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

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).

Marijuana may not only protect against lung damage, but also help nicotine product users regulate or quit their product, and has the potential to aid with other chemical dependencies.

Marijuana may not only protect against lung damage, but also help nicotine product users regulate or quit their product, and has the potential to aid with other chemical dependencies.

One of the most persistent reasons that people favor marijuana use, legalization, and regulation is due to the assertion that smoking marijuana does not do damage to the lungs, while tobacco smokers have a high certainty of dying from their habit. While the claims have been modulated to some extent, this assertion has held true in cohort studies of medical and recreational marijuana use in California, and attempts to determine causality actually found that the smoke from marijuana offers a protective effect to the lungs of users.

Something that has not been addressed as fully, is the impact of THC on the brain and fighting addiction. Nicotine is among the most addictive substances in the world when taken in amounts of 15-20 mg per day and greater for an extended period of time, the threshold for chemical dependence. It has also been shown to do damage to the dentate gyrus of the brain, which contains about 90% of the brain’s memories, at these levels of intake.

Marijuana smokers experience an increase in functional connectivity in the brain, which has been causally associated with an increase in IQ. The dentate gyrus is among the parts of the brain which experience elevated levels of neurogenesis as a result of exposure to an active compound in marijuana, THC. Recent research conducted at Duke University found that tobacco smokers who were able to quit experienced elevated levels of connectivity in the brain as well, while those who relapsed or became heavier smokers tended to lack this connectivity.

This research is of extreme importance as both nicotine products and other addictive substances or pharmaceuticals grip many users in this country. While it is important to make these activities less addictive, for example by limiting the amount of nicotine in a dose, ironically enough the opposite of what manufacturers of cigarettes did decades ago (though to be fair this may have been a simple reaction against hyperbolic at the least and malevolent or unfounded research at the worst targeted at tobacco), or educating people about what level of intake can be diagnosed as chemically dependent, and should be seen as a warning sign of addiction (as a good doctor will do with any prescription), it is also important to develop methods of ensuring successful recovery in the event of chemical dependence.

While marijuana has been prescribed before prohibition, and has a cultural connotation as a substituting product allowing people with chemical dependence to recover past withdrawal for centuries, the nature of its medical value is just starting to be explored now. Of particular interest is whether the factors affecting recovery for nicotine can contribute to recovery from other substances; research carried out suggests that the underlying genetic factors behind addiction are “highly correlated” at the least. Using brain scan technology to see this effect will be exciting at the least, and this particular vein of research is among the most enticing for public health.

Works Cited:

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

Addicott, Merideth A., et al. “Increased Functional Connectivity in an Insula-Based Network is Associated with Improved Smoking Cessation Outcomes.” Neuropsychopharmacology (2015).

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.

Fried, Peter et al. “Current and Former Marijuana Use: Preliminary Findings of a Longitudinal Study of Effects on IQ in Young Adults.” CMAJ: Canadian Medical Association Journal 166.7 (2002): 887–891.

Doweiko, Harold. Concepts of chemical dependency. Cengage Learning, 2011.

Hashibe, Mia, et al. “Marijuana use and the risk of lung and upper aerodigestive tract cancers: results of a population-based case-control study.” Cancer Epidemiology Biomarkers & Prevention 15.10 (2006): 1829-1834.

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.

Kempker, Jordan A., Eric G. Honig, and Greg S. Martin. “Effects of Marijuana Exposure on Expiratory Airflow: A Study of Adults who Participated in the US National Health and Nutrition Examination Study.” Annals of the American Thoracic Society ja (2014).

Kendler, Kenneth S., John Myers, and Carol A. Prescott. “Specificity of genetic and environmental risk factors for symptoms of cannabis, cocaine, alcohol, caffeine, and nicotine dependence.” Archives of General Psychiatry 64.11 (2007): 1313-1320.

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.

Lung Cancer and Smoking in the UK

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

Females and males stopped smoking in the same rates.
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 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 in the 1970’s, and there is solid science that shows inhaled radioactive particles cause lung and other cancer for 30-60 years after detonation.


Source: http://ratecalc.cancer.gov/ratecalc/archivedatlas/pdfs/maps/acc-maps.pdf
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.

 



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.


Study Estimating Thyroid Doses of I-131 Received by Americans From Nevada Atmospheric Nuclear Bomb Tests, 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 to be safe up to 2 rads annually, it is now known there is virtually no safe level of radiation exposure, with even a single rem additional exposure adding cancer mortalities) 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 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. 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.

 

New research suggests that nicotine creates cellular drills, targeting and perforating smooth muscles over a period of six hours.

