TUD is a first-order health problem worldwide. In 1984, the World Health Organisation (WHO) recognised this addiction as a public health problem directly related to Chronic Obstructive Pulmonary Disease (COPD), lung cancer, ischaemic heart disease and stroke, which is the leading cause of preventable death in the world. There are groups that are especially vulnerable to this addiction, among them young people and especially those with other mental disorders, for whom the TUD approach constitutes a priority need (1), as will be detailed below, since the prevalence of TUD for them is much higher and more difficult to address than for the general population (2) .
People with severe mental disorders have a prevalence of addiction to tobacco and other substances above 75% (3), more than twice the prevalence in the general population (33%). People with severe mental disorders die on average 15-20 years earlier than the general population, largely due to preventable causes such as TUD (4).
People with severe mental disorders start smoking earlier, smoke more cigarettes per day, inhale more intensely to extract nicotine and are more vulnerable to developing tobacco-related diseases than the general population (5).
The problem of tobacco addiction in patients with other mental disorders is twofold: firstly, the high prevalence of TUD in this group and, secondly, the scarcity of studies and treatment guidelines that specifically address how to approach this clinical condition in dual disorders (6-9). Therapeutic proposals tend to focus on TUD as a behavioural problem, ignoring that it is a chronic brain disorder, like other mental disorders. For these reasons, it is imperative to prioritise studies in this field to establish the most appropriate treatment strategy for each of the mental disorders.
PHARMACOLOGICAL TREATMENTS FOR DUAL TUD
In the SUD field, medication is frequently labelled (indicated) according to its main symptomatic effects; for example, anticraving drugs or old concepts such as replacement therapy, although the perspective of neuroscience offers a more rational vision based on the mechanism of pharmacological action (10).
Neuroscience-based nomenclature (NbN) has been developed in the last decade to classify the treatments used in this field of mental health, including SUDs (11).
For example, there are drugs approved labelled as anticraving, which describes the therapeutic expectations but not their mechanism of action, and replacement therapy, which simplistically alludes to identifying the class of drugs they actually are. In relation to this review, it is proposed to talk about nicotinic drugs, which modulate nAChRs (10).
Returning to traditional indications, there are currently three pharmacological treatments approved by the Spanish Agency for Medicines and Health Products (AEMPS), the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) for the indication TUD with coadjuvant motivational therapy: nicotine, varenicline and bupropion (12).
There are also other unconventional treatment approaches that deserve special attention due to their peculiarity. The mechanism of action, dosage guidelines, advantages and disadvantages of each of these are detailed below.
Nicotine replacement therapy (NRT): These treatments act as modulators of nAChRs with acetylcholine being an important brain neurotransmission system involved in vital physiological functions, such as mood regulation, vigilance, motility, memory and learning (13). This receptor system is also involved in the reward process and regulates dopaminergic transmission at the mesolimbic and mesocortical levels, mainly as an agonist of nicotinic cholinergic receptors (nAChR) α4, β2 and α7, which lead to dopamine release in the dopamine brain reward system.
Dopamine is essential in the development of addictive behaviour and until now the mechanism has been considered to depend on dopamine-dependent plasticity processes within neural networks. However, drug exposure also triggers cellular and molecular adaptations that go beyond dopamine (14), and they would go a step further in the identification of the neurobiological mechanisms of addiction.
When nicotine treatment is started, it acts on the nAChRs and in particular on receptor subtypes such as α4, β2 and α7 (10).
The symptomatic action includes a wide clinical range, such as improving withdrawal, craving and symptoms not related to physiological dependence, such as irritability, anxiety, depression, drowsiness, difficulty concentrating, headache, hunger and sleep disorders.
Administration approved by nicotine regulatory agencies includes a variety of formulations that are administered as follows: orally (e.g. chewing gum, sublingual lozenges and inhalers), via nasal mucosa (sprays) or with skin patches. The pharmacokinetics for these drugs differs from that for nicotine released from burning tobacco, for example.
In this positioning document, we have already stated that the effects of administering nicotine will depend on individual variables determined by genetic differences, both pharmacodynamic and pharmacokinetic.
This treatment is almost twice as effective as placebo (OR=1.84; 95% CI=1.71-1.99) (15).
Table 3 summarises the dosage guidelines, safety aspects and other clinical considerations related to NRT (16).
Table 3.
Nicotine replacement therapy: dosage guidelines, safety and other clinical considerations
| NICOTINE |
Patches |
Chewing gum |
Tablets |
Oral spray |
| Format |
24-hr release:
7, 14 and 21 mg
16-hr release:
10 and 15 mg |
2 and 4 mg |
1, 2, 1.5 and 4 mg |
1 mg |
| Dosage |
> 10 cig/day:
21 mg/day (4–6 weeks)
14 mg/day (2 weeks)
7 mg/day (2 weeks)
≤ 10 cig/day:
14 mg/day (6 weeks)
7 mg/day (2 weeks) |
1st cig ≤ 30 min after getting up: 4 mg
1st cig > 30 min after getting up: 2 mg
1-6 weeks: 1/1-2 h
7-9 weeks: 1/2-4 h
10–12 weeks: 1/4-8 h |
1st cig ≤ 30 min after getting up: 2 mg
1st cig > 30 min after getting up: 1 mg
1-6 weeks: 1/ 1-2 h
7-9 weeks: 1/2-4 h
10–12 weeks: 1/4-8 h |
1-2 sprays in the mouth (6 weeks) if you feel like smoking; reduce progressively afterwards |
| Precautions |
Recent myocardial infarction (≤ 2 weeks); serious arrhythmias; angina pectoris; pregnancy and lactation; adolescents (< 18 years)
Temporomandibular dysfunction (with gum) and bronchospasm (with spray) |
| Most common side effects |
Local skin reaction (pruritus, heat, erythema)
Sleep disorders associated with nicotine absorption at night (insomnia, vivid dreams) |
Oral and pharyngeal irritation
Inconvenience
Gastrointestinal discomfort (dyspepsia, nausea)
Hiccup
Jaw muscle pain |
Oral and pharyngeal irritation.
Gastrointestinal discomfort (dyspepsia, nausea)
Hiccup |
| Advantages |
High adherence
Can be combined with other therapeutic drugs
24-hour release |
Possibility of oral replacement therapy
Lower weight gain
Individual dosing to control withdrawal and other symptoms
Can be combined with other drugs for TUD |
| Disadvantages |
No adjustments allowed in monotherapy.
