Treatment Of Nicotine Addiction Research Articles

P1.01A.04 Point-of-care Nicotine Replacement for the Treatment of Nicotine Addiction in a Provincial Cancer System

P1.01A.04 Point-of-care Nicotine Replacement for the Treatment of Nicotine Addiction in a Provincial Cancer System

Evaluation of (S)-T1 and (S)-T2 ligands targeting α3β4 nAChR as potential nicotine addiction pharmacotherapy.

Substance use disorders (SUDs) represent a significant global health concern, demanding the development of effective pharmacological treatments. To address this, an investigation was conducted to examine the anti-addictive properties of two compounds, (S)-T1 and (S)-T2, which specifically target the α3β4 nicotinic acetylcholine receptor (nAChR). The effects of (S)-T1 and (S)-T2 on nicotine-induced conditioned place preference (CPP), locomotor activity and dopamine levels in particular brain regions associated to addiction were investigated and compared in male C57BL/6N mice. The results demonstrate that neither (S)-T1 nor (S)-T2 induced place conditioning or conditioned place aversion (CPA), suggesting the absence of rewarding or aversive effects. Both compounds significantly attenuated nicotine-induced CPP, with (S)-T1 exhibiting a dose-dependent effect. Furthermore, the co-administration of (S)-T2 (10mg/kg) with nicotine markedly reduced locomotor activity compared to nicotine treatment alone. Additionally, dopamine analysis revealed that nicotine increased dopamine levels in the nucleus accumbens (NAc) and dorsal striatum, whereas the co-administration of (S)-T1 (1, 3, and 10mg/kg) and (S)-T2 (10mg/kg) significantly decreased dopamine levels in these brain regions. No significant effects were observed in the prefrontal cortex (PFC). These findings suggest that (S)-T1 and (S)-T2 hold promise for treating nicotine addiction by attenuating nicotine-induced CPP and modulating dopamine release in key reward-related brain regions. Further research is needed to gain insights into the underlying mechanisms behind their anti-addictive effects and substantiate their potential for treating nicotine addiction.

Rational Design of a Flavoenzyme for Aerobic Nicotine Catabolism.

Enzymatic therapy with nicotine-degrading enzyme is a new strategy in treating nicotine addiction, which can reduce nicotine concentrations and weaken withdrawal in the rat model. However, when O2 is used as the electron acceptor, no satisfactory performance has been achieved with one of the most commonly studied and efficient nicotine-catabolizing enzymes, NicA2. To obtain more efficient nicotine-degrading enzyme, we rationally designed and engineered a flavoenzyme Pnao, which shares high structural similarity with NicA2 (RMSD = 1.143 Å) and efficiently catalyze pseudooxynicotine into 3-succinoyl-semialdehyde pyridine using O2. Through amino acid alterations with NicA2, five Pnao mutants were generated, which can degrade nicotine in Tris-HCl buffer and retained catabolic activity on its natural substrate. Nicotine-1'-N-oxide was identified as one of the reaction products. Four of the derivative mutants showed activity in rat serum and Trp220 and Asn224 were found critical for enzyme specificity. Our findings offer a novel avenue for research into aerobic nicotine catabolism and provides a promising method of generating additional nicotine-catalytic enzymes.

Combining neuroimaging and brain stimulation to test alternative causal pathways for nicotine addiction in schizophrenia

The smoking rate is high in patients with schizophrenia. Brain stimulation targeting conventional brain circuits associated with nicotine addiction has also yielded mixed results. We aimed to identify alternative circuitries associated with nicotine addiction in both the general population and schizophrenia, and then test whether modulation of such circuitries may alter nicotine addiction behaviors in schizophrenia. In Study I of 40 schizophrenia smokers and 51 non-psychiatric smokers, cross-sectional neuroimaging analysis identified resting state functional connectivity (rsFC) between the dorsomedial prefrontal cortex (dmPFC) and multiple extended amygdala regions to be most robustly associated with nicotine addiction severity in healthy controls and schizophrenia patients (p = 0.006 to 0.07). In Study II with another 30 patient smokers, a proof-of-concept, patient- and rater-blind, randomized, sham-controlled rTMS design was used to test whether targeting the newly identified dmPFC location may causally enhance the rsFC and reduce nicotine addiction in schizophrenia. Although significant interactions were not observed, exploratory analyses showed that this dmPFC–extended amygdala rsFC was enhanced by 4-week active 10Hz rTMS (p = 0.05) compared to baseline; the severity of nicotine addiction showed trends of reduction after 3 and 4 weeks (p ≤ 0.05) of active rTMS compared to sham; Increased rsFC by active rTMS predicted reduction of cigarettes/day (R = −0.56, p = 0.025 uncorrected) and morning smoking severity (R = −0.59, p = 0.016 uncorrected). These results suggest that the dmPFC–extended amygdala circuit may be linked to nicotine addiction in schizophrenia and healthy individuals, and future efforts targeting its underlying pathophysiological mechanisms may yield more effective treatment for nicotine addiction.

