Nicotine [Through A Peat Prism?]

Discussion in 'Alcohol, Tobacco, Drugs' started by Dopamine, Mar 1, 2016.

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  1. Dopamine

    Dopamine Member

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    Nicotine is the main active compound in tobacco and thus the main active compound in tobacco cigars and cigarettes. Many studies have painted a picture of the negative health effects brought on by smoking. It is important however to differentiate between smoking tobacco and consumption of nicotine isolated from tobacco. With the advent of E-Cigarettes, nicotine gum, and nicotine patches- The isolated effects of nicotine are being studied and show many potential benefits. I posit nicotine as being similar in effect to caffeine- a drug which is well known on the forum for its pro-metabolic effects. Nicotine however must be seen in its own light for its unique and potentially useful effects.

    Nicotine Effects on Resting Metabolic Rate (RMR)
    Acute effects of nicotine on resting metabolic rate in cigarette smokers. - PubMed - NCBI
    Increased 24-hour energy expenditure in cigarette smokers. - PubMed - NCBI
    The 1st study shows an increase in daily energy expenditure of around 6%. The 2nd study shows an increase in daily energy expenditure of around 10% which correlates to an extra energy expenditure of around 200kcal per day. This would equal weight loss of around 10kg/22lbs per year if caloric intake does not increase and remains consistent. Nicotine has been demonstrated in numerous studies to raise basal metabolic rate and body temperature. Nicotines ability to raise metabolic rate and increase thermogenesis is similar to caffeine.

    Effects of caffeine ingestion on NE kinetics, fat oxidation, and energy expenditure in younger and older men | Endocrinology and Metabolism
    In this study- caffeine boosts energy expenditure by an average of 10%. This is similar to the effects demonstrated by the nicotine studies.

    The effects of nicotine and caffeine are dose- dependent but likely harbor similar potential for raising metabolic rate and energy expenditure. Both Caffeine and Nicotine consumption are associated with lower incidence of obesity and leaner body mass due to their actions of increasing energy expenditure.

    Nicotine Effects on Pituitary Hormones
    “On the level of the whole organism, stress causes overactivity of the pituitary, and removal of the pituitary extends life, and retards the hardening of the extracellular connective material
    (Everitt, et al., 1983).”

    “Several of his [Everett] experiments strongly pointed to the prolactin-growth hormone family as the aging factors. Removal of the pituitary caused retardation of aging similar to food restriction.”
    (Ray Peat PHD)

    “The “little mouse,” and the experiments of Denckla and Everitt, show that a simple growth hormone deficiency or lack of pituitary function can double the life span: Intervention in the many other self-stimulating excitatory pathways can produce additional retardation of the aging process, acting at many levels, from from the extracellular matrix to the brain.” (Ray Peat PHD)

    Smoking may alter physiological systems involved in the stress response. Smokers show attenuated (Lowered) cortisol and systolic blood pressure response to acute stressors when compared to nonsmokers. The extent to which absent cortisol response is due to an enhanced negative feedback caused by the higher basal cortisol concentrations or to attenuated sensitivity to stress-related physiological activation is not yet clear. Potential central mechanisms involved in the altered stress response include a reduction in the number or affinity of receptors mediating effects of nicotine in different central nervous system structures that integrate the neuroendocrine stress response (al'Absi et al., 2003). Chronic nicotine consumption may also lead to lower responses of other stress hormones (ACTH, prolactin, growth hormone) to a variety of stimuli (Kirschbaum et al., 1994).

    -Thyroid Stimulating Hormone (TSH) Is released to stimulate the thyroid to produce more hormones. Having low TSH is generally an indicator of good health and means that thyroid hormone is being used efficiently by the body.
    -Growth hormone (GH) Teams up with estrogen and nitric oxide to produce edema. Growth hormone also increases the release of free fatty acids into the blood stream.
    -Prolactin (PRL) Stimulated by TRH and Estrogen and suppressed by dopamine and progesterone. Increases with stress and age and likely contributes to osteroperosis.
    -TRH-Follicle-Stimulating Hormone (FSH) Increases aromatase and estrogen. "The activity of aromatase increases with aging, and under the influence of prolactin, cortisol, prostaglandin, and the pituitary hormones, FSH (follicle stimulating hormone) and growth hormone. It is inhibited by progesterone, thyroid, aspirin, and high altitude." (Ray Peat PHD)
    -Luteinizing Hormone (LH) "Estrogen's stress-mimicking action probably tends to increase the secretion of LH, in ways that can be corrected by supplementing progesterone and thyroid." (Ray Peat PHD)
    -Adrenocorticotropic Hormone (ACTH) Stimulates stress hormone and androgen production.

    Studies seem to show mixed results in that acute exposure to cigarettes and/or nicotine may increase or decrease certain pituitary hormones. Overall however chronic nicotine intake is associated with reductions in the pituitary hormones suggesting that nicotine induces adaptive mechanisms that support the body. These same adaptations are seen in caffeine studies in that acute intake can increase stress and pituitary hormones however chronic users adapt and show reduced amounts. Most of the benefits of nicotine seem to come from chronic use and many of these adaptations take place in around 3 days.