Not suitable for patients with dermatological disorders |
Requires adequate dose control
Not suitable for patients undergoing dental treatment
Requires training in the form of use to achieve adequate effectiveness |
Requires adequate dose control |
Varenicline: The development of varenicline is preceded by experiences with cytisine, an alkaloid, nicotinic partial agonist, with limited passage to the brain that has been used for years in Bulgaria as a treatment for TUD and is now marketed in the rest of Europe. Varenicline is a partial agonist drug. The mechanism of action of varenicline is attributed to the binding to nAChRs through the α4, β2 nicotinic receptors that are particularly expressed in the brain reward system, giving rise to two complementary effects. The first is a partial agonist effect, substituting nicotine, which causes a dopamine release of 50-60% in the NA, compared to 100% that would be produced by a pure agonist. This effect is responsible for the decrease in withdrawal symptoms and craving. It also has a second antagonistic effect on nAChRs that decreases the reward when administering tobacco, when the patient is in treatment.
In a meta-analysis, the efficacy of varenicline for TUD was found to be almost three times higher than placebo (OR=2.88; 95% CI=2.40-3.47) (15). In some European countries, it is recommended as a second therapeutic option, only after failure with nicotinic agonists (17), although this recommendation is not based on evidence.
The efficacy of varenicline in patients with TUD and other mental disorders such as depression, anxiety or psychosis has shown no differences and does not vary with diagnosis (18). In patients with dual disorders with schizophrenia, it is as safe as in the general population. However, despite the fact that benefits similar to those of nicotine would theoretically be expected, it has not been shown to improve cognitive performance (19).
Another important effect of this drug, according to the perspective of neuroscience-based nomenclature (NbN), is that it acts on other mental functioning dimensions; for example, to reduce the number of standard alcohol consumptions per day in patients with alcohol use disorder; however, no significant reduction in consumption was seen (20).
Other actions of varenicline were improvements in: hyperactivity symptoms in patients with subclinical ADHD (21); efficacy in depressive symptoms related to the need for tobacco; in the treatment of TUD in smokers with depression (22) and with anxiety symptoms (23).
It is clear that modulating the nicotinic cholinergic system produces effects on mental functioning that go beyond tobacco addiction.
The side effect profile includes nausea, gastrointestinal symptoms, sleep disturbances and, very rarely, mood changes with occasional suicidal ideation (10,24). The serious potential appearance of suicidal ideation should always be monitored, although it is very rare. For gastrointestinal side effects, it is recommended to associate drugs such as sulpiride or antiemetics, at least in the first weeks of treatment, although there is no evidence for this proposal.
In July 2021, some batches of varenicline were withdrawn from the market due to a notification of the possible presence of the impurity N-nitrosovarenicline at a higher than allowed concentration. After an evaluation carried out at the European level, a more restrictive limit was established for the presence of this impurity in September 2021, which led to the complete withdrawal of the entire stock of varenicline. Taking into account the available data, an immediate risk has not been identified for patients treated with this drug, since the oncogenic capacity in short-term treatment is not proven (25). At the date of the last revision of this text, no specific deadlines are known for the remarketing of the active ingredient.
Bupropion: This is a monocyclic antidepressant that inhibits the reuptake of norepinephrine and to a lesser extent dopamine, marketed under different names depending on whether it is used as an antidepressant or for TUD. Bupropion acts by inhibiting norepinephrine reuptake and as a weak dopamine reuptake inhibitor, along with activation of the serotonergic system by action on the dorsal raphe nucleus (26). It also has an antagonistic action, not a broad spectrum, on the nAChRs. Its efficacy is less than other available treatments, although its combined use with varenicline or others can be considered. Its therapeutic action also goes beyond TUD; treating depression, anxiety or some ADHD symptoms, for example.
Table 4 summarises the dosage guidelines, safety aspects and other clinical considerations for varenicline and bupropion (16).
Table 4.
Dosage guidelines, safety aspects and other clinical considerations for Varenicline and Bupropion
|
Varenicline |
Bupropion |
| Formats |
1st week of treatment: 0.5 mg tablet
Rest of treatment period: 1 mg tablet
Follow-up: 1 mg 150 mg extended-release tablets |
150 mg sustained release tablets |
| Dosage |
Days 1–3: 0.5 mg /24 h
Days 4–7: 0.5 mg /12 h
Stop smoking between days 7 and 10
Day 8–12 weeks: 1 mg/12 h
Start: 1 week before stopping
Take with water after eating
Dose adjustment in patients with renal insufficiency
Duration: 12 weeks, with possible extension of 12 weeks
Possible start 1 month before D-day with a weekly reduction regimen |
Days 1-6: 150 mg/24 h
Day 7 and following: 150 mg twice a day with at least 8 hours between doses and not close to bedtime
Stop smoking during the 2nd week of treatment
Duration:7-9 weeks |
| Precautions |
Adjust dose for kidney failure (clearance
< 30 mL/min consider half the dose)
Contraindicated in end-stage renal failure, pregnancy and lactation |
Drugs that lower the proconvulsive threshold
Liver disease
Adolescents
Pregnancy and lactation |
| Contraindications |
|
History of seizures
Eating disorders
Sudden interruption of alcohol or benzodiazepine consumption (risk of seizure)
Use of MAOIs in the previous 2 weeks. |
| Side effects (most common) |
Nausea, headache, insomnia, nasopharyngitis, gastrointestinal disorders |
Nausea, headache, insomnia, dry mouth, anxiety, gastrointestinal disorder s and seizures |
| Advantages |
Most effective drug in monotherapy
Two daily doses and good adherence
Different mechanism of action in second treatments
Absence of hepatic metabolism.
Lower risk of interactions |
Good adherence
Less weight gain
Useful in patients with depression
Possible combination with NRT |
| Disadvantages |
|
Seizure risk |
Other drugs have been studied for the treatment of TUD and considered effective, but are considered as 2nd line, due to their side effect profile or because they were not found in the Spanish market.
Nortriptyline: A second generation tricyclic antidepressant, which acts primarily as a norepinephrine reuptake inhibitor. It can increase dopaminergic transmission in the frontal cortex and at high doses can increase serotonergic transmission (27).
Several studies have been done for its efficacy in TUD (28-30), and it is currently considered as a second-line pharmacological tool; not so much because of its low efficacy but because of its common moderate-severe side effects (e.g. dry mouth, dysgeusia, dizziness).
The nortriptyline doses used are 75 and 100 mg, depending on the study, for 6-13 weeks. It was shown to almost double the long-term abstinence rate compared to placebo, although its efficacy in patients with defined dual disorders is unknown.
Another study with interesting results included a comparison between smokers with a high Fagerström test score (≥ 7), considered severely dependent, with smokers with lower scores. Nortriptyline was significantly more effective than placebo in the severely dependent group (60.4% vs 7% abstinence, p=0.001) but not in the lower scoring group (31).
Another study in combination with NRT did not demonstrate superior efficacy over placebo (32).