Application of glutamate weighted CEST in brain imaging of nicotine dependent participants in vivo at 7T.

With nicotine dependence being a significant healthcare issue worldwide there is a growing interest in developing novel therapies and diagnostic aids to assist in treating nicotine addiction. Glutamate (Glu) plays an important role in cognitive function regulation in a wide range of conditions including traumatic brain injury, aging, and addiction. Chemical exchange saturation transfer (CEST) imaging via ultra-high field MRI can image the exchange of certain saturated labile protons with the surrounding bulk water pool, making the technique a novel tool to investigate glutamate in the context of addiction. The aim of this work was to apply glutamate weighted CEST (GluCEST) imaging to study the dorsal anterior cingulate cortex (dACC) in a small population of smokers and non-smokers to determine its effectiveness as a biomarker of nicotine use. 2D GluCEST images were acquired on 20 healthy participants: 10 smokers (ages 29-50) and 10 non-smokers (ages 25-69), using a 7T MRI system. T1-weighted images were used to segment the GluCEST images into white and gray matter tissue and further into seven gray matter regions. Wilcoxon rank-sum tests were performed, comparing mean GluCEST contrast between smokers and non-smokers across brain regions. GluCEST levels were similar between smokers and non-smokers; however, there was a moderate negative age dependence (R2 = 0.531) in smokers within the cingulate gyrus. Feasibility of GluCEST imaging was demonstrated for in vivo investigation of smokers and non-smokers to assess glutamate contrast differences as a potential biomarker with a moderate negative age correlation in the cingulate gyrus suggesting reward network involvement.

Varenicline and Maltodextrin Combination: A Promising Approach for Reducing Nitrosamine Impurities in Solid Dosage Forms

This research article investigates the use of varenicline and maltodextrin combination to reduce the nitrosamine impurities in varenicline tablets, a medication used to treat nicotine addiction. Nitrosamines are carcinogenic compounds that have been found in varenicline, raising concerns about its safety. Drug excipient compatibility was initially performed with all possible excipients, including maltodextrin, to identify potential approaches for reducing nitrosamine impurities. The results showed that maltodextrin was more effective than other excipients in reducing nitrosamines in the drug product. This finding provided an indication for the use of maltodextrin as a potential solution to the nitrosamine problem in varenicline tablets. The study involved preparing varenicline-maltodextrin formulations and analyzing the formulations for nitrosamine impurities. The finished formulation was prepared by simple mixing of varenicline, maltodextrin, disintegrant, filler, lubricant, and compression using suitable tooling, followed by aqueous film coating. The formulated tablets were tested for assay, content uniformity, dissolution in release media, and multimedia, and the results were found to be satisfactory. The results showed that the varenicline-maltodextrin combination significantly reduced nitrosamine content, and all other parameters were satisfactory. In addition, the nitrosamine impurity levels were significantly reduced to less than 3 ppm after 30 days of storage at 50±2°C/75±5 % RH. Moreover, more than 85% of drug release was observed in all tested release media, meeting the predefined specifications for BCS-based biowaiver. These findings suggest that the use of varenicline and maltodextrin combination is a promising approach to improve the safety of varenicline.

How is Membrane Permeation of Small Ionizable Molecules Affected by Protonation Kinetics?