    Nicotine Lowers TSH, LH, FSH, and GH:
    Acute effects of nicotine on serum glucose insulin growth hormone and cortisol in healthy smokers. - PubMed - NCBI
    "A secondary finding observed in the overall study group (primarily in females) was that nicotine caused a 29% median decrease in serum growth hormone (P =.02)."
    Involvement of cholinergic nicotine-like receptors as modulators of amine turnover in various types of hypothalamic dopamine and noradrenaline nerv... - PubMed - NCBI
    "Nicotine significantly reduced serum prolactin and TSH levels, and after H 44/68 it also reduced LH and FSH serum level"

    Haidut Posted a Study Showing That Caffeine Also Lowers TSH and Growth Hormone:
    Effects of caffeine on anterior pituitary and thyroid function in the rat. - PubMed - NCBI
    "Caffeine lowered serum TSH and GH in a dose-dependent manner with ED50 values of 30 and approximately 50 mg/kg, respectively."

    Chronic Nicotine Significantly Lowers Prolactin
    Acute nicotine administration stimulates prolactin release (Wilkins et al., 1982; Rasmussen, 1995). However, serum prolactin levels are significantly lower in both male and female chronic smokers who smoke more than 10 cigarettes per day (Andersen et al., 1984). This apparent discrepancy could be explained by a similar mechanism to that with ACTH (Fuxe et al., 1989).

    Nicotine acts directly on pituitary GH3 cells to inhibit prolactin promoter activity. - PubMed - NCBI
    "Nicotine was also observed to yield a concentration-dependent inhibition of the stimulation by thyrotrophin-releasing hormone (TRH) of PRL promoter activity, implying that nicotine can also interfere with hormonal regulation of the PRL gene."

    Chronic nicotine treatment increases dopamine levels and reduces dopamine utilization in substantia nigra and in surviving forebrain dopamine nerve... - PubMed - NCBI
    "Chronic nicotine treatment under the present conditions did not significantly alter serum levels of corticosterone and reduced prolactin serum levels in sham-operated rats."

    Involvement of D1 dopamine receptors in the nicotine-induced neuro-endocrine effects and depletion of diencephalic catecholamine stores in the male... - PubMed - NCBI
    "Nicotine treatment and to a minor degree also acute intermittent exposure to cigarette smoke produced a reduction in serum prolactin, LH and TSH but not in serum FSH, vasopressin and testosterone levels."

    Effects of chronic nicotine treatment and withdrawal on hypothalamic proopiomelanocortin gene expression and neuroendocrine regulation. - PubMed - NCBI
    "Chronic daily nicotine administration induced significant changes in serum corticosterone, serum prolactin, MBH TH mRNA, and MBH POMC mRNA concentrations that tended to persist through day 3 of withdrawal; serum prolactin and MBH POMC mRNA concentrations were suppressed whereas serum corticosterone and MBH TH mRNA concentrations were stimulated."

    -Estrogen raises prolactin[1] therefore chronic aromatase/estrogen inhibition by nicotine should lower prolactin.
    -Thyrotropin-releasing hormone (TRH) has a stimulatory effect on prolactin release. Nicotine lowers TRH.

    [1]Role of estrogen in the dopaminergic control of prolactin secretion. - PubMed - NCBI
    "Treatment of ovariectomized rats with estradiol benzoate (25 microgram/kg, sc) daily for 5 days resulted in a marked elevation of the serum PRL concentration."

    Effects of maternal nicotine exposure on thyroid hormone metabolism and function in adult rat progeny. - PubMed - NCBI
    "Levels of both TRH and TSH were lower in offspring exposed to Nicotine..."

    Chronic Nicotine Use has Neutral Effect on ACTH Levels
    In contrast to the acute effect of smoking on ACTH levels, the latter are not altered in chronic smokers (del Arbol et al., 2000). This is probably due to desensitization of the central nicotinic cholinergic receptors involved (Fuxe et al., 1989).

    Several of the symptoms of tobacco abstinence are characteristic of the stress response; the latter is associated with increases in plasma levels of ACTH (Selye, 1976). If tobacco withdrawal is a stressful event, nicotine abstinence would be expected to lead to increases in the plasma levels of ACTH. However, ACTH levels did not significantly increase during nicotine abstinence over ad libitum smoking levels (Pickworth et al., 1996).

    Neuropsychopharmacology - Chronic Nicotine Self-Administration Augments Hypothalamic-Pituitary-Adrenal Responses to Mild Acute Stress
    "On day 1 of acquisition of nicotine self administration, plasma levels of both adrenocorticotropin (ACTH) and corticosterone were significantly increased 15–30 min after the first dose of nicotine. These hormonal changes were no longer significant on day 3, when adrenocorticotropin levels were <60 pg/ml and corticosterone levels were <110 ng/ml during the hour after the first dose of nicotine."

    Nicotine Effects on Estrogen, Aromatase, and Testosterone
    Again it is important to differentiate between cigarettes and isolated nicotine. Polycyclic aromatic Hydrocarbons are present in cigarette smoke which increase estrogenic activity. These are the same estrogenic compounds found in many plastics. Cigarette smoke also increases carbon monoxide in the body which is estrogenic. Nicotine and its metabolite cotinine however are strong anti-estrogens and aromatase inhibitors.

    Nicotine Inhibits Aromatase (The Enzyme Which Converts Testosterone to Estrogen)
    Nicotine Blocks Brain Estrogen Synthase (Aromatase): In Vivo Positron Emission Tomography Studies in Female Baboons
    "The size of the effect (more than 50% of the maximal inhibition obtained with a blocking dose of vorozole) suggests that nicotine is capable of inhibiting the activity of aromatase in the primate brain."

