Neurogenesis Suppression in Dentate Gyrus Induced by Moderate to Heavy Nicotine Use Finally Shown to Have Negative Impact on Memory Functions?

There is a stereotype that marijuana smokers have hazy or weak memories as a result of their use. Tobacco smoke, on the other hand, is usually discussed in terms of the positive effect on cognition by virtue of the very mild stimulant effects delivered by nicotine. Over a decade ago, however, researchers in Nice, France showed in rats that administration of nicotine, without smoke, induced a suppression of new neuronal births in the dentate gyrus, the part of the brain that handles about 90% of a person or animal's memories. In the last decade as well, researchers from the Chinese Military, Canada, and Maryland have shown that marijuana actually encourages the birth of neurogenesis in the hippocampus (which is responsible for most remaining memories) by 40%, when a pure THC copycat chemical, named for Hebrew University where the compound was made, is administered to rats. Researchers at Princeton University and the Department of Nutrition in Brazil also showed that there was no effect from THC on the dentate gyrus of rats, even at levels producing "gross behavioural intoxication".

This provides a general understanding of the effect of THC on the brain, which should be reproducible in human or population studies which have been conducted. More recent brain scans have also shown this to be true as conducted with human populations, with negligible changes, positive or negative, found in most parts of the brain, though functional connectivity has also been shown to increase in a significant manner with marijuana use this last year.

Most recently, a study from Spain claimed that while virtually every mode of behavioural measurement was equal between marijuana smokers and control groups, a significant (though still within the realm of normal fluctuation) decrease in memory function was noted. This speaks in the face of research that has been conducted about THC or the marijuana that contains it. Even with patients using 10 times the responsible adult use in the sample, and the average number of marijuana cigarettes, or spliffs, smoked in a lifetime being around 42,000 (with one participant smoking over a massive 256,000 times) among those included in the study, the results do not match with rats who were administered high levels of THC; the results should have been positive and not negative.

There is a difference between the human and rat studies, though which is not addressed. In the Spanish study, noting a decrease in memory function, the research explicitly emphasizes that tobacco users were not omitted from the study, and about 75% of the participants were actively smoking tobacco when the study was conducted.

A little background, for the American marijuana user, is necessary. In Europe, people smoke spliffs generally made with hashish and tobacco. The unfiltered smoke doubles the nicotine intake (in some countries there are lower limits on nicotine levels, but in Spain this probably means quite similar to American cigarettes, as there has not been a strict concentration of absorbed nicotine enforced throughout the European Union yet), and this dominates the marijuana culture there. While more efficient, this also means that it is very difficult to smoke marijuana regularly without crossing the threshold of 5-10 mg of nicotine daily at which point positive effects are eclipsed by neurogenesis suppression, assuming the user is smoking on work breaks or at certain timepoints and not regularly throughout the day (the research indicates that doses of more than 3-5 mg of nicotine in the blood at a time is the crossover point from positive to negative effects).

The research in Nice, France, which originally shows the negative impact of moderate to heavy nicotine use on the dentate gyrus, emphasizes that further research is needed to confirm this neuronal difference actually translates to a cognitive change. Research from Riba et al. should be used in conjunction with other research done in this field to confirm this fact, as has been shown above. It is still worth investigating the impacts of age, obviously at certain ages nicotine has a positive effect, while it can be assumed that while a brain is developing such stunting of neurogenesis must induce extreme cognitive defects. For those concerned about absorbing too much nicotine, in the last 70 years absorbed nicotine in cigarettes has increased almost 3-fold in the USA (though in some parts of Europe the composition of a cigarette is much the same as in the early days of the tobacco industry) as companies and governments attempt to limit tar or air pollution intake (read previous research on cancer mortality and smoking for more), one viable option is to use pipe tobacco instead of cigarette tobacco. While the curing process for pipe tobacco means there is more nicotine per gram in the cigarette or bowl, the wide cut of the leaves lowers absorbed nicotine by around 13 times (or 2-4 times in comparison to low nicotine European cigarettes). Normal use of pipe tobacco is also associated with levels of cancer and smoking-related disease more similar to the general population than to the cigarette smokers.

Works Cited:

Abrous, Djoher Nora, et al. "Nicotine self-administration impairs hippocampal plasticity." The Journal of neuroscience 22.9 (2002): 3656-3662.