According to the pH-partition hypothesis, the aqueous solution adjacent to a membrane is a mixture of the ionization states of the permeating molecule at fixed Henderson-Hasselbalch concentrations, such that each state passes through the membrane in parallel with its own specific permeability. An alternative view, based on the assumption that the rate of switching ionization states is instantaneous, represents the permeation of ionizable molecules via an effective Boltzmann-weighted average potential (BWAP). Such an assumption is used in constant-pH molecular dynamics simulations. The inhomogeneous solubility-diffusion framework can be used to compute the pH-dependent membrane permeability for each of these two limiting treatments. With biased WTM-eABF molecular dynamics simulations, we computed the potential of mean force and diffusivity of each ionization state of two weakly basic small molecules: nicotine, an addictive drug, and varenicline, a therapeutic for treating nicotine addiction. At pH = 7, the BWAP effective permeability is greater than that determined by pH-partitioning by a factor of 2.5 for nicotine and 5 for varenicline. To assess the importance of ionization kinetics, we present a Smoluchowski master equation that includes explicitly the protonation and deprotonation processes coupled with the diffusive motion across the membrane. At pH = 7, the increase in permeability due to the explicit ionization kinetics is negligible for both nicotine and varenicline. This finding is reaffirmed by combined Brownian dynamics and Markov state model simulations for estimating the permeability of nicotine while allowing changes in its ionization state. We conclude that for these molecules the pH-partition hypothesis correctly captures the physics of the permeation process. The small free energy barriers for the permeation of nicotine and varenicline in their deprotonated neutral forms play a crucial role in establishing the validity of the pH-partitioning mechanism. Essentially, BWAP fails because ionization kinetics are too slow on the time scale of membrane crossing to affect the permeation of small ionizable molecules such as nicotine and varenicline. For the singly protonated state of nicotine, the computational results agree well with experimental measurements (P1 = 1.29 × 10-7 cm/s), but the agreement for neutral (P0 = 6.12 cm/s) and doubly protonated nicotine (P2 = 3.70 × 10-13 cm/s) is slightly worse, likely due to factors associated with the aqueous boundary layer (neutral form) or leaks through paracellular pathways (doubly protonated form).

Efficacy and safety of non-invasive brain stimulation techniques for the treatment of nicotine addiction: A systematic review of randomized controlled trials.

Non-Invasive Brain Stimulation (NIBS) techniques seem to be effective in treating tobacco use disorder. We aimed to analyze what kinds of protocols are used to treat nicotine addiction in term of cessation and/or reduction and to evaluate the long-term effects of NIBS techniques. We searched PubMed, Scopus, and Web of Science for papers published, with combinations of the following search terms: "Non-invasive brain stimulation OR TMS OR transcranial magnetic stimulation OR tDCS OR transcranial direct current stimulation OR transcranial electrical stimulation OR TES AND Nicotine addiction". We conducted a preliminary search, which revealed papers on the topic. Articles were included in the review according to the following inclusion criteria: English language, publication in peer reviewed journals, articles about studies performed on non-invasive brain stimulations techniques, and RCT studies. Studies involving clinical populations with organic or psychiatric diseases were excluded. We found 280 articles. Of these, at the first screening and conducted by title and abstract, 63 studies were excluded after duplicates were removed (118). After the second screening conducted by full-text examination, 45 articles were excluded. Ten studies met the inclusion criteria and were included in the review. The clinical benefits of NIBS, including the fast onset and minor side effects, showed that this kind of treatment could be helpful in patients with a long history of smoking in terms of cessation and abstinence rates.

The relationship between anxiety and emotional distress in nicotine addiction

This study investigates the interrelationship between anxiety and emotional distress in the context of nicotine addiction. Multivariate statistical analysis was applied to determine whether anticipatory anxiety is associated with increased levels of emotional distress, and whether this association is mediated by severity of nicotine dependence. Results indicate a significant correlation between anxiety and emotional distress, with nicotine dependence serving as a partial mediator. These findings suggest that clinical interventions designed to reduce anxiety may play a key role in reducing emotional distress and potentially facilitating smoking cessation. The study contributes to the existing literature by emphasizing the importance of addressing psychological comorbidity in the treatment of nicotine addiction and provides insight for the development of more effective therapeutic strategies.

Anti-smoking drugs cytisine and varenicline reduce cardiac reperfusion injury in rat model of myocardial ischemia

Evidence to date indicates that activation of nicotinic acetylcholine receptors (nAChRs) can reduce cardiac injury from ischemia and subsequent reperfusion. The use of nAChR agonists in various animal models leads to a reduction in reperfusion injury. Earlier this effect was shown for the agonists of α7 nAChR subtype. In this work, we demonstrated the expression of mRNA encoding α4, α6 and β2 nAChR subunits in the left ventricle of rat heart. In a rat model of myocardial ischemia, we studied the effect of α4β2 nAChR agonists cytisine and varenicline, medicines used for the treatment of nicotine addiction, and found them to significantly reduce myocardium ischemia-reperfusion injury, varenicline manifesting a higher protection. Dihydro-β-erythroidine, antagonist of α4β2 nAChR, as well as methyllycaconitine, antagonist of α7 and α6β2-containing nAChR, prevented protective effect of varenicline. This together with the presence of α4, α6 and β2 subunit mRNA in the left ventricule of rat heart raises the possibility that the varenicline effect is mediated by α4β2 as well as by α7 and/or α6β2-containing receptors. Our results point to a new way for the use of cytisine and varenicline as cardioprotective agents.