    JCI - Nicotine, cotinine, and anabasine inhibit aromatase in human trophoblast in vitro.
    "In choriocarcinoma cell cultures, nicotine, cotinine (a major metabolite of nicotine), and anabasine (a minor component of cigarette tobacco) all inhibited androstenedione conversion to estrogen in a dose-dependent fashion. Removal of nicotine, cotinine, and anabasine from the culture medium resulted in the complete reversal of the inhibition of aromatase."

    Potential Contribution of Aromatase Inhibition to the Effects of Nicotine and Related Compounds on the Brain
    "Thus, we have shown that nicotine doses producing plasma levels comparable with those found in smokers are capable of a significant but partial (∼50%) inhibition of aromatase."

    Nicotine Also Directly Lowers Estrogen and Helps Clear it From the Liver
    Smoking, estradiol metabolism and hormone replacement therapy. - PubMed - NCBI
    "However, it has been proven that, depending on the type, duration and intensity of nicotine consumption, smoking can reduce or completely cancel the efficacy of orally administered estrogens."
    "The reduction or loss of therapeutic efficacy is mainly caused by dose-dependent elevated hepatic clearance, partially in conjunction with lower estrogen levels, and has been demonstrated only with oral estrogen applications."

    Nicotine raises DHT by decreasing conversion of DHT to alpha-androstanediol (estrogenic)
    Nicotine and cotinine effects on 3 alpha hydroxysteroid dehydrogenase in canine prostate. - PubMed - NCBI
    "The results suggest that nicotine and cotinine are competitive inhibitors of the HSD, an important enzyme involved in the metabolism of DHT and produce an accumulation of DHT."

    Progesterone and Chronic Caffeine Consumption Also Raise DHT:
    http://www.karger.com/Article/Pdf/12299
    "At 6–8 h after administration of Progesterone, serum T and DHT levels were consistently increased without any alterations in the serum LH and FSH levels. "
    Chronic caffeine intake increases androgenic stimuli, epithelial cell proliferation and hyperplasia in rat ventral prostate
    "Our results show that caffeine intake increased the concentrations of T and DHT, organ weight, epithelial cell proliferation and AR tissue expression in the ventral prostatic lobe."

    Nicotine and Testosterone
    Hormones.gr
    Evaluation of the effects of cigarette smoking on testosterone levels in adult men. - PubMed - NCBI
    http://www.biomed.cas.cz/physiolres/pdf/62/62_67.pdf
    Effect of cigarette smoking on levels of bioavailable testosterone in healthy men | Clinical Science
    There are conflicting opinions as to whether or not nicotine raises testosterone. This is probaly due to the fact that many studies on nicotine and testosterone levels use cigarettes which have both estrogenic and anti-estrogenic compounds. Most studies demonstrate that smokers have at least normal if not higher levels of testosterone than non-smokers. Nicotine will most certainly lower estrogen and many symptoms of low testosterone are really caused by high estrogen. Therefore nicotine can have a positive effect on people experiencing symptoms of low testosterone.

    Nicotine, Progesterone, DHEA, and Memory
    Hormones, Nicotine and Cocaine: Clinical Studies
    "Progesterone treatment decreases nicotine self-administration under a progressive-ratio schedule"
    Effects of pregnancy on nicotine self-administration and nicotine pharmacokinetics in rats. - PubMed - NCBI
    "NSA (Nicotine Self Administration) decreased over the course of pregnancy with NSA significantly lower in the third trimester compared to nonpregnant controls."
    Progesterone effects on subjective and physiological responses to intravenous nicotine in male and female smokers. - PubMed - NCBI
    "Progesterone also suppressed smoking urges by nicotine as assessed by the Brief Questionnaire on Smoking Urges"

    When progesterone is high (such as in pregnancy)- nicotine use and cravings decrease. This suggests that nicotine may compensate for low progesterone or may directly increase progesterone.
    Indeed This Study Shows That Nicotine Increases Neuro-Steroid Levels of Pregnenolone, Progesterone, and Allopregnanolone:
    Neurosteroids in nicotine and morphine dependence. - PubMed - NCBI
    "Acute intraperitoneal administration of nicotine (0.3-2 mg kg-1) or morphine (5-30 mg kg-1) induced dose- and time-dependent increases in the cerebrocortical and plasma concentrations of pregnenolone, progesterone, and allopregnanolone."

    Caffeine Does the Same Thing
    Caffeine-induced increases in the brain and plasma concentrations of neuroactive steroids in the rat. - PubMed - NCBI
    A single intraperitoneal injection of caffeine induced dose- and time-dependent increases in the concentrations of pregnenolone, progesterone, and 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) in the cerebral cortex.

    Drug Withdrawal Caused by Reduced Neuro-Steroids?
    Neurosteroid coadministration prevents development of tolerance and augments recovery from benzodiazepine withdrawal anxiety and hyperactivity in m... - PubMed - NCBI
    Chronic neurosteroid treatment prevents the development of morphine tolerance and attenuates abstinence behavior in mice. - PubMed - NCBI
    The neuro-steroids progesterone and pregnenolone seem to eliminate tolerance and withdrawal symptoms from long term drug use. I think it is likely that nicotine/caffeine withdrawals come from the bodies adjustment to reduced neuro-steroids on cessation of the drug.

