We can begin with some stats. 70-90% of those with schizophrenia use nicotine and up to 50% of all cigarettes are consumed by those with mental illness. This should already be quite suspicious. What do cigarettes do though? They bind to acetylcholine receptors as an agonist, and more relevantly, some research shows that nicotine may treat some of the cognitive deficits involved in schizophrenia via nAch7 receptor agonism. This is in support of a more common hypothesis for the correlation of nicotine consumption and schizophrenia, the self-medication hypothesis. Although there may be some truth to this, when we explore the mechanisms further we might see why this proves problematic. Here is a study that is challenging this self-medication hypothesis.

Important highlights quoted from the study:

But, as with many dogmas in science, the dominance of the self-medication hypothesis has been so complete that little attention has been paid to the limitations of its suppositions. For instance, do schizophrenia patients generally become “compulsively compliant” on medications just because they have proven efficacy? No.

Do patients with disorders involving cognitive and nAChR deficits similar to those in schizophrenia (which might also improve with nicotine treatment) generally pick up smoking? No. For example, while cross-sectional studies have shown decreased rates of smoking (but schizophrenia-like declines in nAChR densities [Kadir, Darreh-Shori, Almkvist, Langstrom, & Nordberg, 2007]) in patients with Alzheimer’s disease, midlife smoking is actually a disease risk factor, and not a protective agent, for later dementia (Reitz, den Heijer, van Duijn, Hofman, & Breteler, 2007).

Do schizophrenia patients generally use reinforcing drugs because of their positive cognitive psychoactive effects? No. Substance disorders involving cocaine, alcohol, and cannabis—drugs widely known to impair cognition and/or generate or exacerbate psychosis—are all increased in schizophrenia at rates above those in the general population and with proportional increases similar to smoking (Dixon, 1999; Regier et al., 1990).

Perhaps the most detrimental aspect of the self-medication hypothesis, as a widely held dogma, has been a lack of interest and effort in exploring alternative hypotheses. For instance, might nicotine addiction in schizophrenia represent a case of a far more general, non–drug specific, and involuntary vulnerability to addiction due to an interaction between both disease processes (Chambers, Krystal, & Self, 2001)? Or might smoking in adolescence (when smoking usually starts) actually predispose to or enhance mental illness trajectories in vulnerable populations (Slotkin, 2008)?

With respect to nicotine as a causative agent for mental illness, recent preclinical studies have demonstrated that adolescent nicotine exposure produces long-lasting effects on adult brain function. These include declines in cholinergic transmission and its modulation of monoamine transmitters (e.g., serotonin), a prolonged nicotinic withdrawal syndrome involving sustained cognitive deficits, enhancement of anxiety, and altered nicotine receptor levels that resist abstinence-induced renormalization (Slawecki, Thorsell, El Koury, Mathe, & Ehlers, 2005; Slotkin, 2008).

These results demonstrated that NVHL rats are not merely insensitive to nicotine (as in the cognitive testing) but in fact are hypersensitive to it in a functional domain that is relevant to involuntary processes underlying addiction.

Although nicotine, cocaine, and alcohol are well known to have quite different psychoactive profiles mediated by diverse neurotransmitter effects, they are all addictive via more shared neurotransmitter effects involving common cortical-striatal circuits that govern motivated behavior, addiction, and behavioral sensitization. Given that schizophrenia patients abuse nicotine, alcohol, and illicit drugs like cocaine with rates exceeding those in the general population (Figure 2), our preclinical findings are suggestive of a fundamental neurocircuit-based vulnerability to the addiction process in schizophrenia that is neither voluntary nor drug-specific.

Let’s explore psychosis a little bit before continuing. Researchers have formed a dopamine hypothesis for schizophrenia. It is commonly known that D2 dopamine receptors are implicated in schizophrenia. Another common hypothesis for schizophrenia and psychosis is that hypoactivity of NMDA receptors is involved. It is known that trauma during childhood can be a precursor to psychotic illness later in life. Trauma has been linked to Kappa-Opioid receptor (KOR) activity as well as the endogenous neurotransmitter for KOR, dynorphin. Dynorphin is the neurotransmitter involved in aversion learning, where it opposes reward learning. Dissociation is known to be a common reaction to trauma. This book explores the possibility that NMDA receptors are the main mechanism for dissociative reactions to trauma, which you can find in chapter 22. The class of dissociative anesthetic drugs typically block NMDA receptors, producing dissociative and psychotomimetic symptoms.