Filbey, Francesca M., et al. "Long-term effects of marijuana use on the brain."Proceedings of the National Academy of Sciences 111.47 (2014): 16913-16918.

Jiang, Wen, et al. "Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic-and antidepressant-like effects." Journal of Clinical Investigation 115.11 (2005): 3104.

Kochman, Linda J., et al. "Despite strong behavioral disruption, Δ 9-tetrahydrocannabinol does not affect cell proliferation in the adult mouse dentate gyrus." Brain research 1113.1 (2006): 86-93.

Ling, H. W., and CB Wynn Parry. "The amount of nicotine absorbed in smoking." British journal of pharmacology and chemotherapy 4.3 (1949): 313-314.

Riba, J., et al. "Telling true from false: cannabis users show increased susceptibility to false memories." Molecular psychiatry (2015).

Nicotine shown to have half the constrictive properties on veins as alcohol, and marijuana actually will make them bigger (with vasorelaxatory properties identified in THC)!

Nicotine and vein constriction:

"Smoking was associated with significant changes in the aortic pressure-diameter relation that denote deterioration of the elastic properties and were maintained during the whole study period: the slope of the pressure-diameter loop became steeper (baseline, 35.43±1.38; minute 1, 45.26±1.65; peak at minute 10, 46.36±1.69 mm Hg/mm; P<.001) and aortic distensibility decreased (baseline, 2.08±0.12; minute 1, 1.60±0.08; nadir at minute 5, 1.54±0.07×10⁻⁶ cm²·dyne⁻¹; P<.001). In contrast, no changes in aortic elasticity indexes were observed with sham smoking."

http://circ.ahajournals.org/content/95/1/31.short

Alcohol and vein constriction:

"Blood ethanol levels achieved at 60, 120, and 180 minutes were 649+-48, 1,285±81, and 2,546+-130jug/ml, respectively. LAD cross-sectional area was reduced significantly from control at the end of each of the three dosing periods (-24± 5%, -40± 3%, and -53±.3%; p<0.004). a-Adrenergic blockade had no effecton LAD cross-sectional area, while nicardipine partially reversed the ethanol-induced vasoconstriction. No significant change in vessel cross-sectional area took place in control dogs."

 http://circ.ahajournals.org/content/78/1/165.full.pdf

Marijuana and vein relaxation:

"The present results provide strong evidence that THC is a PPARγ ligand, stimulation of which causes time-dependent vasorelaxation"
This results in a lower blood pressure and better athletic performance.

http://www.sciencedirect.com/science/article/pii/S0006291X05021352

Lung Cancer and Smoking in the UK

Britain has half the man-made and natural radiation combined as the US has just man-made.

http://news.bbc.co.uk/2/hi/uk/4709394.stm

Females and males stopped smoking in the same rates, from 41% and 52% to 23% and 25% (respectively).

http://www.cancerresearchuk.org/prod_consump/groups/cr_common/@nre/@sta/documents/image/mort_asr_uk_lung_png.png

Lung cancer mortality rates have remained the same (55 to 45 per 100,000), and actually increased for women (17 to 30 per 100,000). 

Confounding research on Chronic Inhalation Exposure to Mainstream Cigarette Smoke Increases Lung and Nasal Tumor Incidence in Rats - Human consumption of tobacco lowers lung lesions, tumours, and other malignancies

