The Relationship Between Nicotine and Psychosis

The relationship between nicotine and psychosis

Review for Therapeutic Advances in Psychopharmacology

Introduction

It has long been acknowledged that there is a strong relationship between cigarette smoking and psychotic disorders such as schizophrenia. More recently, smoking has also been found to be associated with psychotic experiences in the general population [1, 2]. Rates of cigarette smoking in individuals with psychosis are 2-3 times greater than those without a psychiatric disorder [3]. Moreover, tobacco smokers with psychosis display patterns of heavy smoking, severe nicotine dependence [3] and are less likely to quit than non-smokers .  There is an increased risk of tobacco-related morbidity and excess mortality in this population [4], thus constituting a major contributor to health inequalities.

The reasons underlying the smoking-psychosis association are unclear.  A number of non-exclusive explanations have been proposed:

1. Reverse causation: High rates and intensity of smoking in individuals with psychosis is secondary to the illness itself, whether through self-medication to alleviate symptoms or antipsychotic-induced side effects, to improve attention and working memory, or through a process of institutionalisation.

2. Shared liability: Psychotic disorders and cigarette smoking share some liability, likely genetic, and the high prevalence of tobacco smoking in this population is a manifestation of this common liability.

3. Confounding: Tobacco smoking is associated with established risk factors for psychosis, be they social (e.g. adversity) or environmental (e.g. other drug use), which may be causally related to psychosis. 

4. Smoking may be causally related to psychosis: Inferred from temporality and dose-dependent effects, smoking could be a primary cause of psychosis, or a mediator on the pathway to developing psychosis.

In this paper we review the evidence for these competing hypotheses, using findings from the latest epidemiological, neuroimaging, genetic and preclinical work.

Effects of nicotine on the brain

The main components of tobacco smoke are nicotine, which is an alkaloid found in tobacco leaves and the neurologically active agent responsible for the addictive properties of cigarettes, and tars, the term given to the resinous, partially combusted particulate matter (which includes polycyclic aromatic hydrocarbons) produced by the burning of tobacco and responsible for its toxic effects. Inhalation of smoke from a cigarette distils nicotine from the tobacco in the cigarette. Nicotine attaches to tar droplets and is absorbed by tissues in the mouth, nose, throat and alveoli in the lungs, where it is absorbed into the pulmonary venous circulation. Nicotine is then pumped into the arterial circulation and distributed through the bloodstream, crossing the blood–brain barrier and reaching the brain 10–20 seconds after inhalation [5].

The nicotinic cholinergic receptor and neurotransmitter release

Once in the brain, nicotine binds to nicotinic acetylcholine receptors (nAChRs). These are presynaptic receptors located throughout the brain, with the highest density seen in the thalamus, followed by the basal ganglia, and frontal, cingulate, occipital, and insular cortices (REFs). Neuronal nAChRs exist as multiple subtypes of pentameric structures with unique combinations of at least seventeen (α1–α10, β1–β4, γ, δ, ɛ) genetically-distinct subunits; these have different distributions, functional properties and pharmacological profiles [6]. Nicotine demonstrates highest affinity for nAChRs that contain α4 and β2 subunits, these are the most abundant nAChRs in the brain [7]. Nicotine binding opens an intrinsic ion channel in the receptor and allows the flow of cations (Na+, Ca2+, and K+) through the cell membrane, activating voltage-gated calcium channels and leading to neurotransmitter release. Nicotine is known to alter the release of virtually all major neurotransmitters (including dopamine, acetylcholine, endogenous opioid peptides, GABA, glutamate, noradrenaline and serotonin) [8].

