provides general information regarding cytisine

Quit Smoking with Tabex
Sopharma Shop
By John Vandermosten, CFA




Achieve Life Sciences, Inc. (NASDAQ:ACHV) is developing cytisinicline, historically known as cytisine, for nicotine addiction. The drug is currently available over the counter (OTC) in several eastern European countries for this indication and has been successful with annual revenues in excess of $20 million there; however, it is not approved by the FDA or EMA. Achieve has licensed cytisinicline for development and commercialization in the United States and most other geographies around the world including parts of Europe, the Middle East, Africa and Asia. The drug formulation has been used by over 20 million smokers in Central and Eastern Europe for smoking cessation and also in over 2,000 subjects in previously conducted investigator-led Phase 3 clinical trials. Given the clinical and in-market data available, the safety and efficacy profile are well characterized and provide a degree of confidence that successful regulatory trials can be conducted for FDA approval.

Cytisinicline is an attractive alternative to current smoking cessation products and in comparisons conducted by the Cochrane Group, has shown similar efficacy to Pfizer’s Chantix, the current leading prescription product, and may provide an improved safety and side effect profile. Prescription treatments also show greater success in stopping smoking as compared to over-the-counter patches, gums and lozenges.

There are approximately 1 billion smokers in the world, with an estimated 40% attempting to quit annually. Solutions available to this group include prescription only drugs such as Chantix (varenicline) and Zyban (bupropion) plus nicotine replacement therapies (NRTs) such as patches, gums and lozenges. Behavioral therapies and counseling are also important non-drug treatments that can be used independently and more successfully in conjunction with medication. While the current paradigm of treatment does help some individuals, success rates are low and only about five to six percent per year stop smoking after an attempt to do so. According to the Center for Disease Control (CDC) it can take 8-11 quit attempts before success. The highly addictive nature of nicotine, social influences, adverse effects associated with NRT and non-nicotine medications, and other factors are faulted for the low success rate.

The single most beneficial action a smoker can take to improve their own and surrounding family’s health is to stop smoking. Approximately 30% of all cancers and up to 87% of lung cancer is caused by the addictive habit. Additional diseases associated with smoking include cardiovascular and respiratory disease, diabetes and macular degeneration. Despite the damage caused by this vexing habit, nicotine is highly addictive and quitting is very difficult. Nicotine addiction can be as strong as other addictive substances such as heroin and cocaine.1 The effect on health and health care costs of the estimated greater than one billion persons smoking in the world is estimated to be $1 trillion annually with over $300 billion in the U.S.2

With a serious health risk from smoking and only modest benefit from existing treatments, it is clear that an unmet need exists. Introducing cytisinicline beyond Eastern Europe may provide an additional tool for smokers who have failed using other approaches and provide a product with a potentially improved side effect profile and shorter duration of treatment. Cytisinicline may present fewer incidences of nausea, vomiting, sleep disorders, insomnia and headache as compared to its most direct competitor, Chantix. With the completion of successful clinical trials, we see cytisinicline as a potential solution for the high unmet need in this space with potentially similar efficacy to Chantix and greater efficacy over NRT and antidepressant medications (such as bupropion) and improved side effect profile compared to Chantix.

Achieve currently holds one development product in its portfolio, cytisinicline, which is currently in preparation for two Phase III trials. The first trial is anticipated to be an 800 person study with two arms (1.5 mg versus placebo) which will start before year end 2019 and will last for approximately one year. The second (1.5 mg, 3.0 mg versus placebo) is a 1,500 person three-arm study starting first half 2020 and lasting for approximately 18 months. Following the anticipated favorable results from the two studies, we anticipate a submission of an NDA to the FDA in early 2022.

The company held $13.1 million in cash and equivalents on its balance sheet as of September 30, 2018 and subsequent to the quarter end raised an additional net $5 million. Based on forecasted cash burn rates, we anticipate a cash balance of approximately $15 million at year end, which should support operations for the next two or three quarters. However, management has made clear they will require additional capital prior to the start of the Phase III trials and we anticipate this to take place in the Q2/Q3 2019 timeframe and after additional analysis of Phase IIb data. As the Phase III trials advance over the next two years, we forecast an acceleration in cash burn. Capital requirements may be mitigated from commercial partnering activities in the U.S. and elsewhere.