Cytisine: An alkaloid of plant origin, with a chemical structure similar to nicotine. It acts as a partial agonist of the alpha4-beta2 nicotinic acetylcholine receptor. Its fundamental action is to reduce tobacco withdrawal symptoms and reduce the positive effects of consumption (33).
It is a generic drug, which has been available since the 1960s, with and without the need for a prescription, mainly in Eastern European countries.
Knowledge of its beneficial effects for stopping smoking led to the study, synthesis and commercialisation of varenicline.
Several systematic reviews support its efficacy in TUD (3 times higher than placebo) after both 6-month and 12-month follow-ups, (RR 3.29, 95% CI -1.84 5.90-) (34,35).
Gastrointestinal, sleep disturbance and headache side effects are similar to, but less intense than, those of varenicline. Nausea is less common than varenicline due to its low affinity for 5-HT3A receptors (36).
More recently, studies have been done comparing it with both nicotine replacement (NRT) and varenicline, with a similar efficacy to the latter and higher than NRT being seen (36-38).
The main difference with respect to varenicline is the administration schedule (Table 5); due to its pharmacokinetics, more frequent doses are required. The recommendation of the data sheet is to stop smoking as soon as possible but no later than the 5th day of treatment.
Table 5.
Cytisine administration schedule, according to the technical data sheet (40)
| Treatment days |
Recommended dose |
Maximum dose |
| Days 1-3 |
1 tablet /
2 hours |
6 tablets |
| Days 4-12 |
1 tablet /
2.5 hours |
5 tablets |
| Days 13-16 |
1 tablet /
3 hours |
4 tablets |
| Days 17-20 |
1 tablet /
5 hours |
3 tablets |
| Days 21-25 |
1-2 tablets / day |
2 tablets |
Also noteworthy is its low price in the countries of origin, although not in the EU. If cytisine is shown to be as efficacious as varenicline, it could provide yet another therapeutic option, perhaps leading to savings for health systems and consumers (39). However, a price increase is expected for marketing in the EU, as well as not being directly included in the financing.
Other Strategies not approved by the Regulatory Agencies
The arrival on the market of new nicotine release or heat-not-burn products has been seen recently and should be reviewed by regulatory agencies such as the FDA and the EMA. These new products that have gained some popularity in the exposed population must be shown to reduce exposure or disease risk. They should also benefit not only individual smokers, but also the health of the population as a whole (41).
In July 2017, the UK Department of Public Health published its new UK Tobacco Control Plan, entitled “Towards a Smoke-Free Generation”. It stated that the Government will support smokers, who have been unable or unwilling to stop smoking, to adopt the use of alternatives to traditional cigarettes as a way of reducing exposure to tobacco smoke. Among its objectives are helping people to stop using cigarettes, maximising the availability of lower-risk alternatives and using technologies that considerably reduce the risk of smoking.
Also, a report published by this body in 2015 and updated in October 2018 under the title, Smokefree mental health services in England, it stated that people with mental disorders smoke more and are more dependent on nicotine. In line with this document, the Public Health Department in England proposes to promote research the safety and efficacy of the electronic cigarette, a nicotine-releasing device without tobacco, as a strategy for harm reduction in this population group (42).
Continuing with the United Kingdom, where more public recommendations in this regard have been made, it must be remembered that the British Parliament accepted the recommendation on electronic cigarettes published by the Science and Technology Committee in 2018, which stated that these devices “are significantly less harmful” than conventional tobacco and that “they should not be treated in the same way as conventional cigarettes”.
The Committee believes that the risk of smokers continuing to use conventional cigarettes outweighs the uncertainty associated with long-term use of electronic cigarettes (43).
Furthermore, the Committee on Science and Technology stated in this report that the percentage of smokers among people with mental health conditions remains high, while declining in the rest of the population; with people with mental health problems being almost 2.5 times more likely to smoke compared to the general population.
Therefore, they consider that the default policy should be to allow the use of electronic cigarettes in all mental health units in the British Health System (44).
Electronic cigarettes
The new electronic devices for administering nicotine, electronic cigarettes (vaporisers), should be taken into account within the treatment strategies marketed. Although the long-term biological effects of these devices are still unknown, the reality is that there is a reduction in exposure to potentially harmful components. An electronic cigarette. according to the definition of Law 28/2005 and Directive 2014/40/EU, is “a product that can be used for consumption of nicotine-containing vapour via a mouth piece, or any component of that product, including a cartridge, a tank and the device without cartridge or tank. Electronic cigarettes can be disposable or refillable by means of a refill container and a tank, or rechargeable with single use cartridges” (45). E-cigarettes do not contain tobacco, but rather an electronic liquid that contains vegetable glycerin, propylene glycol and may contain nicotine, which is heated to generate an aerosol that the user inhales.
After years of no regulation, the FDA extended the New Tobacco Products Act to e-cigarettes for the first time in May 2016. E-cigarette manufacturers will be required to register with the FDA and provide a detailed description of the contents of their products as well as their manufacturing processes. Manufacturers will need to apply to the FDA for permission to sell their products, will be subject to FDA inspections, and will not be allowed to market their products as light or mild without FDA approval. In practice, this means that any e-cigarette currently on the US market must file a premarket application with the FDA; otherwise, they are being traded illegally. Finally, in 2020, the FDA issued a guide that essentially prohibits any electronic cigarette that incorporates a flavour in its “cartridge”, other than tobacco or menthol; electronic cigarettes for which the manufacturer has not taken adequate measures to prevent access by minors; and any electronic cigarette that is directed at minors or whose use may be promoted by minors. The EU has not yet promoted any similar measure, which, as well as being soundly judged, tries to advance in giving guarantees to users, most of them with dual TUD, of this new reality of the e-cigarette (41). However, the UK Medicines and Healthcare products Regulatory Agency (MHRA) has issued a policy under which they can approve the use of electronic cigarettes for medical prescription (going through the drug approval process) for people who want to stop smoking (46). To do this, it has drawn up a guide that includes the requirements the product must meet both in terms of quality and advertising (47). The US Preventive Services Task Force, in its 2015 update, continues to state that there is still not enough evidence to recommend this method of nicotine administration, although its use in the affected population has been spreading (48) and is a reality that cannot be dismissed only with the fact that “there is a lack of evidence and it is as harmful as tobacco”. Most recently, in October 2021, the FDA announced the marketing authorisation of a new tobacco product in three formats, marking the first set of electronic nicotine delivery system products cleared by the FDA under the Premarketing Tobacco Application (PMTA) process. This is for the product Vuse®, which showed that participants who used only these products were exposed to fewer harmful and potentially harmful components (HPHC) from aerosols compared with users of traditional combustion cigarettes (49).