Development and Validation of LC-MS/MS Method for Determination of Cytisine in Human Serum and Saliva.

Cytisine (CYT) is a quinolizidine alkaloid used for nicotine addiction treatment. Recent clinical trial data regarding cytisine confirm its high effectiveness and safety as a smoking cessation treatment. CYT's popularity is growing due to its increased availability and licensing in more countries worldwide. This increased use by smokers has also resulted in an urgent need for continued drug research, including developing appropriate analytical methods for analyzing the drug in biological samples. In this study, a simple, fast, and reliable method combining hydrophilic interaction liquid chromatography and electrospray ionization quadrupole time of flight mass spectrometry (HILIC/ESI-QTOF-MS) for the determination of CYT in human serum and saliva was developed and validated. This was undertaken after the previous pre-treatment of the sample using solid-phase extraction (SPE). A hydrophilic interaction liquid chromatography (HILIC) column with a silica stationary phase was used for chromatographic analysis. In a linear gradient, the mobile phase consisted of acetonitrile (ACN) and formate buffer at pH 4.0. The proposed method was fully validated and demonstrated its sensitivity, selectivity, precision, and accuracy. The method was successfully applied to determine CYT in serum and, for the first time, in saliva. The findings indicate that saliva could be a promising non-invasive alternative to measure the free concentration of CYT.

Nicotinic regulation of microglia: potential contributions to addiction.

Clinical and preclinical studies have identified immunosuppressive effects of nicotine, with potential implications for treating nicotine addiction. Here we review how nicotine can regulate microglia, the resident macrophages in the brain, and corresponding effects of nicotine on neuroimmune signaling. There is significant evidence that activation of α7 nicotinic acetylcholine receptors (nAChRs) on microglia can trigger an anti-inflammatory cascade that alters microglial polarization and activity, cytokine release, and intracellular calcium concentrations, leading to neuroprotection. These anti-inflammatory effects of nicotine-dependent α7 nAChR signaling are lost during withdrawal, suggesting that neuroimmune signaling is potentiated during abstinence, and thus, heightened microglial activity may drive circuit disruption that contributes to withdrawal symptoms and hyperkatifeia. In sum, the clinical literature has highlighted immunomodulatory effects of nicotine and the potential for anti-inflammatory compounds to treat addiction. The preclinical literature investigating the underlying mechanisms points to a role of microglial engagement in the circuit dysregulation and behavioral changes that occur during nicotine addiction and withdrawal, driven, at least in part, by activation of α7 nAChRs on microglia. Specifically targeting microglial signaling may help alleviate withdrawal symptoms in people with nicotine dependence and help to promote abstinence.

E-Cigarette, or Vaping, Product Use-Associated Lung Injury (EVALI) Continues: An Opportunity for Pharmacist Intervention.

Electronic cigarette (e-cigarette), or vaping, product use-associated lung injury (EVALI) was first identified and reported in 2019, but media coverage and reporting of cases drastically decreased when the COVID-19 pandemic started in early 2020. The syndrome has continued to occur since that time and it is critical that pharmacists are aware of how EVALI presents, and when it should be considered as a potential diagnosis. Inpatient and outpatient pharmacists play a vital role in the treatment of EVALI, and should be knowledgeable of the utility of corticosteroids, even though data are extremely limited. Pharmacists should understand the importance of collecting detailed and accurate information about vaping from patient interviews. Pharmacists also play a leading role in cessation counseling and treatment, selecting medications that can be used to treat nicotine addiction from vaping, and assisting with transitions of care and follow-up.