The low rates of success with current smoking cessation therapy and the high rates of side effects for varenicline and bupropion create an unmet need that cytisinicline may partially address. Cytisinicline may be able to show impressive quit rates when combined with behavioral support and a lower side effect profile compared to current market leader varenicline to penetrate a medication market of near $5 billion.

Smoking is one of the most pervasive and preventable health issues faced today. Over one billion or about 20% of people smoke worldwide and almost 40 million or 15% smoke in the United States. The CDC estimates that about 70% of these individuals want to quit and over 50% have attempted to quit in the US. However, one of the components in tobacco, nicotine, is highly addictive, making the effort to stop smoking very difficult. There are many good reasons to quit with lung and other types of cancer, heart disease, stroke and pulmonary diseases all advanced by smoking. The CDC also estimates smoking reduces lifespan by about 13 years for men and 14 years for women, which is in addition to a lower quality of life during the later years.

One popular method to stop smoking in recent years is the use of e-cigarettes, or vaping, which deliver liquid nicotine into a mist or vapor which is inhaled. This method of consumption avoids the chemicals that are associated with smoke, but e-cigarettes are not FDA approved and may have other health and safety issues associated with them. The FDA considers e-cigarette use as an epidemic particularly in youth with almost 5 million juveniles using e-cigarettes during 2018, an increase of 78% over the prior year.3 While not exposed to the chemicals in smoke, the e-cigarette user remains addicted to nicotine and is exposed to other chemicals with undetermined side effects. Other approaches to smoking cessation include nicotine gum, patches, lozenges, sprays and inhalers. Prescription medications are other methods and include Zyban and Chantix. The currently approved products have varying rates of success and adverse effects that can limit effectiveness. 2018 sales of NRT and smoking cessation medication is approximately $4.6 billion.4 Chantix alone had global revenues of $1.1 billion in 2018, a, 8.7% increase from 2017, of which 76% came from the U.S. market.

Cytisinicline is a smoking cessation product that has been used in Central and Eastern Europe since the 1960s and is a natural extract from the Cytisus Laburnum plant. Cytisinicline provides a pharmacological action similar to nicotine that helps with the cravings and withdrawal symptoms associated with quitting smoking. The compound has been examined in several investigator-led Phase III studies and has been used by over 20 million smokers. The wide use of the molecule and well-understood safety profile provide confidence that it can show sufficient efficacy and safety to obtain FDA approval following successful conclusion of the two required Phase III studies. The FDA considers cytisinicline to be a New Chemical Entity (NCE) because it has never been approved in the U.S.

Achieve has a license and supply agreement with partner Sopharma to provide support on development and manufacturing as well as an exclusive supply of cytisinicline. While cytisinicline is considered a natural product and cannot be patented, a successful approval from the FDA will provide five years of exclusivity for the product in the US and ten years in EU countries. Additionally, a novel salt-form of cytisinicline has been patented which could provide future protections for the product beyond the regulatory exclusivity periods. An improved product offered to a large global population that is trying to quit provides an attractive market for Achieve Life Sciences, especially given there have been no new smoking cessation treatments in over a decade. With over half of the population of smokers trying to quit, we estimate there will be about 25 million Americans and several hundred million individuals globally in the addressable market when cytisinicline is approved.

Key reasons to own ACHV shares:

‣ Proven asset with use in over 20 million smokers
‣ Preliminary data shows improved efficacy and favorable side effect profile vs. current products
‣ Shorter therapy duration vs. other NRT or Chantix
‣ Dual acting MoA reduces cravings, withdrawal symptoms & prevents rush from smoking
‣ Previous Phase III studies completed in over 2,000 subjects demonstrate safety and efficiacy
‣ Pursuing smoking population of ~40 million in US and over one billion worldwide
‣ Smoking cessation medication market value of $4.6 billion in 2018
‣ Company maintains sufficient cash to complete currently active trials

In the following sections we estimate the number of smokers worldwide and review the addictive nature of cigarettes. We then examine the hazards of cigarette smoke on health and its association with some of the most common diseases that occur today. Next is a summary of competing products as well as their benefits and shortcomings. Cytisinicline is introduced along with its history and mechanism of action (MoA) followed by a discussion of clinical trials that have taken place to evaluate the drug and future trials that will be sponsored by the company. Finally, we review Achieve’s financial performance, partners and management team, evaluating strengths and weaknesses. Our evaluation is concluded with an analysis of the market potential for cytisinicline under Achieve’s control and a discussion of the valuation parameters and price target. With favorable outcomes expected from the upcoming Phase III trials, we anticipate a successful 2023 launch of the product.

