Learning About Marijuana From Washington University

640px-Hemp_plants-cannabis_sativa-single_3Whether or not a drug is legal, simplistic slogans, scare tactics and moralizing never help people make responsible choices. Education is the best tool we have, and Washington University has put together the most readable and up to date marijuana web site I have seen.

While being fairly comprehensive, they do not pretend to have all the definitive answers. I will highlight those areas along with more clear-cut ones that were nebulous in my mind thanks to rumors, self-biases and our media’s tendency to put truth through a juicer. In certain cases, I will also provide more detail.

Effects on Memory

Some marijuana users get lost in their thoughts, forget what they are doing, and let immediate objectives slip away. It’s one of the drug’s attractions, allowing people to temporarily escape from drudgery or problems. This in part is due to weed’s effects on short term memory. Hippocampus_smallThere are receptors (proteins) which interact with marijuana compounds known as cannabinoids. One receptor- type, CB1, is concentrated in the sea-horse shaped hippocampus, a brain structure involved in memory formation. Long-term impairments may also be possible, but more investigations are needed to see if that concern is real.

More on Cannabinoids

300px-Tetrahydrocannabinol.svg
(−)-trans-Δ9-tetrahydrocannabinol (C21H30O2). Like all cannabinoids, THC has 21 carbon atoms and a C5H11 tail bonded to a phenolic group.

There are close to 100 known cannabinoids,
most of which are not psychoactive. Those that do not act on CB1 receptors but on CB2 receptors are found in the immune system and spleen. The main mind-altering compound acting on CB1 receptors is  (−)-trans9-tetrahydrocannabinol or THC. A single serving in a marijuana edible contains 10 mg of THC. In smokable forms of the drug, the THC concentration of dried leaves, flowering tops and hashish oil ranges from 1 to 20%. Since a joint’s mass is between 0.25 to 1 gram, it translates into a range of 2.5 mg to 200 mg of THC. This is two to seven times stronger than weed from the 1970s, not a factor of 30, as reported in the media.

345px-Cannabidiol.svgCannabidiol (CBD) and its related isomers can make up almost 40% of cannabis resin, and so are the most common group of canniabinoids found in hemp. Although not directly psychoactive, it has other positive effects sought after by medical researchers and patients.  Until recently, American marijuana was unfortunately low in cannabidiol, which has a low affinity for both types of receptors but controls the way other cannabinoids interact in the brain and elsewhere in the body. For instance, it may decrease three side effects of THC: anxiety, sleepiness and dependency. This is an example of what researchers Machoulam and Ben-Shabat call the entourage effect. Many marijuana compounds, in individual purified form from the lab, do not act on the human body like they do in a group, as when the plant is smoked or eaten. According to a review of the literature in the British Journal of Pharmacology evidence supports the entourage effect, which is important in medicinal chemistry:

Considered ensemble, the preceding body of information supports the concept that selective breeding of cannabis chemotypes rich in ameliorative phytocannabinoid and terpenoid content offer complementary pharmacological activities that may strengthen and broaden clinical applications and improve the therapeutic index of cannabis extracts containing THC, or other base phytocannabinoids.

Smoking and Driving

A safety margin of 3 to 4 hours is needed to drive after smoking pot and at least 5 to 6 hours if brownies are eaten because the effects of the latter only kick in a couple of hours after ingestion. Under the influence, reflexes can slow down and some “buzzed” drivers do not stay on their lane with optimal ability. Alcohol will accentuate these effects.

Teenage Use

Use by adolescents presents higher risks because the brain is in a rapid growth stage, and such early use is more likely to lead to dependence. Cannabis’ short term effects on memory can impact success in school, and if marijuana has any long term effects, a jump start in usage will increase the probability that such effects will materialize. These reasons motivated the setting of the legal age for consumption and purchase of marijuana in Washington state and Colorado at 21, the same for alcohol elsewhere in the country.

Other People Who Place Themselves At Higher RiskPregnant-woman-no-to-smoke1

Schizophrenics or people genetically predisposed to the condition are at a higher risk of a psychotic episode while under the influence of cannabis, which is a very rare side effect.

THC crosses the placental barrier, and although its effects on the fetus are unknown, pregnant women are advised by doctors to stay clear of it and treat it like tobacco, alcohol or any other psychoactive drug.