The scientific community has been divided regarding the role of e-cigarettes in controlling TUD. Other recent studies show that a strategy of replacing traditional cigarettes with e-cigarettes would produce substantial gains in years of life, even under pessimistic assumptions regarding cessation, initiation and relative harm (50).
In an experimental study with a small group of patients followed for 3.5 years with non-smokers using nicotine vaping devices, no associated health problems were demonstrated. However, it cannot be excluded that some damage might occur in later stages (51).
These devices have been widely accepted by subgroups of people with TUD who are trying to stop or at least reduce tobacco use. To compare its efficacy with approved nicotine products, a randomised controlled study (sponsored by the National Institute for Health Research and Cancer Research UK) was conducted on 886 patients who were followed up for 1 year. Both groups also underwent behavioural therapy. The percentage of abstinence achieved was 18% in the e-cigarette group compared to 9.9% in the nicotine group approved by regulatory agencies. The most frequent secondary symptoms were mouth and throat irritation in vaporiser users and nausea in the nicotine group. Adverse respiratory events were more frequent in the e-cigarette group, although without reaching statistical significance. Respiratory infections, however, were reduced in the e-cigarette group due to a likely antibacterial effect of glycerine and propylene glycol. The participants were able to choose the type of nicotine replacement (e.g. patches or spray) and even a combination of them. The other group received an e-cigarette starter pack with a device containing 18 mg/mL of nicotine. In those who did not achieve abstinence, the reduction in smoking was clearly more pronounced for those who used a vaporiser, compared to traditional nicotine. Notably, nearly 100% of subjects continued to use e-cigarettes, while the nicotine replacement cohort stayed off conventional cigarettes for a shorter period of time (52).
Non-treatment issues were discussed, such as whether they may pose a risk of initiation in populations that have never used tobacco, or the risk of nicotine solutions for young children, which are not relevant to the therapeutic approach of people with TUD.
Other nicotine release devices used
Snus: This is a moist powdered smokeless tobacco product placed between the lip and the gums for prolonged periods, and was the first tobacco product to be authorised by the FDA as an MRTP in 2019. It was marketed with the claim that “exclusive use of the snus products instead of cigarettes puts you at a lower risk of mouth cancer, heart disease, lung cancer, stroke, emphysema and chronic bronchitis”. So far, it is the only product that has been allowed such a claim (the highest possible health claim). The FDA granted this authorisation after reviewing the scientific evidence submitted by the company supporting the claim. The fact that this product had a long tradition in Sweden helped, as it was able to provide epidemiological data studies confirming this long-term safety claim (53). Since 1992, the sale of snus has been expressly prohibited in most EU countries, with only Sweden, Norway and recently Switzerland (nonEU countries) providing an exemption. This is one of the most paradoxical cases, in which the EU authorities allow the sale of conventional cigarettes and prohibit the sale of an alternative tobacco product when scientific evidence, including long-term epidemiological studies, shows a lower risk of cancer, heart disease and chronic bronchitis.
Due to fears of this new tobacco product spreading across Europe and aggressive marketing tactics directed at young people, the European Parliament called for a total EU-wide ban on “oral tobacco” sales in September 1987. This was preceded by a WHO recommendation urging countries with no history of smokeless tobacco use to ban this type of tobacco preventively, in order to prevent a public health problem in the future. In 1992, an EU-wide ban on oral tobacco sales was enacted under the amended Labelling Directive. This ban was reaffirmed in 2001 and again in 2014 (54).
Tobacco heated without combustion: This heat-not-burn cigarette contains tobacco heated without combustion at a low temperature. Cigarette smoke emissions are mainly produced by distillation, pyrolysis and combustion reactions when tobacco is burned. Some studies have shown that heating tobacco to temperatures below pyrolysis and combustion temperatures has the potential to reduce or eliminate some toxic substances found in tobacco smoke heated to temperatures above 600ºC.
New products have been marketed to heat tobacco below 300ºC. They have been designed to eliminate the combustion of tobacco while being heated to release nicotine, tobacco volatiles and glycerol to form its aerosol (55).
In a narrative review on heated tobacco by Spanish authors, a total of 52 studies were analysed (46 from the review and 6 found manually). Despite some differences between the studies, most of them point to a reduction in emissions of harmful and potentially harmful constituents (HPHC), as well as exposure to toxic substances and, therefore, on the biological and clinical impact of heated tobacco compared to conventional cigarettes (56).
Despite the controversy, there was an official response in an FDA statement dated 07/07/2020 authorising the marketing of the IQOS (I Quit Ordinary Smoking) heated tobacco product (HTP) system as a “modified risk tobacco product”, which reopens the debate on its use for TUD, since most scientific associations do not recommend it (57), despite there being no pronouncements from mental health associations, which should be involved in therapeutic responses to this dual disorder. The therapeutic object would be those patients with severe dual TUD unable to abandon or reduce compulsive use.
The individual benefits of using this type of device have been evaluated in various studies (58-60). The results have shown that switching from conventional cigarettes to heated tobacco reduces exposure to toxins and improves risk markers: reduction of 8-epi-prostaglandins, thromboxanes, intracellular adhesion molecules and exposure biomarkers, such as carboxyhaemoglobin or mercapturic acids. Therefore, its use in TUD could be useful for patients to stop or reduce the use of conventional tobacco, as has been shown in studies in patients with mental disorders in which both the number of daily cigarettes and the levels of CO were reduced, obtaining good adherence levels (61,62). However, the existing studies present a very small sample, so the effect in larger populations would have to be evaluated.
From the population point of view, it is crucial to ensure that the introduction of heated tobacco devices does not lead to a general increase in tobacco consumption. In other words, it would not be beneficial to reduce the individual risk in smokers who switch to heated tobacco while increasing its use among non-smokers, young adults and adolescents. A study from Japan shows that sales of conventional cigarettes decreased when heated tobacco products were made available for sale (63). It is recommended to monitor the use of these products and carry out long-term studies that can show that any increase in tobacco consumption due to heating comes from decreasing the sale of conventional cigarettes.
This is the second product to be authorised as a modified risk tobacco product, MRTP, (the first was snus, which was also the first tobacco product to receive a “risk modification” order). Its sale is allowed with the following information: “IQOS heats tobacco but does not burn it. The absence of combustion significantly reduces the production of harmful or potentially harmful chemicals. Scientific studies show that switching completely from cigarettes to IQOS significantly reduces your body’s exposure to harmful or potentially harmful chemicals” (64).
The FDA indicates that, although risk reduction has not been demonstrated, the totality of the evidence presented suggests that a measurable and substantial reduction in morbidity or mortality among individual tobacco users in subsequent studies is reasonably likely. Despite the concerns that may be raised by some unknowns, the FDA concluded that the available scientific evidence demonstrates that the issue of exposure modification orders for IQOS would be appropriate to promote public health.