How Prevalent is Tobacco Smoking?

The National Institute for Health (NIH) and the World Health Organization (WHO) estimate that there are 1.1 billion smokers in the world5 and almost 40 million6 in the United States. There are 6.3 million deaths from cigarette smoking for primary users and almost 900,000 for those exposed to secondhand smoke.7 Countries with the highest rates of smoking include Belarus, Russia, Greece and China. China is also the most populous nation with over 300 million individuals craving a puff according to the WHO. The problem is particularly prevalent in developing countries which lack strict smoking laws and may have governments that rely on tax revenues generated from the industry. Smoking is associated with a range of diseases including multiple types of cancer, emphysema, heart disease, increased risk of blindness and decline in mental function among other maladies. The U.S. Centers for Disease Control and Prevention say that smokers shorten their lives by 13 to 15 years compared to non-smokers.

Nicotine Addiction

Smoking is difficult to quit due to the addictive nature of nicotine. Nicotine is a component of tobacco and is carried to the smoker’s lungs when they inhale the smoke. It enters the bloodstream through the lungs and disperses throughout the body providing pleasant physical and mood altering effects. Within seconds of inhaling tobacco smoke, nicotine will reach the brain. The toxic alkaloid stimulates the release of neurotransmitters including acetylcholine, beta-endorphin, dopamine, norepinephrine, serotonin, vasopressin, arginine and ACTH. This causes vasoconstriction, tachycardia and increased blood pressure in the body. The smoker feels enhanced pleasure, decreased anxiety, and a state of alert relaxation. The drug’s profile changes from stimulant to sedative in increasing dosages and use. Nicotine addiction promotes drug-reinforced behavior, compulsive use, and frequent relapse following abstinence.

Drug addiction begins by building a tolerance in the body and brain. As exposure levels of a drug, including nicotine, are increased over time, tolerance builds up in the system and greater levels of nicotine are required to achieve the same effect. The nicotine from cigarettes is absorbed through the lungs and into the bloodstream, then carried through to the brain where the molecules attach to acetylcholine receptors. This has an immediate effect on breathing and heart rate, along with memory and ability to learn. Binding of nicotine to the acetylcholine receptors stimulates production of dopamine, a neurotransmitter associated with pleasure and reward. The feeling of pleasure and reward is the mechanism that draws smokers back to that next cigarette.

Source of Nicotine

Nicotine is an alkaloid, fat soluble molecule that naturally comes from plants in the nightshade family. The most common source is Nicotiana tabacum, or the tobacco plant which is grown globally, particularly in China, India and Brazil. The chemical compound is an oily liquid that will mix with water and has a boiling point of 247 °C. Nicotine will burn at a temperature below its boiling point, and its vapors will combust at 35 °C in air despite a low vapor pressure. As a result, most of the nicotine is burned when a cigarette is smoked; however, enough is inhaled to provide the desired effects. When exposed to heat, a portion of the nicotine vaporizes and the rest is transferred to the small airways and alveoli of the lung. The drug is dissolved and transferred across cell membranes at a rate dependent on pH to reach the bloodstream then the brain.

View Exhibit I – Tobacco Plants8

Nicotine Mechanism of Action

Nicotine acts as an agonist on nicotinic acetylcholine receptors (nAChRs) which are found throughout the body, autonomic ganglia, at neuromuscular junctions, in the adrenal medulla and the brain. The receptors are also located on the pre-synaptic axon terminals of the central nervous system. This action facilitates neurotransmitter release and thereby mediates the complex actions of nicotine in tobacco users.

Neurotransmitters are released when nicotine acts on receptors. These include dopamine, glutamate, acetylcholine and gamma aminobutyric acid. These have short term euphoric effects such as pleasure, increased attention and mental processing ability and improved working memory. Nicotine binds to nAChRs located in muscles and in the ventral tegmental area of the brain. As the stimulant interacts with the receptors, this causes release of dopamine in the nucleus accumbens providing the sense of pleasure that the smoker seeks. Nicotine interferes with the normal binding of acetylcholine, which is an important neurotransmitter and increases the level of activity with the nAChRs. This increase in activity creates an imbalance which triggers a reaction to reduce the production of acetylcholine. Over time, the receptors become desensitized and the number of receptors increases in response to constant nicotine exposure.9 As the number of receptors increase, this creates tolerance and higher levels of nicotine are required to achieve the same effect.

