Abstract
The health risks of smoking are well known, yet people continue to smoke, even after diagnosis of smoking-related cancer. Relapse is common even after years of abstinence. This review integrates the latest neurobiopsychological research to illuminate why smokers keep smoking. Nicotine has a virtually global effect, facilitating release of multiple neurotransmitters throughout brain and body. As well as acting on the cholinergic system, nicotine is a pharmacological chaperone for other systems involved in learning and reward, including endocannabinoid, dopaminergic, serotonergic, and opioid systems, thus facilitating multiple addictive pathways. Nicotine activates the same opioid receptors as morphine, and treatment with the opioid antagonist naltrexone is more effective than nicotine-directed treatments. There is some indication of a genetic propensity to smoking, and consistent evidence of structural and functional brain damage that likely serves to maintain the addiction and inhibit quitting. Smokers show widespread white matter and grey matter atrophy, and sex differences are evident. Nicotine and smoking affect the brain differently, although both are correlated to lasting, potentially irreversible damage. Damage to amygdalae may decrease effective threat-response behaviour. Transcranial Magnetic Stimulation and pharmacological treatments with naltrexone, ketamine, and psilocybin show stronger effects in achieving long-term smoking cessation than risk-awareness raising or nicotine replacement therapy. It may be helpful to increase public awareness of smoking/nicotine-related brain damage; for smokers to access appropriate support and newer, more effective, treatments; and, given nicotine’s pharmacological chaperoning qualities, to treat tobacco and substance abuse concurrently.
Keywords: chronic smoking, nicotine addiction, smoking-related brain damage, smoking treatments, tobacco use disorder, substance abuse disorder.
Why smokers keep smoking: a review of evidence and new approaches to treatment.
Each year smoking is associated with approximately 15,000 deaths in Australia (Kring et-al., 2018), and around 6 million globally (Peacock et-al., 2018). Australia’s policy-focus to reduce smoking has been on raising public awareness of the risks (Commonwealth of Australia, 2012): yet less than 5% of smokers who try to quit succeed (Greenhalgh, Stillman & Ford, 2018). In the USA, a surprising 64% of patients with smoking-related cancer continue smoking after diagnosis (Tseng, Moody-Thomas, Martin, & Chen, 2012). Clearly, awareness of risks alone is insufficient to induce quitting: those in the 64% likely have keen awareness already.
This review integrates the latest neurobiopsychological research on smoking and nicotine’s impact on the brain and body to illuminate why smokers keep smoking. It finds the underpinning mechanisms are complex, involve multiple dependencies and addiction pathways, and involve brain damage which may serve to sustain the addiction. The findings suggest risk-awareness is inadequate to effect long-term cessation, and that tobacco and substance abuse should be treated concurrently.
Tobacco Use Disorder (TUD) and Substance Use Disorder (SUD) are recognised separately by DSM-5, although they frequently co-occur (Schroeder, 2017). Nicotine is the principal addicting agent of tobacco, reported to be as addictive as heroin and methamphetamine, and has widespread effects on the brain (Chawla & Garrison, 2018). Nicotine acts as an agonist on nicotinic acetylcholine receptors (nAChRs), which are abundant throughout the brain—in cell bodies and axon terminals—and across multiple pathways associated with learning and reward (Chawla & Garrison, 2018). Nicotine’s activation of nAChRs facilitates the release of multiple neurotransmitters, including acetylcholine, dopamine, noradrenaline, glutamate, and GABA. nAChR binding occurs extensively across the cerebral cortex, thalamus, hypothalamus, midbrain, and hindbrain (Zarrindast & Khakpai, 2019). Nicotine binding also occurs extensively throughout the body—in the endocrine system, autonomic nervous system, and peripheral nervous system—and induces homeostatic and cellular changes (Chawla & Garrison, 2018). Thus, evidence suggests that nicotine addiction exists globally throughout the brain and body.
Evidence also suggests that addiction may extend beyond nicotine. Nicotine recruits other neurotransmitter systems involved in learning and reward, including nitric oxide, endocannabinoid, dopaminergic, serotonergic, and opioid systems, thus acting as a ‘pharmacological chaperone’, facilitating multiple addictive pathways (Zarrindast & Khakpai, 2019). Nicotine activates the same opioid receptors that are activated by morphine (Scott et-al., 2007). Nicotine causes the release of endogenous opioid peptides: it widely stimulates opioid peptides and receptors in the striatum; and prolonged use activates opioid receptors in the cingulate cortex, integrally linked to reward. Changes also occur in endogenous endorphins and enkephalins throughout the body, both after nicotine administration and after nicotine withdrawal (Berrendero et-al., 2010). Endogenous enkephalins and activation of opioid receptors are necessary for the physical manifestations of nicotine withdrawal (Zarrindast & Khakpai, 2019). Thus, plausibly, opioids, not nicotine, may be the source of pleasure from smoking, and potentially why smokers keep smoking. Supporting this suggestion, treatment with the opioid-antagonist naltrexone is more effective for quitting smoking than nicotine-directed treatments (Kohut, 2017).