According to Mitch Zeller, the director of the FDA Center for Tobacco Products, about this decision, “Through the modified risk tobacco product application process, the FDA aims to ensure that information directed at consumers about reduced risk or reduced exposure from using a tobacco product is supported by scientific evidence and understandable.”
Other commercial brands have joined the market with a similar mechanism (Glo) and its manufacturers want to provide it with increasing scientific evidence on its less harmful effects (65).
TUD IN DIFFERENT DIAGNOSTIC CATEGORIES OF OTHER MENTAL DISORDERS
Although we have expressed our preference for the transdiagnostic perspective offered by neuroscience and precision psychiatry, we will review the TUD data in the different diagnostic categories of the DSM-5.
The shared vulnerability for TUD and other mental disorders based among others on the deregulation of the nAChR system must be remembered (69).
Schizophrenia
The relationship between TUD and schizophrenia has been known for more than 30 years, with various studies showing TUD ratios greater than 80% in this group of patients (70).
Across all settings and nationalities, specific research found a 78% prevalence of TUD and 58% of severe TUD and a 2.6-fold higher probability for psychotic patients with TUD compared to patients with other mental disorders (71). They have also been described to smoke more cigarettes per day and inhale more deeply than other smokers, reaching higher blood nicotine levels than smokers without serious mental disorders (9).
The research evaluates the involvement of nAChRs in schizophrenia and suggests ways in which this system may contribute to the pathophysiology of this illness. Nicotine receptor expression is reduced in schizophrenia and, given these findings, it has been suggested that vulnerability to both disorders may be related (72). Recent studies show that nicotine administration normalises the hyperconnectivity of the Default Mode Network topography in schizophrenia, providing direct evidence that the biological basis of addiction is different in people with and without this mental disorder. These findings suggest that the high prevalence of nicotine use in patients with schizophrenia may be an attempt to correct a network deficit that interferes with the cognitive impairment they suffer (73).
Neurocognitive deficit (NCD) is nuclear to schizophrenia, present in 80% of cases and constitutes an endophenotype of schizophrenia, stable in all phases of the disease and inheritable. NCD could constitute a vulnerability factor for the initiation and maintenance of TUD. This shared vulnerability of schizophrenia and TUD would be due to the deregulation of nAChRs. Pre-clinical evidence links this system to neurotransmitters, such as dopamine, glutamate and GABA, while certain associated NCD (reaction time, spatial working memory, sustained attention and sensory synchronisation) improve after nicotine administration in schizophrenia (69).
There are different meta-analyses and reviews that demonstrate the safety and efficacy of varenicline in schizophrenia. Although there is controversy regarding the usefulness of varenicline to improve cognitive impairment in patients with schizophrenia, more powerful trials are desirable, since current evidence cannot confirm its usefulness in this regard (67,68,74).
Available systematic reviews have shown that the use of varenicline is associated with an increase in tobacco abstinence of up to 5 times for this group of patients; with bupropion, the increase in cessation is 3 times higher. For nicotine replacement therapy, a lower effect has been observed in patients with schizophrenia than in the general population, despite the fact that for many authors it represents the first-line treatment for smokers with mental illness (75,76).
Within the non-conventional approaches for TUD in schizophrenia, it has been postulated that electronic cigarettes could be useful as part of the tobacco harm reduction strategy; however, there are very few studies, of mostly very small samples, so research efforts in this field need to be increased (77-80).
Despite the proven efficacy of these treatments in people with mental disorders (81), there is a delay in their use that can affect patients. In a survey carried out by the WHO in several countries, it was highlighted that the delay in the treatment of mental disorders is widespread. Specifically, the median delay in SUD treatment was found to be between 6 and 18 years. In Spain, the median is 6 years, the lowest of the countries surveyed. This country also shows the highest number of patients who are indicated for treatment for SUD in the first year of contact, 18.6%.
For one thing, many patients never make any attempt to treat their disorders, particularly in developing countries, where the financial and structural barriers to accessing mental health services are more notable. Failure to seek help also seems to be greater for disorders in which the need for treatment is poorly perceived, such as SUDs, for which more than half of the cases did not make any treatment attempt at all in most countries (82).
Bipolar Disorder (BD)
Little is known yet about the neurobiological interaction between bipolar disorder and TUD; however, for having one of the highest prevalences, there is a need to advance in its knowledge (83,84).
A study that included Spanish researchers found that TUD and bipolar disorder have a bidirectional relationship. In addition, the risk of developing one disorder after the other was higher at the beginning of the disease. Most of the individuals with TUD had previously suffered bipolar disorder (72.6%), an earlier onset of tobacco use and a greater number of manic episodes that could be attributed to greater severity (85).
There are also few treatment studies in subjects with bipolar disorder (86). In general, the efficacy of varenicline in smokers with bipolar disorder is similar to the main results reported by the EAGLES study. Varenicline may be well tolerated and effective for TUD with bipolar disorder. Regarding bupropion and nicotine replacement therapy, despite being effective, they had a smaller effect size than varenicline (87).
Another important study was after a standard 12-week pharmacotherapy course, where people with schizophrenia and bipolar disorder were more likely to suffer TUD relapse when stopping varenicline maintenance treatment. Maintenance pharmacotherapy was able to improve long-term results and not for short periods of time (68). This proposal should be extended to other therapeutic modalities for longer periods of time.
Depression
TUD and depression are reciprocally related. Tobacco is the leading preventable cause of illness and death in patients with depression, and depression is one of the most important risk factors for the development of TUD. It has been shown that patients with depression have a higher prevalence of TUD than the general population and that there is a probable relationship between the severity of consumption and depressive symptoms (88,89).
Based on the currently available evidence, the results of a Cochrane review support the effectiveness of adding a psychosocial mood management component to a smoking cessation intervention for depressed smokers. The results also appear to support the effectiveness of bupropion use for smokers with past depression, although the evidence is relatively weak due to the small number of studies using post hoc subgroups. For interventions without specific mood management components for depression, including nicotine replacement therapy and psychosocial interventions, insufficient convincing evidence was found to support their use in clinical practice for smokers with depression (90).
Despite decades of research on this dual disorders, treatment success rates for TUD in this population remain consistently lower for depressed smokers than for smokers in the general population; highlighting the need for theoretical models of TUD and depression.
Theoretical models, such as incentive learning theory, postulate that depressed smokers experience greater effects on the expected value of smoking (91).
The relationship between emotional regulation disorders and the brain’s nicotinic cholinergic system is evident. Depressed patients have a lower availability of β2-nAChR than healthy subjects. Modulation of nAChRs, specifically those containing the β2 subunit, may be effective in treating patients with major depressive disorder (92).
