A recent longitudinal study (2016-2021) published in JAMA of children who had used any form of nicotine found, using neuroimaging outcomes, “a significant association … of early-age initiation of tobacco use with lower crystalized cognition composite score and impaired brain development in total cortical area and volume. Region of interest analysis also revealed smaller cortical area and volume across frontal, parietal, and temporal lobes” in children who had smoked. Importantly, the study controlled for socio-economic factors and other substance use.

A key tenet of vaping theology insists that when claims about nicotine harming cognitive development are made, the dismissive “pure speculation” flag must be rapidly run up the pole. Vaping advocates have a lot of fun pointing out that the abundant evidence about this has almost come from animal studies, particularly with rats like this, this and this.

Unlike in animal studies, experimental exposure of children to nicotine to assess cognitive or other impacts would never be accepted by human ethics research committees, so observational cohort studies like the JAMA study above are the best data we have.

In this piece from 2018 , local Aussie vaping apostle Dr Colin Mendelsohn weighed in on this issue stating “There is no evidence so far that nicotine harms the human brain in adolescence. Concerns of harm to brain development from nicotine are based on rat and mouse studies. … As one review concluded, animal tests generally ‘fall far short of being able to predict human responses.”

Dr Col, as he likes to call himself, must have spent a good while searching for an authoritative reference to bolster that claim.  The first author of the paper linked above gives his affiliated organisation as an outfit dedicated to opposing the use of animals in research called Americans For Medical Advancement, listed by Quackwatch as a possibly “questionable organization”.

In 2023 Dr Col doubled down on this in a video where at 2m30s he claims: “Teens who smoke don’t have significant differences in adulthood in IQ, educational achievement or cognitive function compared to those who’ve never smoked.”

Oh really? This prospective cohort study examined the association between early to midlife smoking trajectories and midlife cognition in 3364 adults  (1638 ever smokers and 1726 never smokers) using smoking measures every 2–5 years from baseline (age 18– 30 in 1985–1986) through year 25 (2010–2011). Five smoking trajectories emerged over 25 years: quitters (19%), and minimal stable (40%), moderate stable (20%), heavy stable (15%), and heavy declining smokers (5%). Heavy stable smokers showed poor cognition on all 3 measures compared to never smoking. Compared to never smoking, both heavy declining and moderate stable smokers exhibited slower processing speed, and heavy declining smokers additionally had poor executive function.

In this Finnish longitudinal cohort twin study data (n=4761) from four time points (ages 12, 14, 17, and 19-27 years) “were used to estimate bivariate cross-lagged path models for substance use and educational achievement, adjusting for sex, parental covariates, and adolescent externalizing behaviour.”

Smoking at ages 12 and 14 “predicted lower educational achievement at later time points even after previous achievement and confounding factors were taken into account. Lower school achievement in adolescence predicted a higher likelihood of engaging in smoking behaviours … smoking both predicts and is predicted by lower achievement.”

Against the  authority of Dr Col on the doubtful relevance of animal studies for humans, we can look at the track records of all 225 Nobel Prize winners in the Medicine and Physiology category between 1901-2021. Of these, 188 (83.6%) used animals in their research.

So across 120 years, the judges of the most prestigious global prize in medical research seem to think animal research is of immense importance in understanding of human health. But Dr Col, a former Sydney GP with no masters or PhD and a very slim track record in publishing  research with original data in peer reviewed journals (search for “Colin Mendelsohn” in Google Scholar) claims to know different.

One such  Nobel Prize winner is Columbia University neuroscientist Eric Kandel  (2000) who in 2014 with his wife (who orginally conceived of the gateway hypothesis in 1975) published The molecular basis for nicotine as a  gateway drug in the New England Journal of Medicine where they set out molecular experimental evidence for the gateway hypothesis in mice.

In a likely throw to the Kandels’ work, as shown above, Dr Col wrote (see below) that “it is also theorised that nicotine may sensitise the brain to other drugs and increase the risk of substance abuse. However, there is no evidence to support this theory in humans.” This is of course because experimental and randomised controlled trials involving introducing nicotine naïve human subjects to nicotine would never be ethically acceptable.

Eric Kandel summarised his paper this way:

“The results we obtained by combining epidemiologic and biologic studies suggest a model in which nicotine exerts its priming effect on cocaine by means of HDAC inhibition and provide a molecular explanation of the unidirectional sequence of drug use observed in mice and in human populations. Nicotine acts as a gateway drug and exerts a priming effect on cocaine in the sequence of drug use through global acetylation in the striatum, creating an environment primed for the induction of gene expression. Long-term potentiation in the nucleus accumbens is blocked when long-term exposure to nicotine is followed by cocaine use, which presumably lessens constraints on dopaminergic neurons in the ventral tegmental area and leads to the enhanced release of dopamine.¹⁹ For all the measures we studied — locomotor sensitization, conditioned place preference, long-term potentiation, and FosB expression — reversing the order of nicotine and cocaine exposure was ineffective: cocaine did not enhance the effect of nicotine. The priming effect of nicotine depended on its being given for 7 days before cocaine. Priming did not occur when nicotine was given for only 24 hours before cocaine.”