There are a number of procedural errors in this study which will be addressed as follows. Firstly the bias or affiliation of the study, published by Oxford University, is listed as pfizer, a corporation that makes smoking substitution products, and was caught bribing academics (in unlisted affiliations) with the intent of maintaining marijuana prohibition. Furthermore, the study was conducted in New Mexico, a part of the USA with high atmospheric radiation at this time, the non-smoking control received filtered air, while smoking groups were exposed to non-filtered air. The study asserts that in mice testing, supporting data was gathered that cigarettes cause pulmonary damage. 
The mice are divided into a control group, a "low-smoking" and a "high-smoking" group. The low-smoking group was exposed to the equivalent of between 20-30 cigarettes smoked continuously for six hours without stopping. The high-smoking group was exposed to the equivalent of 60-80 cigarettes per day continuously over a period of six hours and should have been disregarded as non-evident of human consumption patterns at any time in history. For the purposes of reality, the low-smokers (which in humans is at levels classified as heavy cigarette use), will be used in this evaluation. In addition, in this study the high smoking rats were starved (food consumption 60% of non-smokers), which also indicates this data is not reliable.
Despite the conclusion and abstract's assertion, the data is actually quite positive for regular smokers. Incidence rates of neoplasia in the nasal cavity was lower for smokers than non-smokers.  The survival rate for smoking rats is higher by a significant amount, from 752 days to 779 days. Lung weight of smoking rats was the same as non-smoking rats (an increase was seen by 60 cigarettes per day). Ciliated cuboidal cell metaplasia (mucus in the lungs, a deformity frequently observed with aging that has not been definitively connected to cancer, except in epidermal cases, and then only correlatively) was noted in a small amount in smoking rats. Squamous metaplasia was not observed in smoking rats, but were noted in the 60 cigarette per day group. Keratinizing squamous cysts were not observed in smoking rats, but were noted rarely at 60 cigarettes per day. There were no consistent trends in lung lesions, with sometimes lowest levels in the group smoking 60 cigarettes per day (eg. hyperplasia), sometimes lower in smoking rats (eg. malignant neoplasia) and other times in non-smoking (eg. benign neoplasia), though it should be noted this occurred in non-significant levels in all rats. There is no increase in nasal neoplasia for smoking rats. 
After all this, the study asserts that cigarettes are the cause of problems, but admits, "The reason this study produced significant increases in lung tumors in rats while previous studies did not cannot be determined with certainty." It is fairly clear that while, previous studies have linked regular human consumption to health benefits, the concept of gassing rats with 60 cigarettes per day had simply not occurred. See previous articles for data on cancer mortality rates in the USA and the probability that tobacco use in humans has numerous health benefits. While there is not data here on radiation exposure necessary to lower white blood cells in a rat, it is safe to assume these fall along similar lines with humans, and exposure to an unmeasured number of mrems of radiation was a significant factor in the development of malignancies in the rats. It is possible that filtered air might make a difference in mucous accumulation in rats as well as humans, though this is not definitively connected with cancer or malignant symptoms.

Mauderly, J. L., Gigliotti, A. P., Barr, E. B., Bechtold, W. E., Belinsky, S. A., Hahn, F. F., Hobbs, C. A., March, T. H., Seilkop, S. K., and Finch, G. L. (2004). Chronic inhalation exposure to mainstream cigarette smoke increases lung and nasal tumor incidence in rats. Toxicol. Sci. 81, 280–292. 

Increasing cancer mortality rates despite technological advances and drastically lower tobacco use in the USA: 1950-2015, 65 years of cancer theory down the drain?

There is no explanation for why cancer mortality rates have not gone down (and have gone up) despite medical advances as the entire nation has stopped smoking. Investment in screening and treatment can ensure near 100% recovery, yet all budgeting goes to cheaper "prevention" which does not work. Since the US cracked down on tobacco use, with success in white males, the overall cancer mortality rate has increased from 184 per 100,000 in 1950-69 to 209 per 100,000 from 1970-1994. Today that rate holds steady at 203 per 100,000. In white females and in other demographics cancer mortality rates have been steady or changed in negligible amounts, but these demographics have had increasing tobacco use rates. Cancer is a painful and unnatural death that can often involve long battles with the disease and should be combatted with all resources available, in treatment and in prevention. While lung cancer rates have fallen, technological advances have allowed earlier detection of lung cancer, which at stages 0 and 1 is among the least deadly forms of cancer, but at later stages is among the most deadly. Without adjustments for technological advances in medical care, no positive statement can be made in regards to success or negative results from anti-smoking campaigns. Meta-data from overall cancer mortality does show that the resources in the war on cancer have been squandered and had an overall detrimental effect on the national health of the country, and some policy change is necessitated, although it must be noted there is no current biological explanation for the lower cancer rates in countries and places with higher tobacco use, these have been correlative not causal links. Atmospheric nuclear weapons testing does match up with the population data, it was ended by the 1970's with the Limited Test Ban, and in the continental USA in 1962, and there is solid science that shows inhaled radioactive particles cause lung and other cancer for 30-60 years after detonation.