Addictive and cognitive effects

Nicotine causes dopamine release in broad target areas throughout the brain. The addictive properties of nicotine appear to be associated primarily with mesolimbic dopaminergic pathways; activation of nAChRs in the ventral tegmental area (VTA) results in the release of dopamine in the shell of the nucleus accumbens, which has a role in perception of pleasure and reward. Stimulation of nAChR on dopaminergic neurons increases their firing rates, but these receptors desensitize rapidly. Nicotine also increases glutamate and GABA transmission in the VTA. Moreover, whereas the nicotine-induced increase of GABA transmission rapidly desensitizes, the glutamate response does so to a much lesser extent. Thus, following nicotine administration, there appears to be a net shift in the balance of excitatory and inhibitory inputs to dopaminergic neurons in the VTA such that inhibitory GABAergic transmission is decreased and excitatory glutamatergic transmission is increased. Link to psychosis neurobiology?

Nicotine’s cognitive-enhancing properties appear to be linked at least in part through nicotine-induced release of dopamine in mesocortical pathways connecting the VTA with cortical regions, including the prefrontal cortex [9].

Sensitivity to nicotine in the adolescent brain

Neural development is far from complete at birth, and continues into adolescence and early adulthood [10]. Adolescence is a critical vulnerability period for the initiation of tobacco smoking, with an earlier age of smoking initiation associated with greater severity of nicotine dependence [11]. The relationship between exposure to nicotine and neural structural characteristics varies across developmental epochs, and there is evidence to suggest that nicotine may affect the trajectory of brain development [12]. Nicotine appears to have a role in influencing neuronal growth [16], and Nordman et al. show that stimulation of nicotinic receptors with nAChR agonists (such as nicotine) results in decreased axonal surface areas, whereas nAChR antagonists increase axonal surface areas [17]. In rodents, frontostriatal circuitry appears particularly susceptible to nicotine exposure during adolescence [13], with subsequent cognitive deficits in adulthood [14, 15]. Chronic exposure to nicotine is associated with upregulation of nAChRs [18], and preclinical data indicate that the adolescent brain may be more susceptible than the adult brain to nicotine-associated increases in nAChR expression [19].

The smoking-psychosis association: candidate hypotheses

Reverse causation

Until recently, it was generally assumed that the smoking-psychosis association could be explained by reverse causation, that cigarette smoking was a consequence of psychosis itself. This could arise through: (a) a process of institutionalisation, whereby smoking habits are culturally transmitted via hospitals and other mental health settings; (b) due to psychotic individuals who smoke being less likely to give-up due to more limited access to smoking cessation treatment, misguided attitudes and misconceptions held by mental health staff [20] or through boredom, apathy or reduced motivation; or (c) through the concept of self-medication.

The self-medication hypothesis assumes that psychotic individuals smoke to allay clinical symptoms or treatment side effects. Nicotine has been shown to diminish negative symptoms of psychosis, to reduce distress, as well as decrease sedating and other effects of antipsychotic drugs (i.e. smoking might correct a pharmacological abnormality such as excessive dopamine blockade). Constituents of tobacco smoke can increase the metabolism of antipsychotic drugs through induction of cytochrome P450 enzymes, thereby attenuating their pharmacokinetic effects, whereas use of nicotine prior to psychosis onset could be attributed to self-medication for anxiety in the prodromal stage of illness.  Nicotine has been suggested to improve cognitive deficits in individuals with psychosis, including working memory and attention [21-24], and in this context nAChRs have emerged as priority targets for the treatment of cognitive and negative symptoms [25, 26]. It is hypothesised that nicotine compensates a hypodopaminergic state in prefrontal areas, thought to be responsible for the negative symptoms and cognitive deficits in psychosis [27].  Indeed, a recent study by Koukouli et al. showed that chronic nicotine administration reversed hypofrontality in mouse models of schizophrenia [28].  Moreover, smoking is implicated in improving various physiological deficits associated with psychosis, including P50 inhibition, sensory gating, smooth pursuit, and antisaccadic eye movements (REFs).