There is also some evidence of genetic propensity to smoking. A polymorphism on CHRNA5[1] , a protein-coding gene, increases vulnerability to smoking and predicts quit-failure (Chawla et-al., 2018). Carriers of the AG/GG allele of opioid gene receptor OPRM1[2] display significantly increased dopamine binding following smoking than people with the more commonly occurring AA allele (Domino et-al., 2012), suggesting a genetic link between the opioid and cholinergic systems for those with the at-risk allele, and a genetic propensity to smoking addiction.
Changes in brain structure and functioning may also contribute to ongoing smoking addiction. Although well-known as a risk for cancer, emphysema, heart disease, stroke, and other diseases, smoking is less known for its risk of brain damage. Of 30 articles reviewed, 28 strongly associate smoking with structural damage, from ventricular and sulcal enlargement (Longstreth, Arnold, & Manolio, 2000), to widespread deficits in grey matter (GM) and white matter (WM), across the neocortex, midbrain, and hindbrain (Dome, Lazary, Kalapos, & Rihmer, 2010). Sex differences exist: men and women all exhibit GM and WM atrophy, but in different brain areas and to different degrees (Kohut, 2017). Similarly, smokers who drink alcohol present differently to those who do not, and these different presentations may affect quitting and treatment choices (Cheng, 2019). Structural deficits in smokers are consistent with amplified age-related losses and early Alzheimer’s disease (Durazzo, Meyerhoff, Yoder, & Murray, 2017). Resultant functional deficits manifest in sensory processing, emotional processing, attention and working memory, verbal memory, accelerated cognitive decline, and significantly increased risk of dementia (Chawla et-al., 2018). Structural changes may serve to maintain the addiction and may be irreversible (Wang et-al., 2015).
Although study findings vary, the most consistently reported structural changes are GM atrophy across multiple areas in the prefrontal cortex (PFC), insula, thalamus, hippocampus, and right cerebellum, potentially from ongoing exposure to nicotine’s neurotoxicity in these high-density-nAChR areas (Sutherland et-al., 2016). Amygdalae abnormalities are also found: both impaired neural activity (Shen et-al., 2017), and smaller size (Durazzo et-al., 2017). As amygdalae are strongly involved in threat assessment and response, damage may interfere with the ability to adequately detect and respond to harm signals (Mihov & Hurlemann, 2012), potentially rendering fear-arousal approaches to induce quitting (such as risk-awareness-raising) ineffective. GM and WM increases are found in the putamen, and more pronounced in smokers who started in adolescence, possibly as a result of nicotine’s effect on glial activity and proliferation during adolescence (Wang et-al., 2015). As the putamen is involved in incentive drive and plays a role in drug-seeking behaviour, increased volume may amplify this behaviour.
In addition to GM atrophy, smokers have widespread WM volume and structural integrity loss (cortical thinning), in cortical regions and subcortical regions, including amygdalae, nucleus accumbens, and across the total corpus callosum (Durazzo et-al., 2018). That is, not only are there fewer neurons (GM), the connections between them (WM) are weaker. In smoker’s brains, cortical thinning correlates with higher impulsivity, poorer decision-making and greater risk-taking (Durazzo et-al., 2018), which may impede quitting/staying-quit behaviour.
Damage also occurs in the cerebellum of smokers, involved in pain perception (Bocci et-al, 2016), potentially suggesting that chronic smokers may be self-medicating (Unrod et-al., 2014). Functional Magnetic Resonance Imaging (fMRI) shows decreased cerebellar GM volume and functional connectivity, particularly in the left and right Crus I (Shen et-al., 2018), which is closely linked with executive control via a closed loop circuit with the PFC (Buckner, 2013). Potentially through damage to this loop, Crus I may be associated with cognitive decline in smokers. Positron Emission Tomography (PET) scans also reveal anomalous Crus I neural activity in smokers for reward processing, reinforcement, and regulating emotion (Thiruchselvam, Malik & Le-Foll, 2017).
Despite great gains from neuroimaging in advancing understanding of nicotine and smoking’s effects on the brain, many questions remain. Curiously, across all studies, nicotine-dependence shows different effects to those of cigarette consumption. For example, fMRI studies show that working memory structure and function is affected by chronic smoking, but not by nicotine (Sutherland et-al., 2011). Inexplicably, severely nicotine-dependent individuals show less atrophy both in GM and WM than moderately nicotine-dependent individuals (Peng et-al., 2018): that is, those with mild nicotine-dependence display more structural damage than those with heavy nicotine-dependence. PET studies show different neurological responses to nicotine versus smoking, for example cigarette smoking decreases dopamine receptor binding in the nucleus accumbens, but nicotine administration–without the sensory stimuli of smoking – does not (Thiruchselvam et-al., 2017). This suggests sensory cues from the action of smoking may be necessary for a strong dopamine response: indeed, smoking placebo cigarettes increases dopamine levels, despite the absence of nicotine (Domino et-al., 2013). Lastly, two studies that used brain-dissection of deceased adults found no differences in GM or WM volume between smokers and non-smokers, in any part of the brain. These pathology results are inconsistent with neuroimaging results, and further research is needed (McCorckindale et-al., 2016; 2019).
