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Varenicline: the answer to tobacco addiction, currently
missing in action
Pharmaceutical Roots is a content series from LGC Standards - investigating and outlining the natural
origins of pharmaceutical substances, and offering a deeper dive into their history, uses, risks, and
mechanisms of action. This month, we look at how varenicline - aka Champix, or Chamtix – appeared to
offer a solution to the global ‘tobacco epidemic’ before production was largely halted by the nitrosamine
drug substance related impurity (NDSRI) N-nitroso-varenicline.
From Columbus to a ‘tobacco epidemic’
Christopher Columbus unknowingly
missed the chance to save millions of lives
during his epic first voyage of discovery -
when he had second thoughts about a
new, and seemingly useless plant.
Sailing into what is now the Bahamas in
October 1492, Columbus and his
crewmates were presented by friendly
natives with some strange, dry leaves
that gave off a powerful odour. But, as
they were inedible, they threw them
overboard. It was only weeks later, in
modern-day Cuba, that they observed
local people chewing or smoking rolled
tabacos herbs, as Native Americans had
done for at least two millennia for
medicinal and religious purposes.
The addictive properties of the Nicotiana
tabacum plant soon made it a hit with
Columbus’ sailors, and it was also
famously introduced to Queen Elizabeth
I’s English court by Sir Francis Drake in
the 16th century. Just over 50 years after
being underestimated by Columbus,
tobacco was being grown commercially in
Brazil, while by the 18thcentury American
revolutionary commanders used their
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country's valuable tobacco crops to
fund the War of Independence against
the British.
Although chewing remained the most common way of consuming tobacco until the late 19th century,
automatic production machinery helped make cigarettes the pre-eminent choice soon after. Tobacco use
reached new heights during the First World War – when “Millions of cigarettes were distributed free to
the troops in France, and they became so powerful a morale factor that Gen. John Pershing demanded
priority shipment to the front.”
During the 1920s and 1930s, cigarette companies launched new brands designed to appeal to women –
Marlboro cigarettes were originally marketed with the tagline ‘As Mild as May’ – and tripled the
number of female smokers by 1935.
Although the deadly health effects of tobacco were not widely known at this point, unpleasant smoking
symptoms such as “scorched lungs” had been noted by the Chinese philosopher Fang Yizhi in the early
17th century, while Sir Francis Bacon discussed tobacco’s addictive properties at around the same time.
German doctors began warning pipe smokers about the possibility of developing lip cancer in 1795,
and sharp increases in lung cancer amongst American men between the 1930s and 1950s gradually
led scientists to demonstrate the close links between tobacco and ill health. In 1955, See It Now became
the first television programme to report the connection between smoking and cancer – when its
famously heavy-smoking host Ed Murrow for once declined to light up during the broadcast.
Today, despite overwhelming evidence that tobacco is responsible for numerous cancers – as well as a
host of other conditions including heart and lung disease, stroke, chronic obstructive pulmonary
disease, and arthritis – we remain in what the World Health Organisation (WHO) calls a ‘tobacco
epidemic’. Columbus’ apparently worthless leaves make tens of billions of dollars in profits for the
global tobacco industry per annum, but at the expense of more than eight million lives every year – the
vast majority of them in lower- and middle-income countries. As WHO points out, “All forms of tobacco
use are harmful, and there is no safe level of exposure to tobacco.” The availability of drugs or other
treatments that can save lives by helping people defeat their tobacco addiction is therefore critical.
Answers for addiction
Perhaps the biggest problem with weaning smokers off nicotine – the natural alkaloid present in all
tobacco plants – is that it is a powerful and highly addictive stimulant. Readily absorbed into the
bloodstream, nicotine is able to cross the blood-brain-barrier in just seven seconds, and binds to
cholinergic receptors in the brain, muscles, heart, adrenal glands and other vital organs. In doing so,
nicotine competes with the neurotransmitter acetylcholine, which stimulates receptors in order to
maintain healthy functions - including breathing, heart function, muscle movement, and memory. However,
nicotine disrupts normal brain function, prompting chemical changes and addiction.
Cytisine, first isolated from the Cytisus laburnum shrub in 1865, is an alkaloid whose effects are
“qualitatively indistinguishable from that of nicotine” – so much so that German and Russian soldiers
smoked it as a substitute for tobacco during World War Two. Still relatively unknown outside central
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and Eastern Europe, cytisine was developed behind the Iron Curtain as a smoking cessation aid called
Tabex, which first came to market in 1964 – long before any comparable drugs were approved in the
West. Although Tabex proved superior to nicotine replacement therapies (NRTs) in helping people quit
smoking, it also causes side-effects ranging from cold and flu-like symptoms to nausea and vomiting, sleep
disorders and even hospitalisations. It is therefore not approved for human use by the European Union or
the US Food and Drug Administration (FDA).