Contrary to popular belief, that carbon dioxide level exposure had to be extreme in order to deposit enough tar to permanently damage the lungs, it is now becoming clear that the cause of lung cancer and other smoking related problems is in fact nicotine. It was an old wives’ tale or counterargument from smokers that because people living in big cities inhaled half of a pack to a pack of cigarette in smoke from smog each day, but did not have high lung cancer rates like second hand smokers, there must be something wrong with the tobacco studies that were done. Living in a city with hundreds of thousands of cars cars was equivalent to “two packs of cigarettes a day” while any smoker will have a 24-35 in 100 chance of lung cancer (500-1000 times higher than simply being a city dweller). In Bejing today, this rate is 42 in 100,000. People who use candles or incense frequently only have 7 or 8, slightly more than regular marijuana smokers. This perhaps indicated that in fact smoking cessation products cause lung cancer; that it is not smoke, but nicotine that causes the lung cancer has only been proved this last year. Possible explanations at the time included contaminants to tobacco or asbestos, hence natural brands such as American Spirit advertised as such to me as a teenager.
However, in 2013, a new paper delivered at the American Society for Cell Biology managed to watch the molecules of nicotine fold into drills after being present in the blood stream for a continuous six hours. These target smooth muscles, such as those found in the heart, epidermis, lungs, and reproductive system as well as throughout the body. This helps to explain why a secondhand smoker in a house with a heavy smoker has a greater chance of lung cancer than a light smoker. It is conceivable that users of e-cigs or nicotine substitution products such as the patch or gum living in a big city could give themselves lung cancer as well by pollutant exposure as the body becomes unable to naturally clean itself.
Much credit is deserved for Brown professor Ching-Ming Hai, who discovered these cellular drills called podosome rosettes. By establishing the link between heart disease such as atherosclerosis and nicotine, the way has been opened to investigate the role of nicotine on other organs such as the lungs. Being able to observe this phenomenon suggests a veritable hypothesis that other smooth muscles in the body will and do respond in a similar way, eventually tearing and folding under continued nicotine exposure.
Some research has existed which supports this hypothesis that lung cancer is caused by nicotine, including studies which suggest that lung cancer is sped up by nicotine exposure (Dasgupta). For the first time, it can be assuredly said that in fact the cause is in nicotine. This supports the population data. In all of Mexico, for example the lung cancer rate is 5 in 100,000 (Lazcano). Introducing smoke increases this eight times, to as much as and over 40 in 100,000 with smog and air pollution (Wang). With nicotine exposure, this jumps to the 30,000 in 100,000 or thirty percent that indicates lung cancer is caused by tobacco.
This is affirmed by research using populations in Sweden and in California in which smokers of marijuana were not found to have increased cancer rates, or only slight and suggested links to cancer. Research along these lines were released in the 1990s and 2000s, though did not have at this time any scientific rationale for the phenomenon, which can now be attributed to nicotine. Continuing research along these lines should provide alternatives and safe products, once again, to combat use of sweets and bubblegum which were originally the targets of tobacco advertising.

http://articles.chicagotribune.com/2001-07-05/news/0107050231_1_smog-alert-mexico-city-greenhouse-gases
http://www.ncbi.nlm.nih.gov/pubmed/9428585
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1796573/
http://www.businessweek.com/articles/2014-02-28/rates-of-lung-cancer-rising-steeply-in-smoggy-beijing
http://lungcancer.about.com/od/Lung-Cancer-And-Smoking/f/Smokers-Lung-Cancer.htm
http://www.cnn.com/2013/12/16/health/nicotine-e-cigarettes/
http://www.webmd.com/cancer/news/20060720/nicotine-speeds-lung-cancer
http://link.springer.com/article/10.1007/s10552-013-0259-0
http://link.springer.com/article/10.1023/A:1018427320658

Bibliography:

Dasgupta, Piyali, et al. “Nicotine induces cell proliferation by β-arrestin–mediated activation of Src and Rb–Raf-1 pathways.” The Journal of clinical investigation 116.8 (2006): 2208-2217.

Lazcano, Ponce EC, et al. “Trends of lung cancer mortality in Mexico.”Archives of medical research 28.4 (1996): 565-570.

Wang, Q. “[An analysis of incidence mortality and survival rates of lung cancer in Beijing].” Zhonghua liu xing bing xue za zhi= Zhonghua liuxingbingxue zazhi12.4 (1991): 205-207.


Addendum: It should be noted that this does not indicate that nicotine or tobacco is responsible for cancer. 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 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 combated 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 stage 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.

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