View Exhibit II – Nicotine Chemical Structure (C10H14N2)

When an individual stops smoking, the receptors are not activated due to the absence of nicotine and the pleasure response ceases. This causes withdrawal symptoms including severe cravings, irritability, anxiety, anger, poor concentration, restlessness, impatience, increased appetite, weight gain and insomnia. The brain receptors are also accustomed to stimulation by nicotine in certain situations such as while drinking or after a meal, which can also cause craving for a cigarette when an individual is in one of these settings.

Hazards of Smoking

Smoking cessation is the single most helpful action a smoker can take to improve their health. According to the CDC, cigarette smoking causes more than 480,000 deaths in the United States and is implicated in 90% of all lung cancer deaths and 80% of deaths from chronic obstructive pulmonary disease (COPD). Smokers are also at a greater risk of cardiovascular disease due to the effect chemicals in smoke have on the endothelial cells that line blood vessels. These cells can become swollen and inflamed, thereby narrowing the blood vessels and restricting blood flow and encouraging the formation of plaque.

There are approximately 4,000 chemical compounds10 in tobacco smoke, many of which are associated with a variety of cancers. Some of these carcinogens include formaldehyde, arsenic, ammonia and benzene. According to the American Cancer Society, about half of deaths from twelve cancer types are attributable to cigarette smoking, including cancers of the liver, colon & rectum, lung, oral cavity & throat, esophagus, larynx, stomach, pancreas, bladder, kidney, cervix and acute myeloid leukemia. The chemicals can also damage the tissue in the lungs by attaching to the alveoli and entering the bloodstream.

Smoking is also associated with early delivery for pregnant mothers, reduced fertility, osteoporosis, macular degeneration, rheumatoid arthritis and decreased immune function.

There is a greater risk for those who smoke later in life. Individuals who smoke in their 50s and later are at 10 times more risk than those who stop before age 40. Discontinuing the habit before age 40 can avoid more than 90% of the excess mortality associated with smoking and 97% of this risk can be avoided by stopping before age 30.11 Quitting smoking can reduce the risk of heart attack, stroke and a broad variety of cancers. Halting the use of cigarettes also leads to an improvement in lung function and after 15 years of not smoking, an individual’s risk of coronary heart disease is the same as a non-smoker.

Smoking Cessation Therapies

Despite the large population of smokers throughout the world, many in this group realize the health risks and want to quit. However, the highly addictive nature of nicotine prevents them from being successful. A Center for Disease Control study found that almost 70% of smokers want to quit, over half have tried to quit, but only 6% were able to kick the habit. By the time cytisinicline is approved, we see an addressable market of near 25 million who are actively trying to stop. With only one in five people remaining abstinent at 6 months using most efficacious therapy and the high long-term failure rate of almost 90% for existing therapies, there is a material unmet need for new solutions.

Nicotine Replacement Therapies (NRTs)

Although the harm from smoking is associated with the smoke, it is the nicotine that produces the pharmacological effects that lead to addiction. Nicotine replacement products include a variety of administration types to replace the nicotine that is lost when a patient stops smoking. They can include patches, gums, lozenges, sprays, inhalers and tablets and are most commonly used in an attempt to quit smoking. NRT does not precisely reproduce the exposure of arterial nicotine absorbed in the body through smoking, resulting in some symptoms of withdrawal. While smoking can deliver nicotine to the brain in seconds, NRT approaches can take many minutes or hours to achieve the same effect and the user can suffer withdrawal symptoms during the delay. Despite the imperfect mechanism, the low cost and ease of use are primary reasons why these solutions are used. All of these products are available OTC, except for the nasal spray and inhaler, and can be purchased for around $50 for a month of treatment. NRT therapy12 is expected to last from two to six months, providing a period to taper off the desire for nicotine.

Electronic cigarettes are another approach used for nicotine replacement but are not approved by the FDA. These devices include a system that either vaporizes or nebulizes liquid sealed in a cartridge. The liquid contains glycerol, propylene glycol, water, nicotine and flavors. There are concerns with e-cigarettes regarding labeled and measured nicotine content and there is insufficient information of the effect of the vaporized liquid and whether or not it may be harmful. Although the market for e-cigarettes is large, we do not categorize this as a cessation therapy or competitor, especially for patients trying to eliminate their addiction.