Encouraged by the partial success of Tabex, Pfizer investigated cytisine analogues as alternative
smoking cessation agents, and by 1997 had developed Varenicline. Preclinical trials demonstrated that
“varenicline may not only attenuate nicotine reward and intake, but could reduce the risk of relapse and
mitigate withdrawal symptoms in nicotine-dependent subjects”, while also suggesting that it had low
potential for abuse. Following randomised clinical trials involving more than 3,600 subjects in the US, the
FDA approved varenicline as a smoking cessation aid on May 11, 2006. Marketed as Chamtix, or
Champix, the drug immediately proved a spectacular success, with five million people taking it around
the world by 2008. As of 2023, it has been prescribed to an estimated 24 million people globally,
received approval in 116 countries, and is a WHO Essential Medicine.
Mechanism of action
Varenicline has a dual agonist-antagonist mechanism, consisting of two pharmacological activities, on
nicotinic acetylcholine receptors (nAChRs). It is both a high-affinity partial agonist of the α4β2 nAChR, and
was later shown to be a high affinity partial agonist for α6β2-containing (α6β2*) nAChRs, which also play
a key role in nicotine dependence. Agonist activity is a result of nAChR desensitisation and activation, as
nicotine causes extensive desensitisation of nAChRs. Therefore, replacing nicotine with another nAChR
agonist can reduce nicotine craving. Competition of a nAChR agonist with inhaled nicotine results in an
antagonistic activity by decreasing nicotine receptor occupancy of α4β2 and α6β2* nAChRs.
Synthesis
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The ’global tragedy’ of N-nitroso-varenicline
In July 2021, Pfizer halted varenicline production because of the presence of the potentially
carcinogenic impurity N-nitroso- varenicline, and withdrew all lots of the drug two months later –
“effectively making it unavailable indefinitely”. Although generic alternatives were found in Canada, the US
and Australia, the recall led to an immediate 75 per cent reduction in varenicline prescribing in the USA,
meaning that many patients “simply did not receive treatment”. According to an article in The Lancet in
May this year, the move also means that “varenicline is largely unavailable worldwide and fully
unavailable in the UK, EU, Japan, South America, and most of North America” – a shortage that the UK
NHS warns may continue into the long term. The Lancet also called the recall “a global tragedy for the
fight against the tobacco epidemic”, and “a missed opportunity to prevent chronic diseases or death in
hundreds of thousands of smokers”. Without a safe and regular supply of varenicline, it said, clinicians had
to fall back on less effective regimens, such as NRTs, and “often feel powerless in their efforts to help
patients using tobacco”.
LGC Standards – for all your varenicline testing needs
To support your analysis and help ensure the accuracy of your quality control processes, LGC Mikromol
supplies an ISO 17034-accredited pharmaceutical API reference standard for varenicline tartrate,
and a new impurity standard for N-nitroso-varenicline. Why not browse our fast-growing range of
impurity products in the table below? And explore our full range of Mikromol API, impurity and
excipient reference standards here.
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Also part of LGC Standards, TRC provides a very broad range of research chemicals to support your
varenicline and cytisine studies - including key deuterium labelled products, metabolites, and impurities.
Varenicline tartrate - MM3380.00 N-nitroso-varenicline - MM3380.20-0025
Other related products
Part Number Cas Number Part Description
2,3,4,5-Tetrahydro-1,5-methano-1H-3-benzazepine
MM3380.05-0100 230615-52-8
Hydrochloride
7,8,9,10-Tetrahydro-8-(trifluoroacetyl)-6,10-methano-6H-
MM3380.06-0025 230615-70-0 pyrazino[2,3-h][3]benzazepine
(N-(Trifluoroacetyl)varenicline)
2,3,4,5-Tetrahydro-3-(trifluoroacetyl)-1,5-methano-1H-3-
MM3380.07-0100 230615-69-7
benzazepine-7,8-diamine
7,8-Dinitro-2,3,4,5-tetrahydro-3-(trifluoroacetyl)-1,5-
MM3380.08-0100 230615-59-5
methano-1H-3-benzazepine
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