So, how does dynorphin fit into all of this here? And what does any of this have to do with nicotine?

Well, dynorphin sensitizes D2 receptor’s functions. There is evidence that dynorphin also inhibits NMDA receptors, at least that is part of the effect. Both of these support the idea that dynorphin itself would be psychotomimetic and dissociative. In fact, there is evidence that KOR agonism in general is psychotomimetic. We know that Salvia Divinorum, a drug that binds to KOR as an agonist produces extreme traumatic and dissociative effects, at least according to the majority of users on the internet. There is increasing evidence that dynorphin and the KOR system are implicated in schizophrenia, and another theory posits that postictal and interictal psychosis in epilepsy is mediated by dynorphin. Furthermore, D1-D2 heteromers have been found to localize on dynorphin neurons in amphetamine addicts and those with schizophrenia.

Many models of drug addiction are based on patterns of opioid signaling, including a rise in dynorphin signaling upon withdrawal, which causes dysphoria and leads to reinstatement of drug seeking behavior. Nicotine has been shown to do this as well.

The Theory

Before continuing, I must say that this is only one possible situation. I think more generally, negative experiences can precipitate psychotic effects and the psychotic effects are often perceived negatively which can further bring upon psychotic effects. Then if others in your life identify you as crazy, this is also painful and negative and can worsen the situation. Being afraid that others will find out can be another common issue.

So onto the example.

In childhood we become traumatized due to an extreme stressor. The behavioral reactions to this stressor become strongly learned, but as the source of trauma leaves, the behaviors become latent. Children rarely face the level of stress that adults face, because they are protected from the adult world so they may first grow up. As these latently traumatized people grow, they find that nicotine can offset many of those stressors temporarily. This leads to increased sensitivity to stressors without the drug via KOR/dynorphin pathway upregulation. Once adulthood comes around, at 20 years old or so, life gets increasingly stressful. This is around the age that schizophrenic symptoms may begin to manifest. Once the stress level reaches similar to the initial traumatic event, the behavioral conditioning that is already learned also begins to emerge. Dissociation, thought problems, avoidance, and other symptoms occur, as well as general reactions to stress, or even possibly becoming traumatized by the emergence of one’s own traumatic response, similar to how ruminating on the possibility of having panic attacks may produce panic attacks.

Schizophrenia may simply be PTSD that originates from childhood experiences, where the child has no real awareness of good coping strategies, and is more prone to dissociate, or even lives a life where dissociation is a realistic strategy due to the lack of responsibilities. Once adulthood comes around, we find that their coping strategies are deeply ingrained and programmed as automatic responses to stressors. Nicotine may slowly potentiate this via upregulating the KOR/dynorphin pathway, making individuals more sensitive to stressors as the withdrawals occur.

What’s worse with nicotine compared to other drugs, for example heroin, is that nicotine would have shorter peaks, thus why smokers re-dose so frequently. This might mean there is more time spent coming down from the drug and also more frequent occurrences compared with dosing heroin, which may last up to 8 hours. The more frequent nicotine is dosed, the more time you may find yourself only feeling relieved closer to the peak of the dose. For example, dosing every 3 hours means you may have found comfort for three hours, and the peak may only last 20 mins max, but you gain benefits of relief for long after and the tolerance shift from the peak is only a little bit. But if you were to dose every 20 mins, you will probably find that waiting beyond this peak will be uncomfortable and the dose is too low for relief. This would explain why the users who smoke the most nicotine are linked to having psychotic disorders.

The withdrawal of nicotine, and thus enhancement of the dynorphin system may sensitize individuals to stress reactions. So imagine that you lost your job during nicotine withdrawal, and your dynorphin is spiking both because of the nicotine withdrawal, but also because of the stress reaction from losing your job. This boost in dynorphin may be just the push you needed to develop traumatic syndromes.

With all of this in mind, it could be that the majority of schizophrenia cases are in fact partly caused by nicotine consumption, or more accurately addiction in general. If this were found true, the industry profiting from nicotine sales would be deeply threatened, so we should expect that studies countering this as well as further support for the self-medication hypothesis to continue growing. There would likely also be more money to invest in the self-medication hypothesis than for the ‘nicotine causes schizophrenia’ hypothesis because there really isn’t money to be made if the majority of schizophrenia cases could be reduced by avoiding the consumption of a product.

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