    Nicotine Increases DHEA
    Effects of Low and High Nicotine Cigarette Smoking on Mood States and the HPA Axis in Men
    "After high nicotine cigarette smoking began, plasma ACTH levels increased significantly above baseline within 12 min and reached peak levels of 21.88 ± 5.34 pmol/L within 20 min. ACTH increases were significantly correlated with increases in plasma nicotine (r=0.85; P<0.0001), DHEA (r=0.66; P=0.002), and epinephrine (r=0.86; P<0.0001). Cortisol and DHEA increased significantly within 20 min (P<0.05) and reached peak levels of 424 ± 48 nmol/L and 21.13 ± 2.55 ng/ml within 60 and 30 min, respectively."

    Ray States the Benefits of Progesterone as Follows:
    "Experiments have shown that progesterone relieves anxiety, improves memory, protects brain cells, and even prevents epileptic seizures. It promotes respiration, and has been used to correct emphysema. In the circulatory system, it prevents bulging veins by increasing the tone of blood vessels, and improves the efficiency of the heart. It reverses many of the signs of aging in the skin, and promotes healthy bone growth. It can relieve many types of arthritis, and helps a variety of immunological problems."
    Progesterone Summaries - Progesterone Deceptions - Progesterone Supplementation - Dosage of Progesterone

    -Nicotine and Caffeine Use Both Elicit Many of These Effects, probaly through increasing neurosteroids.

    Nicotine Increases Short Term and Working Memory Similar to Progesterone
    Repeated nicotine exposure in rats: effects on memory function, cholinergic markers and nerve growth factor. - PubMed - NCBI
    "In the present study, male Wistar rats exposed a relatively low dosage of nicotine (0.35 mg/kg every 12 h) for 14 days demonstrated improved memory performance (assessed in two separate water maze testing methods) when compared with controls. Autoradiographic experiments indicated that nicotine increased [3H]-epibatidine, [125I]-alpha-bungarotoxin and [3H]-AFDX384, but not [3H]-pirenzepine binding sites in several learning- and memory-related brain areas."

    Cotinine reduces amyloid-β aggregation and improves memory in Alzheimer's disease mice. - PubMed - NCBI
    "Cotinine (Nicotine metabolite) reduced Aβ deposition, improved working and reference memories, and inhibited Aβ oligomerization in the brains of transgenic (Tg) 6799 AD mice."

    Cotinine reduces depressive-like behavior, working memory deficits, and synaptic loss associated with chronic stress in mice. - PubMed - NCBI
    "Cotinine-treated mice displayed better performance than vehicle-treated cohorts on the working memory task, the radial arm water maze test. In addition, with or without chronic stress exposure, cotinine-treated mice engaged in fewer depressive-like behaviors as assessed using the tail suspension and Porsolt's forced swim tests."
    "Taken together, our results show for the first time that cotinine reduces the negative effects of stress on mood, memory, and the synapse."

    Nicotinic systems and cognitive function - Springer

    Nicotine Increases Bone Growth (Possibly Through Decreasing Prolactin)
    Nicotine Increases Osteoblast Activity of Induced Bone Marrow Stromal Cells in a Dose-Dependent Manner: An in vitro Cell Culture Experiment
    Our study demonstrated a statistically significant effect of nicotine dose on osteoblast activity in vitro.

    Low level nicotine: a novel approach to reduce osteoporosis incidence. - PubMed - NCBI
    Studies also indicated that the prime criminal for osteoporosis is smoking not nicotine. Moreover, low level nicotine has preventive efforts on osteoporosis by stimulating osteoblasts proliferation and differentiation. We present a hypothesis that low level nicotine may be a novel approach to reduce osteoporosis incidence.

    Nicotine Potentially Anti-Epileptic.
    Nicotine as an antiepileptic agent in ADNFLE: an N-of-one study. - PubMed - NCBI
    "In an open study, nicotine patches reduced seizures..."

    -Nicotine is also structurally similar to nicotinic acid (Niacin) which has demonstrated anti-epileptic effects.

    Nicotine, Caffeine, and Progesterone Are Neuro-Protective Against Parkinsons
    Current evidence for neuroprotective effects of nicotine and caffeine against Parkinson's disease. - PubMed - NCBI
    Association of coffee and caffeine intake with the risk of Parkinson disease. - PubMed - NCBI
    Progesterone prevents depression-like behavior in a model of Parkinson's disease induced by 6-hydroxydopamine in male rats. - PubMed - NCBI

    Nicotine, Caffeine, and Progesterone are Carbonic Anhydrase Inhibitors Thus Increasing Levels of CO2 in the Body and Making Breathing Easier.
    Effects of nicotine and vitamin E on carbonic anhydrase activity in some rat tissues in vivo and in vitro. - PubMed - NCBI
    Carbonic anhydrase I and II inhibition with natural products: caffeine and piperine. - PubMed - NCBI
    An association between plasma progesterone and erythrocyte carbonic anhydrase I concentration in women. - PubMed - NCBI

    Smoking Slows Arthritis
    Cigarette smoking and radiographic progression in rheumatoid arthritis
    "heavy smokers (>1 pack‐day) progressed significantly less than non‐smokers or moderate smokers (p<0.001)."