A key principle of the self-medication hypothesis is that psychotic individuals seek out nicotine to alleviate the symptoms associated with the illness or side effects of treatments, that is smoking is initiated upon development of the illness, or initiation of antipsychotic medication. Evidence for this, however, is scarce. Furthermore, systematic assessment of the influence of smoking cessation on psychotic symptoms has also not revealed a major effect [29]. Not all studies have found an improvement in cognition with nicotine use in individuals with psychotic disorders [30-32], and many of those that did assessed patients in acute nicotine withdrawal. A 2008 review stated that the tobacco industry monitored or directly funded research promoting the self-medication hypothesis, in particular, biological research (REF). Such revelations have served to justify continued empirical studies and new and alternative hypotheses to the self-medication concept.

Shared genetic liability

 Large scale genome-wide association studies (GWASs) have identified risk genes for many complex human diseases and traits including schizophrenia and smoking behaviour phenotypes, and these datasets provide an opportunity to examine the genetic relationship between correlated traits, as well as identify shared risk genes. The Schizophrenia Working Group of the Psychiatric Genomics Consortium described 128 separate genetic loci associated with an increased risk of schizophrenia and one of these is located in a cluster of genes—CHRNA5, CHRNA3, and CHRNB5— which code for the α5-α3-β4 nicotinic receptor subunit, the strongest genetic contributor to nicotine dependence [33, 34]. A recent Mendelian randomization study also found that a SNP in the CHRNA3 gene associated with heaviness of smoking and likelihood of being prescribed anti-psychotic medication, which was used as a proxy for risk of schizophrenia, in a sample of smokers [35]. Three further studies have also cast nicotine dependence as a phenotype which shares genetic liability with schizophrenia [36-38].  How much variance explained?

A Swedish study by Kendler et al. found in a co-relative analysis that heavy smokers had an increased risk of non-affective psychosis compared with their non-smoking twin, and there was only a modest decrease in hazard ratio when comparing full siblings to more distant relatives or the general population [39].  It is unlikely, therefore, that the smoking-psychosis association can be explained fully by familial/genetic factors.

Of note, demonstrating shared genetics does not necessarily point to true biological pleiotropy, the phenomenon in which a single locus affects multiple traits. Various scenarios involving mediated pleiotropy, wherein one phenotype is itself causally related to a second phenotype (so that a variant associated with the first phenotype is indirectly associated with the second) are possible. In other words, associations between genetic risk for psychosis and cigarette use might also be consistent with causal effects, reverse-causal effects, as well as pleiotropic explanations (Gage et al. 2016).  Gage et al. use two-sample Mendelian randomisation to show that there is little evidence of a causal association between smoking initiation and schizophrenia in either direction [56]; however, they conclude that this does not rule out a causal effect of smoking on schizophrenia related to heavier, lifetime exposure.

Genetic vulnerability – gene environment interaction?

Confounder, mediator, or a special relationship with cannabis?

To complicate matters further, tobacco smoking is associated with established socioeconomic risk factors for psychosis such as ethnicity, social adversity and childhood trauma, as well as environmental risk factors in the form of illicit substance use.

Cannabis is the most commonly studied illicit substance and its association with psychosis is widely accepted to be causal in nature, and related to its potency (Marconi et al. 2016). Cannabis and tobacco smoking are highly correlated with one another as well as with other substance use, and while many cigarette smokers do not use cannabis, almost all cannabis users smoke tobacco, either in cigarettes (co-use) or as a component of cannabis joint (simultaneous use).

The relationship between these two substances is complex and is challenging to disentangle. The gateway hypothesis posits that tobacco acts as a gateway drug to the use of cannabis (Kandel et al., 1992). However, there is strong evidence for the ‘reverse gateway’ whereby cannabis smoking predicts tobacco onset (Patton et al., 2005), and evidence of genetic factors associated with use of both drugs (Agrawal et al., 2008, Agrawal et al., 2010). Tobacco smoking has been shown to mediate the relationship between cannabis use and cannabis dependence, perhaps due to the more addictive properties of nicotine [57].  Preliminary evidence also suggests that tobacco may offset the effects of cannabis on delayed verbal recall [58]. Co-use leads to poorer psychosocial, cessation and physical health outcomes. Thus, it is plausible that tobacco smoking might directly perpetuate cannabis dependence and relapse in co-dependent users, in this way mediating the risk of developing a psychosis. There might be implications for clinical practice here; there is an extreme lack of empirical research guiding treatments for simultaneous and co-use of tobacco and cannabis (REF) particularly in those with psychotic disorders.