Cotinine, the predominant metabolite of nicotine, appears to act as an antidepressant. Cotinine may be an effective antidepressant that positively influences mood through a mechanism involving preservation of brain homeostasis and expression of critical growth factors (93).
Taking into account the pro-cognitive properties of nicotine, its transdermal use has been tested in patients with depression and cognitive symptoms in the elderly, with promising results (94).
Although most studies of smoking cessation between subjects with and without depression have shown no difference between them, depression was associated with worse outcomes (95). In the TUD group with depression, nicotine replacement therapy has been shown to be more effective than placebo. Bupropion is also an effective treatment for smokers with depression and manages to reduce the relapse rate during abstinence, as does varenicline (96). One of the first studies conducted with nortriptyline (28) included smokers with a history of major depressive disorder (MDD) and was used together with cognitive-behavioural therapy (CBT). The results showed significantly greater efficacy than placebo whether or not the smoker had a history of MDD while the use of CBT was especially effective in smokers with a history of MDD.
A meta-analysis of several studies also described how a change in mental health occurs after stopping smoking. Smoking cessation regulates the affective response and is associated with a reduction in depression, anxiety and stress and an improvement in mood and quality of life compared to continuing to smoke (97). These results are consistent with what is known about neuroadaptations in brain nicotinic pathways that occur in chronic TUD. Neuroadaptations in these pathways are associated with the appearance of a state of depression, agitation and anxiety after smoking a cigarette. However, the neurological functioning of people who stop smoking may return to the same level as that of non-smokers within 3 weeks of stopping smoking (98), which is consistent with the decrease in withdrawal symptoms after a few weeks.
In recent times, there has been great interest in new treatments with new mechanisms of action for depression. One of them is psilocybin, a secondary serotonin receptor agonist. Moderate to high doses (20 and 30 mg/70 kg) of psilocybin, in combination with cognitive behavioural therapy (CBT) for smoking cessation resulted in substantially higher 6-month tobacco abstinence rates than those typically seen with other medications or CBT alone (99).
Another of the new treatments in the field of depression is ketamine and its derivatives such as esketamine. In animal studies, ketamine treatment significantly reduced nicotine self-administration in a dose-dependent manner. In addition, differential sensitivity between the sexes was observed as male rats responded to a lower dose of ketamine and with a greater effect than in female rats. It is concluded that glutamatergic receptor manipulations may offer a novel and potentially gender-dependent intervention in nicotine addiction (100).
As mentioned in previous chapters, the activity of MAO is reduced in smokers, since it increases the availability of some neurotransmitters, such as serotonin, GABA and glutamate, by preventing the degradation of catecholamines. This effect of tobacco smoke would be similar to that of antidepressants in that both tobacco and antidepressants modify the release of neurotransmitters that enhance the effect on the reward system. Loss of MAO inhibition during periods of withdrawal and possible associated mood swings make withdrawal difficult in smokers. Thus, treatment with antidepressants for smoking cessation is being considered since the lack of monoaminergic neurotransmitters would be reduced after smoking cessation and an improvement in the symptoms caused by withdrawal could be observed (101,102).
Anxiety disorders
Most anxiety disorders increase the risk of TUD. For people with phobias or panic disorder and also with PTSD, this risk is multiplied, even if the symptoms have been absent for years, with consumption being higher in symptomatic periods (103). However, in those patients with TUD and anxiety disorder, nicotine replacement therapy and bupropion are associated with a worse response than varenicline (95).
Patients with social or generalised anxiety also have a higher prevalence of TUD than the rest of the general population. In this group of patients, neither monotherapy nor the combination of first-line drugs was more effective than placebo (104). The subanalysis for anxiety disorders (PTSD, GAD, panic disorder) in the EAGLES study showed greater continued abstinence between weeks 9 and 12 for all 3 types of pharmacological treatment compared to placebo (105). In a recent study in patients with anxiety and low tolerance to distress, it was observed that those who tolerated distress or discomfort better were more likely to drop out 4 weeks after D-day if they were treated with replacement therapy with nicotine patches and tablets than only with patches (106).
For patients with TUD and post-traumatic stress disorder (PTSD), a pharmacological treatment pilot trial which randomised placebo and bupropion showed adequate tolerance to the latter, associating 40% abstinence compared with 20% for placebo after 6 months of follow-up; however, the study was carried out with 15 veterans and did not reach a level of significance (107). For nicotine cessation in patients with PTSD, a recent randomised trial with placebo and nicotine patches showed that patch replacement therapy was useful in reducing tobacco consumption; however, this treatment was not considered sufficient due to high dropout rates (108).
Post-traumatic stress disorder (PTSD)
The prevalence of SUD in people with PTSD has been established at 21.6-43.0% compared to 8.1-24.7% of the population without PTSD. In patients with both disorders, the symptoms are usually more severe and are more resistant to treatment. Some theories have been established that could explain this relationship. The first (and most accepted) is that PTSD precedes SUD, through self-medication with substances such as alcohol, cannabis, etc. to improve symptoms. Therefore, when the patient tries to reduce consumption, the appearance of withdrawal symptoms (together with the reactivation of PTSD symptoms) can make the patient more vulnerable. The second theory is the other way around: that SUD precedes PTSD. People who abuse substances face dangerous or traumatic situations to maintain consumption. Its chronic use causes neurosensitisation of biological stress systems, leading to high levels of anxiety and a higher level of vulnerability for the development of PTSD after exposure to trauma (16,109).
The treatment of these patients is based on achieving controlled and stable consumption to stabilise the SUD, when abstinence is not possible, together with individual and group psychotherapeutic treatment to treat PTSD, with close monitoring of symptoms to prevent relapses (16).
Obsessive-Compulsive Disorder (OCD)
OCD is a biologically heterogeneous disorder associated with both impulsive and compulsive neurocognitive mechanisms. It is one of the mental disorders with the lowest incidence of TUD. Patients with OCD and TUD could represent a differentiated phenotype notable for phenomenologically showing greater impulsiveness.
Smokers with OCD scored significantly higher on the Barratt Impulsivity Scale (p < 0.001). compared with non-smokers with OCD. They also scored significantly higher on the Temperament and Character Inventory (TCI) measures of novelty seeking (p < 0.001) and reward dependence (p < 0.001) and significantly lower on measures of harm avoidance (p < 0.001) (110). Therefore, these traits of greater impulsiveness should be taken into account at the time of treatment.
Tourette syndrome
Treatment with nicotine gum or patches seems to reduce complex tics and improve the impaired attention that these patients usually present. A double-blind study with placebo in a small number of non-smoking children and adolescents under treatment with neuroleptics, proposed the intermittent use of therapeutic nicotine, with significant results, which would allow reducing the use of antipsychotics in these patients (111-113). However, there are currently no studies to evaluate this syndrome in patients who have stopped using tobacco.