    Nicotine Effects on Cortisol
    -Again we will differentiate between cigarettes and isolated nicotine. Cigarettes Contain MAO-A inhibitors which increases epinephrine and norepinephrine. Increases of these stimulatory Neurotransmitters will eventually lead to increases in cortisol and ACTH. Carbon Monoxide exposure from cigarette smoke also increases cortisol and ACTH.

    -Many studies show similar effects of acute nicotine and caffeine on increasing cortisol and ACTH. Chronic use of nicotine and caffeine however are adaptive and improve stress biomarkers as evidenced by reduced pituitary activity and increased thyroid activity.

    Stress-like adrenocorticotropin responses to caffeine in young healthy men. - PubMed - NCBI
    The effects of oral caffeine (3.3 mg/kg, equivalent to 2-3 cups of coffee) on plasma adrenocorticotropin (ACTH) and cortisol (CORT) were tested in 47 healthy young men at rest in a double-blind, placebo-controlled, crossover study. Following caffeine, ACTH was significantly elevated at all times from 30 min to 180 min, and CORT was elevated from 60 min to 120 min

    http://www.ncbi.nlm.nih.gov/pubmed/2550038
    Plasma ACTH and cortisol levels after oral administration of nicotine (chewing gum containing nicotine 2 mg) in short and long time (10 and 45 min) were studied in smokers and non smokers. Non smokers after short time administration showed significant rise in ACTH and cortisol. No modifications were seen in the other groups of subjects. [1]

    [1]*Note that only the non-smokers experienced a stress response to acute nicotine and the smokers showed no changes. This is similar to how acute caffeine in infrequent drinkers creates a stress response but chronic users experience the opposite effect- lowered stress and stress adaptation.
    http://www.ncbi.nlm.nih.gov/pubmed/21733336
    "Chronic caffeine intake decreases circulating catecholamines and prevents diet-induced insulin resistance and hypertension in rats."

    Nicotine Effects on Dopamine and Serotonin
    Nicotine activates the sympathoadrenal system and increases the synthesis and release of noradrenaline and adrenaline into circulation, and also alters the bioavailability of dopamine (Pomerleau, 1992). Single and repeated injections of nicotine in rats increase the expression of tyrosine hydroxylase, a rate-limiting enzyme in the catecholamine biosynthetic pathway (Hiremagalur & Sabban, 1995).

    -Increased expression of tyrosine hydroxylase suggests more tyrosine is being converted into dopamine in the body.

    Nicotine Increases Expression of Tyrosine Hydroxylase- Increasing Dopamine
    http://www.ncbi.nlm.nih.gov/pubmed/12538809
    "Chronic nicotine treatment elicited long-lasting, dose-dependent increases in the levels of adrenal TH mRNA, TH protein, and TH activity. In contrast, a single injection of nicotine elicited only a small increase in adrenal TH mRNA levels, which was transient and did not result in the induction of TH enzyme. Chronic nicotine administration also elicited a sustained increase in adrenal TH gene transcription rate, which persisted for up to 7 days after the final nicotine injection. This sustained transcriptional response correlated with a modest sustained increase in adrenal TH AP1 binding, but not in the levels of Fra-2 or other fos or jun proteins. These results demonstrate that repeated nicotine injections administered chronically over 1 to 2 weeks lead to sustained stimulation of the TH gene and consequent induction of TH gene expression in rat adrenal medulla."

    http://link.springer.com/chapter/10.1007/978-3-0348-7457-1_45
    "...implying that as little as a single dose of nicotine is as effective as chronic nicotine administration in increasing tyrosine hydroxylase activity in noradrenergic neurones."

    Nicotine Decreases Expression of Tryptophan Hydroxylase- Decreasing Serotonin
    http://www.ncbi.nlm.nih.gov/pubmed/12165397
    "Based on the results, it can be suggested that the pathogenesis of alcohol- and nicotine-induced neuropsychological disorders involves alcohol- and nicotine-induced suppression of 5-HT synthesis and TPH expression in raphe..."

    Nicotine Decreases rate of Tryptophan Uptake Into Brain and Decreases Rate of Serotonin Production in Brain
    http://www.ncbi.nlm.nih.gov/pubmed/7140821
    "Both the acute and chronic (40 days) administration of nicotine (0.4 mg/kg s.c.) caused a decrease in the rate of formation of 5-HT by hippocampal synaptosomes (P less than 0.05) while 24 h withdrawal of the drug from chronically treated rats resulted in a partial recovery of this effect. Chronic nicotine treatment also reduced the rate of L-tryptophan uptake by hippocampal synaptosomes (P less than 0.01) an effect which appeared to be the result of a reduction in the number of L-tryptophan carrier molecules in the synaptosomal membrane."

    Chronic Nicotine Exposure Acts Like an SSRE Drug by Enhancing Uptake of Serotonin
    http://www.ncbi.nlm.nih.gov/pubmed/14515338
    "A significant increase in [(3)H]5-HT uptake was observed in synaptosomes prepared from both regions. To rule out the possibility that the increases were due to the last injection given, in a separate set of experiments a single injection of nicotine was administered the evening before sacrifice. No change in uptake occurred in either region, suggesting that the increases in uptake caused by nicotine was an effect of chronic exposure and not to an acute treatment."

    http://www.ncbi.nlm.nih.gov/pubmed/16463401
    Nicotine at 4 microM increased [(3)H]5-HT uptake by 75%.

