Nicotine a is naturally occurring parasympathetic stimulant, which is found in plants of the nightshade family and various other plant leaves including Nicotiana tabacum, which is used in the manufacture of tobacco. Acting as a nicotinic acetylcholine receptor agonist nicotine is recognized as being highly addictive, and has a stimulatory effect in humans, impacting the cardiovascular system, respiratory system and central nervous system. Importantly, humans and mammals in general, develop tolerances to nicotine, which is one of the reasons why it is thought to be so addictive.
Although it is absolutely categorically proven that smokers are at a massively increased risk of developing both lung and oral cancers and other pulmonary diseases, at the same time smokers do seem to have a reduced risk of certain other diseases such as the neurodegenerative disorder Parkinsons Disease. Non-smokers are at least three times more likely to die of this than nicotine puffing smokers—interesting, but yet maybe not necessarily surprising.
The widespread physiological effect of nicotine is one of the reasons researchers suggest that it could indeed have medicinal uses outside of the psycho-stimulatory effect of euphoria and relaxation/stress reduction that many smokers associate with it. That’s not to say that nicotine in high doses isn’t dangerous. It is, and the U.S. Center for Disease Control still labels the chemical compound as a toxic chemical, but yet it’s not clearly established if it’s possible to pharmacologically harness any health benefits of the drug.
Merely by its mode of action, nicotine is known to stimulate the release of many neurotransmitters and one of these is endorphins. Endorphins act in a similar manner to morphine and naturally impact the perception of human pain and modulate its pathway. Endorphins may also be involved in creating feelings of euphoria, which can be equally associated with nicotine use. The evidence for this particular physiological response to nicotine is well documented and the pathway understood, lending weight to the potential of nicotine in pain management.
Maybe less well documented and acknowledged is the effect that nicotine may have on vasculature and revascularization. However, in 2000 a group of Stanford scientists accidentally discovered that nicotine, rather than damaging blood vessels, which is what they initially set out to prove, may actually stimulates the growth of new blood vessels, thus increasing and improving circulation. Ulceration is common in diabetic patients due to various factors including hyperglycemia, neuropathy and atherosclerosis. Left untreated ulceration may result in gangrene and limb amputation, having a huge impact on morbidity and mortality of patients. One of the outcomes of this discovery was the development of a nicotine-based topical gel, which has been investigated for its effect on diabetic ulcers. The nicotine-based compound, Targacept, which was being investigated by San Francisco-based CoMentis, entered into human trials in 2007 but in mid-2015 the product was dropped due to not reaching its primary end-point in Stage I/II trials, and consequently heard of no more.
Another area of interest for nicotine is in the area of neurological disorders. There are plenty of theories that the little compound could be beneficial in conditions such as Parkinsons Disease (PD) and Alzheimers Disease (AD). Management of PD with the use of nicotine has been investigated since the mid-late 1960s when Harold Khan, an epidemiologist at the National Institute of Health noticed a misnomer in the prevalence of PD in smokers compared to non-smokers. His theory was that as nicotine stimulates the release of dopamine in the brain, the neurotransmitter, which seems to be less abundant in Parkinsons, and the chemical may well be an effective substitute in stimulating release.
The Michael J. Fox Foundation initiated the first human clinical trial with the use of nicotine for treatment of PD several years ago in 2013. This double-blind trial has recruited over 150 PD patients randomized to either a nicotine patch (15mg) or placebo and is expected to deliver results by the end of 2016. A similar pilot study published by the University of Vermont in 2012 indicated that mild cognitive impairment (MCI) could be positively impacted also by application of a 15mg transdermal patch of nicotine on a daily basis. Many sufferers of the condition already self-treat, rightly or wrongly, with nicotine products. Sometimes, as we say, the proof is in the pudding.
In a similar vein, Alzheimers is thought to be another area where nicotine may prevent, delay or alleviate symptoms. This is thought to be due to a combination of stimulation of production of acetylcholine and glutamine, both having a positive effect on memory, cognition and learning. In 2012 a small research study published in the journal Neurology investigated the same level of 15mg nicotine on long-term memory tests in Alzheimers sufferers and suggested a very similar effect that has been reported in previous investigations.
It remains important however to understand the pharmacology of the action of nicotine in order to move forwards and develop these potential therapies, and many animal models have been investigated. Interestingly the University of Texas has very recently published results on the effect that nicotine has upon appetite in animal models and suggest that this may well be an indication of its ability to protect and modulate the synaptic responses in the brain.
Researchers at the Texas A&M College of Medicine have investigated the effect that feeding animals low and medium concentrations versus high concentrations of nicotine-loaded drinking water has had on their feeding habits. The output of the research is that the lower and medium levels of nicotine water seemed to have no effect on weight gain, food intake and receptors in the brain; however the higher group elicited lower food intake, reduced weight gain and an increased number of receptors. Bearing in mind that appetite is physiologically influenced by hormones and neurotransmitters, is nicotine able to ‘bend the brain’ to influence eating behavior? Could this influence extend to more complex behaviors?
Nicotine seems to have a wealth of evidence behind it from a pharmacological point of view in terms of benefitting—not treating—a lot of pathologies. Yet still there are no FDA approved nicotine treatments for alleviation of any diseases currently on the market. For smoking cessation, yes, but not for any of the above outlined conditions. Maybe we’ve tarred our own brush because the carcinogenic relationship with nicotine is ingrained in so many minds that we’re missing a great opportunity on a readily available compound for Pharma. The risk benefits of e-cigarettes aren’t clearly outlined yet either. For a chemical compound that’s been around for so long it’s an interesting conundrum that no line has been drawn around its benefits but lots of ‘wooly’ research is ongoing looking for proof that nicotine could help many people.
What needs to remain clear is that smoking kills, and that puffing away isn’t the solution to the problem. But it would be amazing if something pharmacologically good could come out of the bad and prove to be an amazing, easily available, cheap therapy for these conditions. Maybe it’s time to give this ‘bad boy’ a chance?
Adele is a design consultant who works in product development for medical and healthcare applications. Her background is in pharma, and she has a degree in applied physiology