LD₅₀

One of the most basic measures in toxicology is the LD₅₀ measure. This is “a standardized measure for expressing and comparing the toxicity of chemicals. The LD₅₀ is the dose that kills half (50%) of the animals tested (LD = “lethal dose”). The animals are usually rats or mice, although rabbits, guinea pigs, hamsters, and so on are sometimes used.”

Substances with LD₅₀ below 5 mg/ kg are classified as highly toxic while substances with LD₅₀ above 15,000 mg/kg are deemed relatively harmless. 

Perhaps Dr Col has forgotten about the LD₅₀ measure from his undergraduate days and that this fundamental measure of toxicity, so central to safe dosage in prescribing, is derived from animal testing. It’s been around since 1927 and is being phased out today due to animal welfare concerns.

Animal studies were critical in early understanding of the pathogenesis of diseases now well-established as being caused by smoking. In 1962, Bock et al demonstrated that painting cigarette tar on mice skin produced  tumours in 41 of 76 mice painted with tar from  unflitered cigarettes and in 15 of 60 mice painted with tar from filter-tipped cigarettes. In every group of mice, some of the skin tumours progressed to cancers within the 1-year period. Guinea pigs develop emphysema from tobacco smoke. Mice get hypertension, increased oxidative stress, impaired NO bioavailability, endothelial dysfunction, and cardiac remodeling when chronically exposed to  cigarette smoke and pregnant mice produce low birth weight offspring when exposed.

So in all these examples, we have unchallenged strong evidence that tar and cigarette smoke harms lab animals in the same way that it harms humans. Yet witness the rush to blithely dismiss concerns about the relevance of animal evidence on nicotine exposure and brain development.

In this earlier blog, I listed a long series of studies mostly but not always  involving animals looking at the role of nicotine in a range of diseases and disease processes. Vaping advocates often seem to have a kind of religious zealotry about nicotine being a benign and indeed beneficial substance in the levels found in inhalable nicotine products. Their rush to shut down concern about nicotine’s impact on young brains is a disturbing sign of their irritation that community concern about the impact of vaping on kids should in any way interrupt adult access to these products. Their regular sarcasm about “won’t someone please think of the children” sees this in full flight.

Other blogs in this series

Vaping theology: 1 The Cancer Council Australia takes huge donations from
cigarette retailers. WordPress  30 Jul, 2020

Vaping theology: 2 Tobacco control advocates help Big Tobacco. WordPress 12 Aug, 2020

Vaping theology: 3 Australia’s prescribed vaping model “privileges” Big Tobacco WordPress Feb 15, 2020

Vaping theology: 4 Many in tobacco control do not support open access to vapes because they are just protecting their jobs. WordPress 27 Feb 2021

Vaping theology: 5 I take money from China and Bloomberg to conduct bogus studies. WordPress 6 Mar, 2021

Vaping theology: 6 There’s nicotine in potatoes and tomatoes so should we restrict or ban them too? WordPress 9 Mar, 2021

Vaping theology: 7 Vaping prohibitionists have been punished, hurt, suffered and damaged by Big Tobacco WordPress 2 Jun, 2021

Vaping theology: 8 I hide behind troll account. WordPress 29 Jun, 2021

Vaping theology: 9 “Won’t somebody please think of the children”. WordPress 6 Sep, 2021

Vaping theology: 10: Almost all young people who vape regularly are already smokers before they tried vaping. WordPress 10 Sep, 2021

Vaping theology: 11 The sky is about to fall in as nicotine vaping starts to require a prescription in Australia. WordPress 28 Sep, 2021

Vaping theology: 12 Nicotine is not very addictive WordPress 3 Jan 2022

Vaping theology 13: Kids who try vaping and then start smoking,would have started smoking regardless. WordPress 20 Jan, 2023

Vaping theology 14: Policies that strictly regulate vaping will drive huge
numbers of vapers back to smoking, causing many deaths. WordPress 13 Feb, 2023

Vaping theology 15: The government’s prescription vape access scheme has failed, so let’s regulate and reward illegal sellers for what they’ve been doing. WordPress 27 Mar 2023

Vaping theology 16: “Humans are not rats, so everybody calm down about nicotine being harmful to teenage brains”. WordPress 13 Jul, 2023

Vaping theology 17: “Vaping advocates need to be civil, polite and respectful” … oh wait. WordPress 3 Oct, 2023

Vaping theology 18: Vaping is a fatally disruptive “Kodak moment” for smoking. WordPress Oct 30, 2023