Several recent lines of evidence suggest the endocannabinoid signalling system as an important component in the behavioral and motivational responses induced by nicotine. Exogenous cannabinoids found in the cannabis plant (the most important being tetrahydrocannabinol (THC) and cannabidiol (CBD)) exert their effects through the endocannabinoid system, which comprises endogenous ligands (such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG)), their receptors (CB1 and CB2 receptors), and the enzymes that synthesize and degrade them. CB1 receptors are a natural target for endogenous cannabinoid ligands such as AEA and 2-AG. Animals chronically treated with nicotine show an increase of AEA content in the limbic forebrain, suggesting that cannabinoid-nicotine interactions mat be related to the ability of nicotine to regulate endocannabinoid signalling by triggering the formation and release of endogenous cannabinoids. Tobacco smoking directly directly enhances the subjective effect of cannabis (Agrawal and Lynskey, 2009), increases the amount of THC inhaled per gram (Van der Kooy). Solinas et al. showed that nicotine potentiates the discriminative effects of low doses of THC, an effect reversed by the CB1 antagonist rimonabant, suggesting nicotine-induced release of endogenous cannabinoids, such as AEA, could account for this potentiation. It has been reported that transient increases in dopamine signals in the nucleus accumbens, obtained with nicotine and other psychostimulants, are under a CB1 receptor control. Thus, increased levels of endocannabinoids may also facilitate the stimulation of dopaminergic neuronal activity in the ventral tegmental area.  Indeed CBD has also been shown to be effective in a recent trial (Hindocha).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3821699/

There is also evidence to suggest a synergistic effect whereby the combination of tobacco and cannabis gives rise to psychotic symptoms [2]. Indeed, cannabis has been shown cause psychosis-like symptoms acutely (following intravenous administration of THC), whereas nicotine has not, however despite hallucinogen intoxication causing states that are similar to psychosis, they have only a modest association with schizophrenia (and less than that of cannabis) (Nielsen et al, 2017).

Causal effect

More recently, attention has been directed towards the possibility that tobacco smoking might be causally related to psychosis. Two meta-analyses have reported strong associations between tobacco smoking and an increased risk of subsequently developing a psychosis, estimating odds ratios in smokers vs non-smokers of 6.04 (95% CI 3.03-12.02) [40] and 3·22 (95% CI 1·63–6·33) [41]. The latter study showed that daily smokers developed psychosis at an earlier age than non-smokers (weighted mean difference −1·04 years, 95% CI −1·82 to −0·26). Longitudinal studies that have examined the temporal sequence of this relationship [39, 42], and a dose–response effect has also been reported [39, 43, 44]. Moreover, the association has persisted in prospective samples after adjustment for smoking onset during a prodromal period, and other risk factors such as socioeconomic status, other drug use, baseline psychotic experiences and parental psychosis and drug use [39, 45]. Daily smoking appears to have a greater effect on positive symptoms of psychosis [46], and there is evidence that schizophrenia with comorbid nicotine dependence is more severe and has worse outcomes [43, 47, 48]. Early initiation of daily smoking is also associated with greater risk of subsequent psychosis, consistent with the idea that exposure during a critical period of brain development may be specifically associated with psychosis risk [45, 49].

If cigarette smoking is causally related to psychosis, we must consider how this might fit with our current understanding of the neurobiology of psychosis, which implicates excess subcortical dopamine synthesis and release. In vivo, nicotine might increase dopamine release directly and to a similar degree as other drugs of misuse (measured by PET in the dorsal–ventral striatum and basal ganglia) [50, 51]. Bloomfield et al., however, show that moderate smoking was not associated with marked effects on striatal dopamine synthesis capacity, in contrast to previous findings of elevated dopamine synthesis capacity in heavy smokers [52].  Nicotine alters the release of virtually all major neurotransmitters, many of which have been implicated in the pathogenesis of psychotic symptoms [8]. There is also an inverse relationship between nicotine and risk of Parkinson’s disease [53], a dopamine deficiency disorder. Nicotine may also have a role in the induction of super-sensitivity of D2 receptors, which has been proposed as an explanatory mechanism for several risk factors for schizophrenia and as a common pathway for psychotic symptoms [54]; this idea has been substantiated by work in animal models suggesting that nicotine exposure might increase D2 high-affinity receptors [55].