Attention Deficit Hyperactivity Disorder (ADHD)
Attention deficit hyperactivity disorder (ADHD) is one of the most common mental health problems in childhood, adolescence and often persisting into adulthood. This diagnosis of ADHD is very prevalent in people with mental disorders and is generally underdiagnosed. ADHD in childhood and adolescence is a strong predictor of tobacco and illicit substance use in adulthood (112,113). Related to environmental and character factors, but above all to genetic and epigenetic factors, young people with ADHD are 2-3 times more likely to smoke tobacco regularly and to develop TUD than those without ADHD (114,115). In addition, subjects with ADHD start smoking tobacco at a younger age and have a more rapid progression to a more severe TUD, generally consuming a greater number of cigarettes per day than those without ADHD (116,117). Also, it has been described that smokers with ADHD would have more intense withdrawal symptoms and craving for smoking during periods of abstinence, and would have greater difficulty stopping smoking (118) with higher relapse rates for TUD (119) than smokers without ADHD.
Patients medicated for ADHD since childhood delay the onset of tobacco smoking (120). Several studies have evaluated the possible efficacy and tolerability of drugs commonly used for ADHD in patients with dual disorders, ADHD and smoking. The efficacy and tolerability of methylphenidate in patients with ADHD and smoking have been explored. A large multi-centre randomised placebo-controlled study evaluated the efficacy of OROS methylphenidate (72 mg/day) as adjunctive treatment to improve smoking cessation rates associated with transdermal nicotine patches (21 mg/day) and individual brief therapy in a sample with 255 adult subjects with TUD and ADHD (121). A significant reduction in ADHD symptoms, number of cigarettes per day and smoking withdrawal symptoms (122) was observed in the OROS methylphenidate group compared to placebo, but abstinence rates were similar for both groups. However, a secondary analysis of the study results found that more severely dependent smokers treated with OROS methylphenidate had significantly higher rates of continued abstinence than those who received placebo; while no difference in smoking cessation rates was found between the two therapeutic options among smokers with less severe nicotine dependence (123). Lisdexamfetamine is another drug evaluated in association with transdermal nicotine patches in patients with ADHD and TUD. In a small randomised, placebo-controlled study of 32 subjects with this dual disorder, a significant improvement in ADHD symptoms was observed compared to placebo, as well as a significant decrease in daily cigarette consumption but which was similar with lisdexamfetamine and placebo (124).
Partly due to its efficacy in the treatment of ADHD and due to its indication and recognised efficacy in the treatment of smoking, bupropion ER has been evaluated in patients with ADHD and TUD. In a small open-label study with 6 weeks of follow-up, bupropion ER (300 mg/day) associated with short-term therapy as a treatment for smoking cessation in an adolescent population, in which 11 of the 16 participating subjects also had ADHD, good tolerability of the drug along with a significant reduction in cigarette consumption was observed in adolescents with and without ADHD (125). To date, there are hardly any data on the efficacy of other drugs used in the treatment of smoking, such as varenicline, a selective partial agonist of the nicotinic cholinergic receptor α4β2, although this drug has been proposed as first-line treatment in dual patients (126).
Considering that ADHD symptoms can interfere with successful smoking cessation, it is recommended that the first priority should be to stabilise ADHD through the use of long-acting psychostimulants, at least in severe ADHD. Subsequently, cognitive-behavioural therapy or motivational interviewing in combination, or not, with NRT or smoking cessation drugs, like bupropion or varenicline, can be used for additional treatment (127,128). In fact, bupropion and possibly also varenicline could be promising agents for the treatment of smoking cessation.
Autism Spectrum Disorder (ASD)
The evidence gathered suggests the nicotinic cholinergic system is involved in the pathobiology of autism spectrum disorder (ASD). Neuropathological studies suggest that nicotinic acetylcholine receptor (ACh) subtypes (nAChR) are altered in the brains of autistic individuals. Furthermore, strategies that increase ACh, the neurotransmitter at nicotinic and muscarinic receptors, appear to improve cognitive deficits in neuropsychiatric disorders and ASD. Recent findings support the hypothesis that the nicotinic cholinergic system modulates social and repetitive behaviours and may be a therapeutic target to treat social and behavioural deficits in ASD (129).
Personality disorders (PD)
Surprisingly, it seems little or no attention has been paid to examining the influence of personality traits, with clear neurobiological underpinnings, on the neural correlates of TUD.
Trait impulsivity, an endophenotype, has been related to craving and relapse in the consumption of certain substances and tobacco. A functional magnetic resonance imaging study showed that the role of impulsivity in cigarette craving was mediated by frontocingulate mechanisms. Given the high prevalence of TUD in various psychiatric disorders characterised by significant levels of impulsivity, further neurobiological studies on this relationship are needed (130).
Various studies refer to the shared and specific pathogenic factors of some categorical personality disorders and TUD and find a relationship between schizotypal, borderline, narcissistic and obsessive-compulsive traits and the hypothesis of self-medication and the role of cholinergic neurotransmission (131).
Borderline Personality Disorder (BPD)
BPD is a heterogeneous disorder with a lot of variability among patients whose symptoms overlap with SUD. This makes it difficult to study the features of BPD-SUD dual disorders. The prevalence of comorbidity between BPD and SUD is high (64-66%), although there are discrepancies with these data. There is a need therefore for studies that describe the different aetiopathogenic models to improve diagnostic and therapeutic strategies. A worse response to treatment is observed in patients with BPD-SUD, as well as a higher risk of suicide, self-harm and self-destructive behaviour in general. In treating BPD-SUD, it is essential to combine psychopharmacological and psychotherapeutic treatment. Normothymic drugs can decrease impulsiveness and the risk of aggressive behaviour in BPD and of SUD, reducing substance use (16,132).
Gambling disorder
This is defined as persistent and maladaptive gaming behaviour, according to the DSM-5, and TUD is the other most common accompanying mental disorder. Clinically, “dual gaming disorder” would be expected and not be the exception, since it is always accompanied by other mental disorders including TUD (133).
People with TUD had significantly more severe gambling addiction symptoms when treated. The severity of TUD has been associated with greater gambling severity and more frequent psychiatric problems (134).
Daily tobacco use, however, is not significantly associated with the number of days played or with treatment completion. Although individuals with TUD had greater problems with gambling, they had similar rates of treatment completion and treatment outcomes as non-users (135).
