially stimulate complexes responsible for releasing epinephrine and other stimulatory agents within the brain. In higher concentration ingestion instances of nicotine, nicotine begins to bind more to nAChr’s mediating dopamine and serotonin release then those involved in musculoskeletal and epinephrine release, leading to pain-relief properties and altered states of consciousness, as well as instigating nicotine dependence. (Griffiths, 1982)

With the rise of electronic cigarettes, liquid nicotine has become more accessible to the public. As nicotine is capable of being absorbed through the skin, this presents another avenue of risk, especially when considering that nicotine found in liquid state is of much higher concentration then nicotine found within a cigarette (up to 36 mg/ml versus ~1.06 mg nicotine per traditional cigarette) (Schroder 2014). With 120 ml bottles of pure 36 mg/ml nicotine retailing  for 12 dollars online, and options for purchase of up to 1 gallon of nicotine concentrate, the capability for accidental misuse is incredibly present. For reference, a 10ml spill of high concentration nicotine on an ungloved hand would have the same potential effects as smoking 360 cigarettes, or 18 packs. As the LD50 for nicotine has been determined to be 6.5–13 mg/kg (Mayer 2014), this small spill would be potentially lethal for a person of 120lb.

In contrast to acute conditions, nicotine dependence is formed over time by way of continued stimulation of serotonin and dopamine levels in the brain. With the original rate of release of these chemicals disrupted, the brain initially responds in a heightened fashion to these stimulated levels before adjusting to the new levels as a baseline for activity. With this baseline established in the presence of nicotine, a lack of nicotine activity effecting the release of neurotransmitters leads to the brain under-producing those same chemicals. With decreased levels of dopamine and serotonin released, the individual can report a plethora of mental health concerns including depression, leading to urges to consume nicotine in order to return to normal operating levels of neurotransmitter activity.


As an acute disorder, nicotine toxicity presents symptoms in a rapid fashion. In lower quantities, excessive stimulation may be observed via increased physiological processes such as respiration and pulse, as well as behavioral changes consistent with an excited state such as more energy and physical activity in the individual. Nicotine toxicity in higher levels acts upon many of the same processes, and slowing down of respirations and pulse may be observed in critical scenarios. Additionally, dizziness and confusion consistent with an altered mental state may be observed in high levels of nicotine toxicity, leading to further implications of drug overdose in the patient.

Blood tests which inspect for cotinine, the predominant metabolite of nicotine, may also be used to effect in determining concentration of nicotine within an affected individual. With gas-liquid chromatography apparatus, samples can be analyzed in as little as 3 minutes, allowing for a quick and efficient determination of nicotine content within a patient’s blood (Feyerbend 1990).

3 Replies to “History and Metabolic Context”

  1. Hey Anthony-I found this to be interesting, since nicotine is in so many legal, oft-used substances. I have a couple questions. First, you mention that nicotine binding (as opposed to acetylcholine) to nAChRs can lead too “poor mediation” of the ion channels. What do you mean by this? Do you mean poorer function, or do you systematic downregulation of receptors? Does downregulation lead to the lack of action potentials? I feel like downregulation seems likely, given that you mentioned that the lack of action potentials increases the more nicotine you use. Clarification would be awesome.

    My second question is one for which I don’t know if there is an answer. Is there a reason why nicotine preferentially activated nAChRs associated with epinephrine first, and then those associated with serotonin and dopamine? This may just be “the way it is,” but I’m pretty interested in why this happens. Are the epinephrine nAChRs just closer in proximity to where nicotine crosses the BBB?


    1. Hi Gabbie,
      Great questions!

      Acetylcholine binding to the designated Ach receptors provokes a systematic and regulated response in regards to action potentials, muscle contractions, and neurtransmitter production. Nicotine ont the other hand binds in a more aggressive manner, rapidly hyper-polarizing the membrane and creating a surge of action potentials before becoming overstimulated by the constant barrage of nicotine as compared to acetylcholine binding activities, restricting their behaviors, and leading to an insufficiency of action potential mediated responses within musculoskeletal tissues.

      As far as the stimulation of epinephrine goes, the primary activity appears to center around the inner part of the adrenal medulla, a location which also happens to process small amounts of stimulation of dopamine neurotransmitter behavior. As such, I would hypothesize that the same pathways leading nicotine to act upon dopamine happen to also affect epinephrine whilst in this area. As far as relative affinity goes, epinephrine appears to have a more easily initiated mechanism of response as compared to dopamine, based on kinetic experimentation done looking at the use of both in the context of Shock treatment.

  2. Hi anthony. I enjoyed reading your page.

    Most of what you discussed has to do with the voluntary consumption of nicotine through cigarettes. How prone are individuals to nicotine toxicity via chewing tobacco? Can someone who is trying to quit other tobacco products consume too much by gum? Have you seen nicotine toxicity levels for other organisms? Many cigarettes are wasted or thrown out before all the tobacco has been smoked. Likewise, chewing tobacco is discarded in its entirety. ‘Discarding’ is often just throwing tobacco out the window or into grasses or mulch. Is there an accumulation in the outside environment where residual tobacco products can leach nicotine into soil, water or can be consumed by other organisms? What is the likelihood of nicotine accumulating and having a toxic effect in this scenario?

    I also noticed you mentioned toxicity for a standard build of 120 lbs. How much is toxic for other heights and weights? I have seen parents holding their children in the right and a cigarette in the left hand. You didn’t mention anything about second-hand smoke. How effected are children from second hand smoke? What is the frequency of nicotine toxicity in small infants and other small children?

    Just some thoughts that came to my head. Thanks in advance for thoroughly answering them all.

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