    Nicotine, Caffeine, and Creativity
    It is amazing see how many creative writers, philosophers, psychologists, actors, and artists are prolific smokers and caffeine drinkers. Many of these people swear by their" vices" claiming that it helps them work and is a source of their creative muse. Stephen King claims it takes him longer to finish a book after quitting smoking and Kurt Vonnegut claimed that smoking sped up his creative process. Sigmund Freud (Father of modern psychology) smoked 20 cigars a day and refused to quit smoking despite countless professional recommendations to do so. Philosopher Voltaire drank 40-50 cups of coffee per day. One must wonder if their is an association between creative genius and the changes in brain physiology brought on by nicotine and caffeine addiction- increased dopamine, metabolism, and neuro-steroids.

    “Be careful when you cast out your demons that you don’t throw away the best of yourself.”
    -Nietzsche

    Final Thoughts
    Please bear in mind that I am not advocating for the use of tobacco or cigarettes. I do think nicotine has many potential benefits and is worth experimentation and further research. Nicotine patches are probaly the safest option for obtaining nicotine however e-cigarettes and vaporisers are likely the most convenient, practical, and cheap option for long term use.

    Ray has expressed concern that nicotine may increase acetylcholine levels in the body. It is hard to find firm evidence as to how nicotine effects acetylcholine levels. Choline uptake into the brain remains neutral or actually decreases in response to nicotine.
    http://www.ncbi.nlm.nih.gov/pubmed/16758358
    "No significant changes in choline uptake after acute or chronic nicotine exposure were observed in whole brain or cortex. Of considerable interest was a significant decrease in regional brain choline uptake measured in the hippocampus after chronic nicotine exposure (28 d). Our data suggest that the increased ACh transmission observed after nicotine exposure does not correlate with increased blood-to-brain transfer of choline. "

    Another thing to note is that exposure to Acetylcholinesterase inhibitors (drugs that increase acetylcholine) generally decrease nicotinic acetylcholine receptors in the brain. The brain decreases its receptors to reduce sensitivity and protect from overload.
    http://www.ncbi.nlm.nih.gov/pubmed/1575351
    "Chronic elevations of ACh observed with organophosphorus poisoning or chronic use of reversible cholinesterase inhibitors results in down-regulation of AChRs."

    Nicotine has the reverse effect of these acetylcholinergic drugs and greatly increases the density of receptors suggesting nicotine may behave differently from other cholinergics.
     
  2. OP
    Dopamine

    Dopamine Member

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    More evidence for nicotine not increasing acetylcholine:
    Acetylcholine increases glycolysis and decreases oxygen usage, Nicotine does the opposite- decreasing glycolysis and increasing oxygen usage.

    Nicotine increases hepatic oxygen uptake in the isolated perfused rat liver by inhibiting glycolysis. - PubMed - NCBI
    "Infusion of 85 microM nicotine caused a rapid 10% increase in oxygen uptake over basal values of 105 +/- 5 micromol/g/h in perfused livers from fed rats, and an increase of 27% was observed with 850 microM nicotine. Concomitantly, rates of glycolysis of 105 +/- 8 micromol/g/h were decreased to 52 +/- 9 micromol/g/h with nicotine, whereas ketone body production was unaffected."

    Maternal nicotine exposure during pregnancy and lactation: I. Effect on glycolysis in the lungs of the offspring. - PubMed - NCBI
    Maternal nicotine exposure during pregnancy and lactation stimulated glucose turnover by 21.6% (P<.01), but suppressed glycolysis by 24.6% (P<.001) and glycogenolysis by 37.9% (P<.001).
     
  3. ecstatichamster

    ecstatichamster Member

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    Thanks. This is great.
     
  4. NathanK

    NathanK Member

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    I just can't get over the substantial increase in FFA. Deal breaker for me.
     
  5. Drareg

    Drareg Member

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    Ray Peat did mention that after a certain age perhaps 60 years that nicotine can have therpeautic effects ,maybe in an interview, he is clear however that it can cause aging by constricting blood vessels a bit too much, I don't have access to where he said this, he does not recommend it for under a certain age from what I gather for those reasons.

    if you read Peats articles you can see he is not completely against nicotine but believes from what I gather there are better and "more" safe substances to use.
    He is ok with choline and recommends eggs,context being everything. Read cardiolipin.
    You would have to give the context in which he Ray Peat said nicotine can increase acetylcholine, T3 for example can increase stress hormones under certain conditions, pregnenolone with poor thyroid function can cause a stress response etc ,the list goes on.

    Sigmund Freud died of a terrible throat cancer, he doesn't compare to Carl Jung IMO. Would not open up to Jungs ideas.
    Freuds daughter is responsible for inspiring the ridiculous carry on of modern capitalism, she is not the overall cause obviously but her philosophy influenced key people.

    What's also amazing is the amount of creatives in any endeavour who don't use caffeine or nicotine in excess, you could say they have a bias for their vice,justification?
    It's similar to a popular theory that all genius is madness, what's seems madness is a popular genius while alive,William Blake and the like.

    Ray Peat does not use nicotine from what I gather , he speaks extensively about being/state as influencing perception therefore what we call genius might be just that.
    The main way to influence this is to have really good environment with healthy stress ,the theory is ,the best is epigentically brought out of us all under said conditions, unfortunetley this life style currently belongs to those with the finance, for the rest of use we can use adaptive substance to try access this state of being rather than be overburdened by helplessness,mania and much worse as times goes on. IMO there is better adaptogens than nicotine but it's certainly not terrible according to Peat.
     