Prescribed Medications

Chantix (varenicline)

Initial development of varenicline was inspired by cytisine. Pfizer closely studied the Laburnum anagyroides plant and its chemical derivative cytisine during the 1990s to create a synthetic drug which could be patented. Varenicline was eventually approved in 2006 and achieved sales of almost $850 million in 2008, after which they declined due to safety concerns related to alleged increase suicide rates in patients. Quit rates have ranged from 14 to 44% in a variety of studies, and in many randomized, placebo-controlled comparisons, varenicline has shown statistically significant and better efficacy than placebo. However, other research has shown no meaningful difference between the drug and NRT therapy.13 Additionally, the highest cited quit rate was at the end of the 12 week treatment period, rather than at six months, the latter of which is more indicative of long-term success. This impressive quit rate was accompanied by ~25 counseling sessions which may not be a component of real-world therapy. Shortly after varenicline was approved, there were complaints of suicidality and neuropsychiatric events which led to a black box warning being added to the label. After several years and the 3-year EAGLES trial, the black box was removed in December 2016; however, concerns may remain regarding the drug’s side effect profile.

Zyban (bupropion hydrochloride)

Bupropion was first approved in 1985 for depression under the brand name Wellbutrin and was removed from the market the following year due to incidence of seizures. In 1997, the drug was approved as a smoking cessation aid under the name Zyban in the United States and in subsequent years, Europe as well. Generic versions of bupropion became available in 2006. The drug belongs to the aminoketone class, and is distinct from other antidepressant agents. It is a weak inhibitor of reuptake of dopamine, noradrenaline and serotonin in the central nervous system. It is also a non-competitive nicotine receptor antagonist and in combination with suppressing the reward transmitters is useful in reducing the cravings for cigarette smoking. Bupropion has been observed to be more effective than NRT when combined with behavioral support14 but less effective than varenicline based on a review of clinical trials.15

Behavioral Therapy

Many studies16 have shown that the addition of behavioral therapy to a smoking cessation plan improves overall success. Smokers with a strong addiction and ingrained habits need to change addictive behaviors. Behavioral therapy can increase an individual’s confidence about being successful and help them avoid smoking triggers and teach methods to cope with the desire to smoke. Behavioral therapy has been used in conjunction with a number of medications in drug trials in an effort to improve smoking cessation rates. The protocol that that has been acknowledged by the FDA and other authorities for use as part of a clinical trial provides up to twelve behavioral support sessions that occur during initial screening, randomization and each visit. Counselors at these sessions will encourage the patients to overcome challenges and discuss anticipated side effects during an estimated 10 minute session.

Something New From Something Old


Cytisine is an alkaloid that is produced naturally in several plants including those in the Laburnum and Cytisus genera. The molecular structure of the compound is similar to nicotine and has similar pharmacological effects. Cytisine is derived from the seeds of the Laburnum anagyroides plant, also known as golden chain, which grows in mild and damp climates in central and southern Europe. The plant is a bush or tree and can reach heights of 23 feet. It produces black seeds, which are very poisonous to humans, goats and horses if ingested whole. From first planting, it takes four to five years for the plant to produce the seeds from which the cytisine is taken. Achieve’s supplier Sopharma AD extracts cytisine from the plant in its production facility by processing the seeds.

The plant and its derivative have a long history associated with smoking. During World War II, the leaves of the plant were used by smokers as a tobacco substitute by Russian soldiers. In the 1960s, clinical trials took place in Central and Eastern Europe and former Soviet states and the product was first marketed in Bulgaria in 1964. In succeeding years it also became available in Poland, Russia and adjacent states as a cost effective clinical treatment for nicotine addiction.

In the fourth quarter on 2018, the United States Adopted Names Council designated cytisinicline as the generic name for cytisine. We use the terms relatively interchangeably, favoring cytisinicline when referring to Achieve’s relationship to the drug.