In this review we have primarily focused on the relationship between nicotine and dopamine. However, a number of other factors and mechanisms have relevance in terms of their relationship with cigarette smoking and the pathoaetiology of psychosis. Firstly, much attention has recently been directed towards inflammation and the neural diathesis-stress hypothesis of schizophrenia [61], and cigarette smoking is highly associated with both release and inhibition of pro-inflammatory and anti-inflammatory mediators (indeed inflammatory processes underlie a number of the physical health consequences of smoking; pre-clinical studies demonstrate that peripheral inflammation can induce neuroinflammation (Dantzer et al. 2014)). Secondly, constituents of cigarette smoke have significant effects on the endocrine system, altering production and metabolism of estradiol, which is thought to contribute to the gender differences in schizophrenia incidence [62] (and is also known to have anti-inflammatory effects), as well as cortisol, which has also been implicated in schizophrenia (and inflammatory processes). Finally, epigenetic processes may mediate the relationship between genetic risk burden, environmental exposure, and phenotype, and increasing emphasis has been placed on the potential role of epigenetic dysfunction in the aetiology of psychosis [63]. DNA-methylation is strongly associated with smoking in a distinct set of loci [64] thus investigation of the tobacco epigenetic signature in individuals with psychosis may provide insight into mechanisms by which tobacco smoking and psychosis are associated.

It is unlikely that schizophrenia is a homogenous disorder with a single pathophysiology; instead, it is more likely a syndrome with distinct neurobiological aetiologies. As the risk that smoking confers in the development of cancer varies considerably as the sub-type of cancer becomes more specific, so might certain parallels be drawn with sub-types of psychosis.

Discussion

In this review we have compared the evidence for four possible explanations for the relationship between smoking and psychosis. The high rates of smoking in those with psychosis led to the uncritical acceptance that these individuals smoke to self-medicate with nicotine, and a self-medication hypothesis proposed nearly four decades ago has remained the default explanation for the association between smoking and psychosis. However, over recent years, studies have exposed that self-medication and reverse causation cannot explain all of the association. Whether tobacco has a direct causal impact on risk for psychosis, or whether the association is confounded by cannabis use or other social or biological factors, remains an open question. Of course, if smoking is a causal risk factor, this does not preclude the possibility that smoking is also used as a form of self-medication, and indeed the dopaminergic effects of nicotine on mesocortical and mesolimbic pathways might support this.

Of growing relevance is the increasing use and popularity of nicotine-containing products, particularly electronic cigarettes. By encouraging the use of such products as part of smoking cessation programmes, clinicians may be inadvertently increasing psychotic symptoms. To our knowledge this has not been studied directly, however Munafo et al. recently reported a modest association with snuff or ‘snus’ use, a form of chewed tobacco, and risk for non-affective psychosis in a large Swedish registry data set [59]. These results are potentially important as they suggest that any causal agent is present in unburned tobacco. Although perhaps the most plausible and widely studied culprit is nicotine, there are other possible candidates, such as monoamine oxidase inhibitors [60]. It might be that different constituents account for different neurobiological effects (some of might alleviate symptoms, while others exacerbate them). Deciphering which constituents are responsible may have important public health implications.

Nevertheless, the dramatic declines in cigarette smoking seen in the general population have not been reflected in individuals with psychosis [65], and there is also stark evidence that the mortality gap is widening . Whilst science continues the challenging task of unravelling this complex relationship, every effort should be made to implement change in smoking habits in this population.

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