  6. michael94

    michael94 Member

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    what about second hand smoke?
     
  7. OP
    Dopamine

    Dopamine Member

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    Well caffeine, nicotine, exercise, and fasting can all raise FFA in similar ways due to increases in catecholamine stress hormones. I am guessing that consuming nicotine after a meal with lots of carbs would reduce or eliminate the increase in FFA because the body has energy to accomodate the increase in metabolism (Peat recommends the same thing for coffee.) Also chronic use of nicotine should adapt the body to the stress response (many studies demonstrate this.) I think increases in FFA are a very valid concern but it doesn't worry me any more than the FFA increases seen with coffee drinking.
     
  8. michael94

    michael94 Member

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    ^ Nicotine even lowers insulin I believe which I don't think caffeine does.
     
  9. OP
    Dopamine

    Dopamine Member

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    Those are all very valid points. I don't actually know if he said nicotine raises acetylcholine, I got that from a second hand source. In regards to vascoconstriction- I believe increased blood pressure and/or stress hormones cause vascoconstriction. As far as im aware caffeine is just as capable as nicotine at elevating blood pressure and stress hormones. I think chronic adaptation to nicotine and eating meals/carbs with nicotine consumption should lower the vascoconstrictive effects. A lot of people light up a cigarette when their blood sugar crashes and they're feeling jittery and distressed which just heightens the stress.

    I used to think more highly of Jung than Freud. I think however as Jung distanced himself from Freuds ideas he moved from science towards metaphysics which I began to disagree with. Freuds libido theory ties in nicely with Ray Peats ideas on the sex hormones (Increased by metabolism) being the main driving force behind vitality of life. Freud saw damming up of libido as being the main cause of depression and mental disfunction. I think its interesting how SSRI drugs are prescribed for depression when their main side effect is that they lower or eliminate libido. Also Jung used tobacco just like Freud and Freud died from cancer brought on by tobacco not nicotine which is important to differentiate.

    I also think the state of our body gives rise to our perceptions. "The self" (body) gives rise to "the ego" (mind). it is hard to be sad when you body is pumped full of MDMA and endorphins. it is hard to be happy when your body is pumped full of serotonin or you are hypothyroid. Laziness for example is not a personality trait, it is the result of a low energy body. Willpower is physical in that it is tied to the body.

    Geniuses are often neurotic and neurotic people are more likely to use drugs.
     
  10. OP
    Dopamine

    Dopamine Member

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    Smoke is harmful because anything brought to the point of combustion/ignition will be destabilized and full of carcinogens and free radicals. E- cigarettes do not get hot enough to create combustion (If you use them properly) therefore they release vapor not smoke and are relatively safe (If the ingredients are). I think with smoking in general the harm outweighs the benefits. Isolated nicotine however is perhaps a different story.
     
  11. superhuman

    superhuman Member

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    Interesting for sure, cool if haidut has something to add if he has researched it

    Great post btw
     
  12. Peata

    Peata Member

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  13. NathanK

    NathanK Member

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    Yes, i agree and you make a very compelling and impressive case for nicotine. I don't think the nootropic doses (2-4mg) that many use it for is a big deal. I think I recall reading a 1965 study showing that in normal healthy cats doses under 10mg made little difference on NEFA. That's maybe 1 cigarette. At 20mg NEFA rose. It also showed something like NEFA release had a lower threshhold than glucose suppression. That said, eating eventually did suppress NEFA, but it lagged and I don't recall how much.

    Overall, to me, it's a little like "picking your poisons". Increasing FFA too much with too many substances while trying to heal my metabolism could be counterproductive as a whole. I make the same case for people jumping to raise their caffeine doses before they can handle it. I can see people taking caffeine pills, drinking strong coffee, don't have an ideal metabolism, have excess adipose, manage psychological stress, etc. could cross that threshhold of healing to harming. Otherwise, I think nicotine in iteself is interesting. I was addicted to it for mor than a decade so I know what it can do :)
     
  14. OP
    Dopamine

    Dopamine Member

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    Thats true. Increasing metabolism without increasing the resources to support it is certainly counterproductive.
     
  15. Drareg

    Drareg Member

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    I cant find the acetylcholine quote either at the moment but he is not fully AGAINST nicotine but only after a certain age. Can it be considered an adaptogen but a highly addictive one ?im not sure how to categorise it.
    I'm not sure what nicotine has that makes it better than other things he advises, nicotine has harsher withdrawal symptoms , coffee for me since following some of Peats advice can be stopped without any side effect ,same goes for many other substances, at the start his recommendations gave me great relief but now keeping diet spot on and manage environmental stress and I'm fine,unfortunetley the environmental stress is only managed to that level at this point in my life while on holidays then I'm back to adaptive substance as a tool.

    I'm not sure Peat sees sex hormones as the main driver of life, feedback loops are relevant within the body but pituitary and thyroid are not something Freud was interested in, hormones are relevant to Peat but much more.
    Damning up of sex hormones the cause of depression was always limited theory, plenty of people that lived through terrible authoritarian cultures used sex and love with a partner as relieve from depression in the environment, context again relevant ,thyroid ,pituitary .