Gains in treating smoking have not been as great as gains in understanding its mechanisms. Nicotine Replacement Therapy (NRT) is barely effective for smoking cessation, with a 6-month successful-quit rate of 7% (Moore et al., 2009), although subsequent relapse rates are high (Akanbi et-al., 2019). Some people use NRT over the long-term to substitute smoking (Shahab et-al., 2017), but this does not treat the underlying nicotine addiction and likely exacerbates nicotine-related outcomes, including comorbid substance abuse and brain damage.
Optogenetics may lead to better treatments. Experimentally, optogenetics has isolated nicotine withdrawal symptoms to a specific location in the brain (the interpeduncular nucleus). Optogenetic activation of these neurons induces withdrawal symptoms regardless of nicotine exposure, and relieves them by blocking incoming neurotransmission from the habenula. Habenula transmission is conclusively linked to nicotine addiction, and Deep Brain Stimulation of the habenula suggested as treatment (Fore, Palumbo, Pelgrims, & Yaksi, 2018). Alternatively, the NMDA antagonist ketamine effectively blocks transmission and relieves withdrawal symptoms (Zhao-Shea et. al, 2013).
Ketamine in sub-anaesthetic doses significantly reduces nicotine self-administration in rats, potentially through its action on glutamatergic receptors, and warrants further investigation as a potential treatment for humans (Rezvani et-al., 2018). Concurrently, ketamine shows promise as a treatment for other addictions including morphine and heroin dependency (Ezquerra-Romano, Lawn, Krupitsky, & Morgan, 2018). Supporting a probable link between cholinergic and opioid systems, naltrexone, traditionally used to treat opioid addiction, significantly increases smoking cessation—80% at one month, 50% at six months—however, the effect diminishes after medication discontinuation to 17% at 12 months
(King et-al., 2012).
Transcranial Magnetic Stimulation (TMS), either single-session or repeated-session, consistently reduces withdrawal symptoms and cigarette smoking. This may be because TMS to the PFC induces an increase in dopamine in the mesolimbic reward pathway, essentially mimicking the effect of nicotine (Maiti, Mishra, & Hota, 2017). Nonetheless, a recent meta-analysis of TMS treatment for smoking found a long-term abstinence rate of 28% was achieved (Vaquez-Beceiro, Marron, & Viejo-Sobera, 2019). Transcranial Direct Current Stimulation (tDCS), conversely, does not appear efficacious either in reducing cravings, or smoking cessation (Alghamdi et-al., 2019; Falcone et-al., 2019).
Psychedelics so far show the most promise. A long-term follow-up study of administration of psilocybin, a serotonin 2A receptor agonist, in combination with cognitive behavioural therapy for smoking cessation showed a 67% success rate as 12 months, and 60% long-term (Johnson, Garcia-Romeu, & Griffiths, 2017). However, sample sizes were small, and more studies are needed.
In conclusion, numerous complex factors interact to keep smokers smoking. Chronic smoking entails a whole brain and body addiction, involving homeostatic and cellular changes, genetic influences, multiple neurotransmitters and reward pathways, and altered brain structure which likely serves to maintain the addiction. Smokers may not respond to fear-arousal campaigns because of an impaired fear-response, due to nicotine-induced damage to amygdalae. Nicotine’s recruitment of the endogenous opioid system implies addiction extends to opioids, supported by evidence that opioid-addiction treatments are more successful in getting people to quit than nicotine-addiction treatments.
This review finishes by suggesting some potentially useful future courses of action. Firstly, although awareness of risks rarely induces permanent quitting, there is need to raise awareness of brain damage associated with smoking, to inform the public and treatment-practitioners. Secondly, public awareness should focus as much on brain-damage risks of nicotine as of smoking, as both are implicated. Nicotine replacement products are frequently used by smokers, as a long-term alternative to smoking, who are likely unaware of the correlates with structural and functional brain damage. Continued use may exacerbate nicotine-related detriments, including comorbid substance abuse, amplified widespread brain damage, and significantly increased risk of Alzheimer’s disease. Thirdly, nicotine acts as a pharmacological chaperone for other reward systems including serotonergic, dopaminergic, and opioid systems, and quitting smoking may be as difficult as quitting heroin. Consequently, awareness-raising campaigns alone are unlikely to be effective. Smokers are unlikely to succeed in quitting without considerable support and access to newer treatments, of which psilocybin, despite its social unacceptability, is most successful. Finally, given nicotine’s pharmacological chaperoning and high comorbidity with other addictions, treating tobacco and substance abuse disorders separately is likely to be futile. Potentially, TUD should be subsumed into SUD.
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[1] CHRNA5 Cholinergic Receptor Nicotinic Alpha 5 Subunit
[2] OPRM1 mu opioid gene receptor