See cancer rates in USA: http://ratecalc.cancer.gov/ratecalc/archivedatlas/pdfs/maps/acc-maps.pdf

It can also be noted that the demographic distribution provided in the atlas is vitally important as the female population increased smoking rates slightly and saw a slight decrease in cancer mortality as well as an increase in life expectancy commensurate with the increases seen before anti-smoking campaigns.



Please note that the modern terminology for measuring radiation exposure is the gray which measures radioactive exposure per kilogram of tissue, as opposed to the rad which was formerly used and is an absolute amount of radioactive exposure. In humans, one gray is equal to about 100 rads.

Study Estimating Thyroid Doses of I-131 Received by Americans From Nevada Atmospheric Nuclear Bomb Test, National Cancer Institute (1997)
Annual dose in rads

It can be seen above that the white and light blue areas of dangerous levels of radiation (previously believed that 2 rads annually were safe, now it is known that virtually no level of radioactive exposure is safe) matches smoking data exactly (as shown below, and later in the article). Cancer mortality on the other hand, has changed drastically as far as geographic distribution over the years. According to research done on rats, lung cancer can be induced in significant amounts with any amount of radiation, and differences between groups exposed to 1 gray of radiation (100 rads) can be seen to be at least 13 times greater than in control groups (LaFuma et al.).

According to mapping of fallout from nuclear weapon's testing the majority of the southern states in the USA are exposed annually to an average of over 1 rad of radiation, from fallout alone, exposure to this level of radiation (lifetime of around 100 rads) radiation results in a, "decrease in the circulating white cells and platelets." This results in a statistically significant increase in cancer in keeping with the findings shown on this atlas as, "The Biologic Effects of Ionizing Radiation report (BEIR V) states that if 100,000 people are exposed to 10 rads of radiation, then there will be 800 additional cancers in that population above the normally occurring amount."   Source: http://cancernews.com/data/Article/264.asp#sthash.qEIXcULD.dpuf

We can expect cancer rates to drop significantly as the average radiation exposure in the USA has dropped since this map was made in 1997, the current average annual exposure is still .6 rads per year, enough that there are a significant number of people with lifetime exposure exceeding 100 rads.
Source: http://www.epa.gov/rpdweb00/understand/calculate.html

Finally, a primary concern of smoking (though the claim asserted by anti-smoking campaigns is that it increases all forms of cancer), has been lung cancer. This disease takes on average 20-30 years to develop (Howlander et al.), and while cigarette consumption had reached 80% and 90% of its peak by 1945 and 1950, respectively, lung cancer peaked in 1991 and 80% and 90% were reached in 1973 and 1980, respectively. Most importantly there are no spikes and dips as with tobacco use rates and consumption, but lung cancer is a smooth increase and decline, in direct communication with radioactive exposure and pursuant half-lives. Lung cancer mortality has not decreased in kind with decreasing smoking rates however, and in fact only plateaus with the ban of nuclear weapon's testing and nuclear power plant construction. While cigarette smoking has dropped by over half since 1975, lung cancer mortality has gone from 75 to 65 per 100,000, an insignificant change which after adjusting for atmospheric radiation actually indicates that smoking cessation has cost many lives.  See image below for lung cancer mortality in the USA.

A doctor I interviewed on this matter mentioned to me that it was a possibility that infectious diseases were accountable for the increase in cancer mortality, but that they did not know for certain, not having looked these statistics up. I have acquired the infectious disease mortality rate, and it has not changed since anti-smoking campaigns went into effect and in fact increased which means that the potential positive effects of tobacco may be even greater than suggested by simply looking at other raw data, possibly due to lost funding diverted to misguided anti-smoking campaigns. In any case the veracity of the failure of anti-smoking campaigns cannot be questioned in the war on cancer, and is a monumental public policy choice that must be reverted immediately.

Works and Sources Cited:

Centers For Disease Control

Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975–2011, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2011/browse_csr.php?sectionSEL=15&pageSEL=sect_15_table.19.html, based on November 2013 SEER data submission, posted to the SEER Web site, April 2014.

LAFUMA, J., CHMELEVSKY, D., CHAMEAUD, J., MORIN, M., MASSE, R., AND KELLERER, A. M. Lung Carcinomas in Sprague-Dawley Rats after Exposure to Low Doses of y Rays. Radiat. Res. 118, 230-245 (1989).

National Cancer Institute at the National Institutes of Health