    Some people get great relief from SSRI as many SSRi have been shown to increase allopregenolone ,this can increase libido, longterm this effect wears off and causes more harm.
    Your correct about Freud dying from the smoke not nicotine, what's more important to note is his arrogance in spite of recommendations, Jung told Freud that based on his own theories(freuds) the cigar symbolised a penis!

    Willpower could be construed as conciousness ,consciousness is not tied to the body in dreams or imagination ,some highly intelligent individuals speculated on the soul and eternity because they could sense the body doing things,willing things they did not want to partake in, when you influence the body with chemicals you can still acknowledge your feeling and perceptions being different.
    Albert Hoffmann said something like this about LSD,psylocibin , he believed abuse of them would leave you feeling like life is just chemicals ,to an immature individual that is, it's like the body will take you for a ride, some are aware of this, others can't get over their feelings to function,acknowledge its the body dragging them down,your soul/spirit call it what you want knows this is wrong,probably why we influence the body/animal with chemicals so we can control it better,excercise the ideal will, unlocking the flow of life with the environmental stress lowered or in many of our cases with coherent chemicals.
    A 10 watt light bulb is just that,make the 10'watt light shine coherently and it becomes a laser than can burn you.

    All humans are neurotic generally brought on by stress,incoherent flow of life, the abuse of chemicals comes under the discussion of what is an adaptogen ?
    The older day geniuses did not have access to the cleaner substances we have now, They exerted huge willpower/desire for truth,David Bohm for example suffered through some depressive stages, I believe he did not smoke or have any extreme addictions, they would have exhausted brain glucose from the visualisation and think processes they used ,incidentally LSD use leaves some people believing they," know all ",after it. Is LSD etc the coherent laser of sort? It corrects electrical current in the body very quickly ,I think Peats overall idea is to do this with substances/behaviour to increase the coherent flow,increase co2 ,correct water structure which all effects electric current,plugging you back into "reality" which is not just the 5 senses material,quantum physics shows this for mainstreamers, many throughout history called it the ether.

    I would not mimic the dietary behaviour of older day perceived genius ,if anything we evolve,all of us on this forum might be considered genius of we could travel back in time far enough.
     
  16. ecstatichamster

    ecstatichamster Member

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    I think just as important, is the hedonic benefit of nicotine. There is so much more to life and health than just scientifically "proven" methods. There is also enjoyment that may be as important or more important than any other factor. There have been many people who smoke or smoked and who live a long time, including some of the longest live people in history. Smoking isn't necessarily terrible. Even if nicotine is good, it's also conceivable that there are other benefits to smoking beyond nicotine, and that may be better than using some kind of clinical patch that transmits the drug or alkaloid without actually being pleasurable.
     
  17. Drareg

    Drareg Member

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    In a certain context yes, maybe the smoke kills bacteria in the lungs etc
    The social hedonic context is also relevant, but IMO these and the above are things of the past that can be replaced with better substance.
    It would be interesting to get a statistic on how many smokers have lived to old age and how many have not,that would really give some context.

    I know of people born pre 1940 that smoked daily that lived until over 80, these people had better diets ,more saturated fats ,cleaner food, it's interesting to note that their children are not doing so good born after 1940. The older folks had good diets at a crucial time in life,childhood, their expectations of life in general were also realistic.

    A lot of that generation were based On the west styled societies where they were payed good salaries and had pensions to retire on, this alleviates a lot of stress, those of us still a way off retirement will probably not have such luxuries.
     
  18. Dan Wich

    Dan Wich Member

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    Great post, thank you Dopaminergic096.

    In addition to the options mentioned, here's some other ways of getting nicotine without smoking:
    1. Nicotine gums.
    2. These weird nicotine toothpicks that only add nicotine, vegetable glycerin, and water.
    3. Topical absorption: some people are experimenting with putting the e-liquids on their skin (there are flavorless products with just nicotine in vegetable glycerin). Although I imagine there's the risk of dangerously overdosing if people don't understand the measurement, mixing, or if they spill too much on their body.
     
  19. DaveFoster

    DaveFoster Member

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    There needs to be clarification on to the choline concept.

    Piracetam likely does not raise acetylcholine levels either, but instead it raises choline precursor levels.

    Nicotine may behave in the same way, but no one knows.

    Background

    This site states how nicotine acts as an agonist on nAChR receptors, which is well-known.

    Acetylcholine receptor - Wikipedia, the free encyclopedia

    If you scroll down, you can see that nicotine does not act upon the muscarinic receptors (mAChR) in the same way as acetylcholine does.

    "Physostigmine is one of only a few drugs that can be used as an antidote for anticholinergic poisoning. Nicotine also counteracts anticholinergics by activating nicotinic acetylcholine receptors. Caffeine (although an adenosinereceptor antagonist) is able to counteract the anticholinergic symptoms by reducing sedation and increasing acetylcholine activity, thereby causing alertness and arousal."

    Anticholinergic - Wikipedia, the free encyclopedia

    Weirdly, the page cites caffeine as a promoter of acetylcholine, but haidut has said the opposite.

    Nicotine impairs histamine-induced increases in macromolecular efflux: role of oxygen radicals. - PubMed - NCBI

    Nicotine does seem to inactivate NO activity induced by histamine; if cholinergic, nicotine should promote histamine and its effects.
     
  20. ecstatichamster

    ecstatichamster Member

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    i think maybe i'd try vaping, given that you can control what you are vaping with. Not sure about that though.

    Meanwhile I smoke a cigar every now and then.
     
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