View Exhibit III Laburnum Anagyroides17

Mechanism of Action

Similar to nicotine and varenicline, cytisinicline binds to nicotinic acetylcholine receptors in the brain. Cytisinicline is a partial agonist for the α4-β2 nicotinic receptors which are central to the reward pathway for nicotine and result in addiction. The plant-based alkyloid stimulates the α4β2 nAChR which results in excitation of the respiratory center, resulting in enhanced reflexes, simulation of adrenaline release by the medullar part of the suprarenal glands and a rise in blood pressure. For smokers, cytisinicline reduces the interaction between nicotine and the corresponding receptors in the gastrointestinal tract. The process decreases and interrupts the physical and psychological addiction to nicotine.
Achieve Life Sciences obtained the rights to develop cytisinicline in the United States and the majority of the rest of world from Sopharma to address a poorly met need for smoking cessation. Despite having been used for many years in Eastern Europe in millions of patients, cytisinicline is considered a new chemical entity in the United States. While a natural substance cannot be patented, the molecule can secure five years of exclusivity in the US if granted FDA approval and patents on new formulations of the drug could provide an extension of this exclusivity period. We see the long history and well-understood safety profile of the drug as strong positives in support of successful Phase III trials. Based on our timing forecasts, Phase III trials can be completed by late 2021 and FDA approval can arrive in time for commercialization in 2023.

While there are a number of solutions for smoking cessation available, the success rate is low and no new therapies have been approved in over a decade. Of this group, varenicline (Pfizer’s Chantix) is recognized has having the best success rates; however, high levels of adverse events are seen as one of the main obstacles to greater efficacy. Cytisinicline, with its anticipated greater specificity for the α4β2 nAChR receptor and fewer off target effects, may show an improved side effect profile resulting in greater compliance and higher success than products that are now available. While it is too early to know what the safety and efficacy profile will be in a trial aligned with FDA protocols, early results are promising.

In summary, we believe that the long historical use of cytisine, generically known as cytisinicline, provides confidence that the upcoming Phase III trials will be successful and will provide the necessary data to obtain FDA approval, presenting a relatively low risk pursuit for a new chemical entity. If Phase III trials are able to show materially improved success over what varenicline has achieved, we anticipate even higher sales than what we forecast in our model. Based on our conservative estimates, shares of ACHV are undervalued relative to their potential and we initiate with a target price of $6.00.
SUBSCRIBE TO ZACKS SMALL CAP RESEARCH to receive our articles and reports emailed directly to you each morning. Please visit our website for additional information on Zacks SCR. 

DISCLOSURE: Zacks SCR has received compensation from the issuer directly or from an investor relations consulting firm, engaged by the issuer, for providing research coverage for a period of no less than one year. Research articles, as seen here, are part of the service Zacks provides and Zacks receives quarterly payments totaling a maximum fee of $30,000 annually for these services. Full Disclaimer HERE.

2 World Health Organization and Centers for Disease Control and Prevention estimates.
3 Youth Tobacco Use: Results from the National Youth Tobacco Survey
4 Coherent Market Insights Global Smoking Cessation and Nicotine De-addiction Products Market Overview.
5 The Society of Thoracic Surgeons
6 Centers for Disease Control and Prevention. Current Cigarette Smoking Among Adults—United States, 2016. Morbidity and Mortality Weekly Report 2018;67(2):53-9 [accessed 2018 Feb 22].
7 Global Burden of Disease Collaborative Network. Global Burden of Disease Study 2016 (GBD 2016) Results. Seattle, United States: Institute for Health Metrics and Evaluation (IHME), 2017.
8 By Derek Ramsey /, CC BY-SA 4.0,
9 Govind, AP, et al. Nicotine-induced upregulation of nicotinic receptors: underlying mechanisms and relevance to nicotine addiction. Biochem Pharmacol. 2009 Oct 1;78(7):756-65.
10 Nordqvist, C., What Chemicals Are In Cigarette Smoke? July 13, 2015. See link for a representative listing of identified compounds.
11 Pirie, K., et al. The 21st century hazards of smoking and benefits of stopping: a prospective study of one million women in the UK. Lancet. 2013 Jan 12; 381(9861): 133–141.
14 Roddy, Elin. Bupropion and other non-nicotine pharmacotherapies. BMJ. 2004 Feb 28; 328(7438): 509–511.
15 Ping, W. et al. ‘Effectiveness of smoking cessation therapies: a systematic review and meta-analysis.’ BMC Public Health. 2006.
16 Sykes, C.; Marks, D. Effectiveness of a cognitive behaviour therapy self-help programme for smokers in London, UK. Health Promotion International, Volume 16, Issue 3, 1 September 2001, Pages 255–260
17 Source: Wikipedia Commons.