Other Substance Use Disorders (SUD)
People with other SUDs show the same interest as smokers in the general population in stopping smoking. In a follow-up study of 272 patients who began a treatment programme for SUD in a US veterans centre, all patients with Alcohol Use Disorder (AUD), 72% of patients with cocaine use disorder and 70.5% of the patients with heroin use disorder were interested in stopping smoking; with 50%, 52% and 42%, respectively, thinking it would be good to do so at the same time as starting treatment to stop the other addictions. Although there is a popular belief, present even in many health professionals, that stopping smoking can precipitate relapses in patients being treated for an addiction, the evidence obtained from research shows the opposite; and it can currently be stated that the joint approach to combat a combination of tobacco use disorder with other addictions can lead to higher rates of alcohol abstinence and a decrease in cocaine use (136). In addition to the explicit benefits of stopping smoking, patients often do not know that it can help them in their other addictions, so giving them this information is a priority.
The best studied relationship within the SUD field is that between TUD and AUD. Previous studies have shown that AUD and TUD frequently occur concomitantly, as well as the relationship between a history of TUD and a history of harmful alcohol use. This association is so evident that severe TUD can be used as a marker for alcohol problems (137), and, likewise, the use of alcohol is one of the psychiatric predictors of tobacco use onset. In other words, the relationship between alcohol and tobacco is bidirectional and dose dependent. Alcohol consumption frequently precedes a tobacco relapse, and active alcoholic patients often fail TUD treatments (138).
The simultaneous use of tobacco and alcohol is associated with premature morbidity and mortality compared to the use of either substance separately. For this reason, it is essential to develop integrated and effective therapeutic approaches. Integrated interventions and new pharmacotherapeutic combinations targeting smoking and drinking behaviours may be promising (139).
Until now, the idea that smoking cessation could make it difficult to abstain from other substances had prevented this association from being addressed from a neuroscientific evidence-based perspective; although there is currently no data that smoking cessation increases rates of relapse in alcohol consumption. However, it is known that smokers with AUD have higher levels of TUD, as measured by higher scores on dependency scales such as the Fagerström test or the DSM criteria for SUD. In addition, they smoke more cigarettes and have more and more intense withdrawal symptoms after stopping smoking.
Regarding treatment, the efficacy of bupropion, widely recognised in the treatment of TUD in the general population, has also been demonstrated among smokers with a history of AUD, although its use in patients actively consuming alcohol is contraindicated due to the increased the risk of causing seizures, and so should be restricted to stable patients in withdrawal. The data are contradictory for nicotine substitutes, since several studies have been found them to be as effective or less effective than among the general population. A clinical trial with consumers of alcohol and tobacco who wanted to stop smoking and reduce alcohol consumption found that treatment with varenicline combined with naltrexone showed reduced alcohol use rates by approximately one drink per occasion (140). However, the combination treatment did not improve smoking cessation rates and perhaps worsened them. Despite these results, other studies have shown varenicline to be safe for alcohol and tobacco users seeking treatment for either behaviour. In fact, it has a broad effect on craving, and promotes the reduction of alcohol consumption (139). Therefore, varenicline could be a first-line pharmacotherapy for TUD in users of both substances; although other possible combination therapies and treatment guidelines should be investigated for these patients with a great variability in consumption patterns (139).
Regarding psychological or support techniques, cognitive behavioural therapy is thought to be particularly useful for these patients.
In the aforementioned Australian study (137), Degenhardt and Hall found an association between regular tobacco use and cannabis consumption, since 20% of those who had not used cannabis in the previous year were defined as regular tobacco smokers, with these rates being 50% in cannabis smokers and 70% in those who met criteria for cannabis addiction. There were no differences, however, between the degree of cannabis use and the use of other substances. Currently, we have few specific data on the treatment of patients with cannabis abuse; however, the high rates of TUD among this population suggest a need for this type of study (141) and that we bear in mind the high dual disorders of tobacco when treating a patient for cannabis addiction problems (142). One study of patients who attended consultation for cannabis use disorder found that those who were also tobacco smokers had more psychosocial problems and responded worse to treatment. In addition to the fact that tobacco use worsens the treatment of people with cannabis addiction, the opposite also occurs, with cannabis use being observed to have a negative impact on TUD. Several studies found that any level of cannabis use in the month prior to TUD treatment worsened abstinence rates (143).
In one of the first studies on nicotine and other substances (144), it was found that patients with cocaine use disorder (CUD) had higher rates of tobacco consumption (75%) than the general population (22%). In addition, patients reported increased tobacco consumption coinciding with cocaine consumption; this was consistent with laboratory studies that showed that stimulants such as cocaine or amphetamine can increase tobacco consumption. In a study of 200 patients trying to stop cocaine use, differences were found in the pattern of this use between smokers and non-smokers, with the former consuming more and on more days, and were also three times more likely to use the injected or smoked route. There were no differences in treatment success according to tobacco use. Another study found that cessation of cocaine use led to a decrease in tobacco use (145). People with CUD have higher levels of TUD. The use of cocaine together with tobacco has been shown to greatly increase cardiovascular risk, which, together with the fact that smokers consume more cocaine than non-smokers, should make us see the importance of comprehensive, integrated treatment in these patients.
For TUD and opioid use disorder, it has been shown that patients in a methadone maintenance programme were more disposed to stop using tobacco than those who had intravenous heroin use. Those with a greater predisposition to stop smoking were generally in methadone maintenance, over 35 years of age and without a recent history of alcohol abuse (146-148). In the USA, there are a large number of opioid-addicted patients in methadone maintenance treatment, approximately 200,000 of the total of 3,000,000 addicted patients (149). For this reason, many studies have been carried out on this type of patient, finding that their patterns of tobacco use are different from those of the general population, with TUD prevalence rates of 85-98%; curiously finding more prevalence among women than men, unlike in the general population (150). They also had worse abandonment rates: 12% compared to 50% in the general population, and a higher number of attempts (150).
In a recent study, it was found that increasing severity of TUD, from non-use, moderate use to severe use, was shown to be a more powerful predictor of cocaine and opiate use than the daily dose of methadone. Initiation of consumption of both cocaine and opiates was found to be associated with the degree of nicotine consumption, such that the greater the consumption of nicotine, the greater the probability of initiating consumption of other substances. These data, together with the very high rates of TUD among opiate users, should prompt us to systematically offer the possibility of TUD treatment to these patients. As in users of other substances, opiate addicts have shown a great interest in stopping tobacco use, with figures from 58% to 80% of patients who defined themselves as very or quite interested in stopping smoking (151).
For the interrelationship between TUD and use of other substances, TUD treatment programmes should be designed for this type of population, since they have particular features that must be included in the approach to TUD to ensure success. Among these are the greater severity of TUD shown and the enhancement of the significant repercussions on health when consuming tobacco with other substances. Above all, the significant interweaving of behaviours, triggers and facilitators of consumption seen when consuming various substances appears as fundamental; stressing the importance of an integrated, comprehensive approach identifying all dual disorders, to prevent focusing on treating partial aspects of this complex clinical condition (152).