Integrated approach to pharmacotherapy in smoking cessation: the role of varenicline, bupropion, cytisine, and nicotine replacement therapy

Introduction: Smoking tobacco is a significant global health issue, contributing to various diseases, including heart disease, cancer, and respiratory disorders. Quitting smoking is not only a beneficial decision for an individual's health but also for society as a whole. Pharmacological therapy plays a crucial role in the smoking cessation process by supporting and increasing the chances of success. Aim: To compare four medications used in smoking cessation: varenicline, bupropion, cytisine, and nicotine replacement therapy, in terms of their characteristics, mechanism of action, efficacy, and adverse effects. Materials and Methods: A review of available data in the PubMed database regarding medications registered in Poland for the treatment of nicotine addiction. Key Results: The efficacy of all four medications in smoking cessation was demonstrated. Individuals using varenicline, bupropion, cytisine, or nicotine replacement therapy had higher chances of quitting smoking compared to placebo groups. Specifically, varenicline showed the highest efficacy among all the medications studied. Despite a high level of safety profile, each therapy can cause various adverse effects, with the most serious being the risk of seizures associated with bupropion. Conclusions: Varenicline, bupropion, cytisine, and nicotine replacement therapy are valuable tools in the process of smoking cessation and increase the chances of successfully quitting the addiction. The choice of a specific medication may depend on individual patient preferences and clinical factors. These findings should be taken into consideration when making therapeutic decisions in the field of smoking cessation.

Resting-state electroencephalography theta predicts neurofeedback treatment 4-month follow-up response in nicotine addiction

BackgroundThe high rate of long-term relapse is a major cause of smoking cessation failure. Recently, neurofeedback training has been widely used in the treatment of nicotine addiction; however, approximately 30%...

State of external respiratory function in chronic obstructive pulmonary disease associated with nicotine dependence

A study of 151 patients with chronic obstructive pulmonary disease was conducted in order to assess the formation and effectiveness of the treatment of nicotine dependence in smokers with COPD. Ipratropium bromide was proposed as a therapy. Nicorette was used as a nicotine replacement therapy. As a result of the study, the proposed algorithm for the combined treatment of nicotine addiction and COPD was adapted for use in the treatment of various degrees of nicotine dependence and COPD severity in smokers in an outpatient setting.

Rare coding variants in CHRNB2 reduce the likelihood of smoking

Human genetic studies of smoking behavior have been thus far largely limited to common variants. Studying rare coding variants has the potential to identify drug targets. We performed an exome-wide association study of smoking phenotypes in up to 749,459 individuals and discovered a protective association in CHRNB2, encoding the β2 subunit of the α4β2 nicotine acetylcholine receptor. Rare predicted loss-of-function and likely deleterious missense variants in CHRNB2 in aggregate were associated with a 35% decreased odds for smoking heavily (odds ratio (OR) = 0.65, confidence interval (CI) = 0.56–0.76, P = 1.9 × 10−8). An independent common variant association in the protective direction (rs2072659; OR = 0.96; CI = 0.94–0.98; P = 5.3 × 10−6) was also evident, suggesting an allelic series. Our findings in humans align with decades-old experimental observations in mice that β2 loss abolishes nicotine-mediated neuronal responses and attenuates nicotine self-administration. Our genetic discovery will inspire future drug designs targeting CHRNB2 in the brain for the treatment of nicotine addiction.

Atención plena compasiva para dejar de fumar en México: un ensayo clínico aleatorizado

Introduction: Compassionate Mindfulness (APC, according to the term in Spanish) is defined as the awareness that arises through paying attention to the present moment, without judging experiences and generating actions motivated by the aspiration to free oneself and others from suffering. Currently the effectiveness of this type of treatment has gained relevance in the context of nicotine addiction treatment. Objective: to evaluate the efficacy of an intervention based on APC as a treatment for smoking cessation in the Mexican population. Method: a randomized clinical trial was implemented involving 62 people recruited from a specialized smoking cessation clinic in Mexico City. These people were randomly assigned to one of two treatment conditions: the control group received the treatment provided regularly at the clinic, while the experimental group received an APC-based treatment. Results: at the end of the treatment, participants who received the APC-based treatment were more likely to quit smoking (OR = 4.33, p .025, IC 95% 1.2-15) and they also displayed greater benefits to their mental health in some of the variables evaluated. Discussion and conclusion: APC is an effective intervention for smoking cessation in Mexican patients, since it has important benefits to the patient’s general mental health, and it is important to continue exploring its effects on both the maintenance of abstinence and relapse of tobacco consumption.

Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

Scottish government considers nicotine addiction treatment for children aged under 12 years

Scottish government considers nicotine addiction treatment for children aged under 12 years