Effects on Lungs

Marijuana smoke is less harmful than tobacco. The former does not obstruct airways or cause emphysema. But it’s not entirely innocuous. The connection to pulmonary infections is not clearly established. And there is more tar deposited in the lungs per joint than per tobacco cigarette, so the link to cancer cannot be easily written off. None of the investigations are conclusive so far, and of course any risk will be in proportion to the quantity smoked.

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Blood Pressure Linked To Gut Bacteria, Bread Preservative & Nasal Receptors

That biology’s four themes— unity, diversity, continuity and interaction— are constantly at play is obvious in a good paper published last month by Jennifer Pluznick and fourteen other lead researchers throughout the United States and France.

Background Information

Propionate (or propanate) is the anion resulting from the split-up of propanoic acid. It’s used as a mold-inhibitor in bread and also found in sweat and milk. It’s one example of a group of 2 to 5-carbon fatty acids known as short chain fatty acids (SCFAs) that bacteria create when breaking down complex carbohydrates and sometimes protein. Also relevant is that SCFAs are found in the colon where they are absorbed into the blood stream.

In a similar way that opioid receptors are found in both the nervous and digestive systems, the type of olfactory receptors that bind to detectable molecules in the nose are also found in kidneys, smooth vessel cells and nerves. One specific renal olfactory-type receptor(Olfr78) in mice binds to the SCFAs acetate and propionate. Olfr78’s human equivalent, OR51E2, behaves similarly towards the two ions, at least in test tube studies that used SFCA-concentrations comparable to those found in our blood plasma.

Evidence That SCFA Receptors Control Blood Pressure in Mice

a) one receptor’s location
Using the reverse transcriptase-polymerase chain reaction, RNA made from the Olfr78 gene was detected in mice kidneys. Other experiments revealed that the gene was expressed in a specific part of the kidney where renin is released. Renin helps regulate body fluids and blood pressure. The diagram reveals the precise location: the juxtaglomelurular arteriole(JGA).

Source of diagram: (http://renalfellow.blogspot.ca/2008/10/review-juxtaglomerular-apparatus.html)

b) bonding of propionate to kidney olfactory receptor leads to renin release
Using fluorescent quinacrine, investigators labeled renin-releasing arteriole granules in solutions made with JGA glomeruli from wild strained mice. As they added propionate, the fluorescence decreased, suggesting that the short chain fatty acid which interacted with Olfr78 increased the secretion of renin. But solutions made from tissue of mice who lacked the Olfr78 receptor were unaffected.

c) live-mice experiments: second olfactory receptor also contributes to control of blood pressure  
When Olfr78-less mice were fed a diet rich in polysaccharides (which led to high plasma levels of propionate), there was not enough renin produced.  Meanwhile, a different olfactory receptor, Gpr41 (a G protein-coupled receptor found in the renal and iliac arteries and in the aorta), bonded to propionate and lowered blood pressure. This happened because without the presence of pressure-raising Olfr78, Gpr41’s action could not be counterbalanced.

To verify that the gut bacteria were indeed the source of propionate, mice were treated with a cocktail of 3 antibiotics for three weeks. This had no effect on the blood pressure of mice possessing the Olfr78 gene. In light of the fact that activated Gpr41 and Olfr78 have opposing effects on blood pressure, this makes sense. Without propionate, neither receptor could play its role. But for antibiotic-treated mice who were without Olfr78, blood pressure actually increased. It’s not as contradictory as it seems on the surface. In the presence of propionate, Gpr41 was acting “alone” in Olfr78-less mice. After taking away the ligand (propionate) for Gpr41, blood pressure rose relative to whatever homeostasis existed previously.

Sources:
SCFAs: The Enigma of Weak Electrolyte Transport in the Colon http://physiologyonline.physiology.org/content/14/2/58.full
Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation

Monsters From The Armpits

tarPitsMonsterThey would have made sculptors drop their chisels. The two women were preparing lunch for us when my friend suddenly became self-conscious of his armpits’ stench. There was no deodorant in sight, but I assured him we could easily concoct something before they returned from the kitchen. A bit of ashes and soap should do the trick, I told him.

When I woke up from the dream, I dismissed the ashes recipe, but I was reminded of an idea I had when I was in college. The nauseating smell of armpits comes from organic acids produced by bacteria. I reasoned that if an enzyme could play the role of a strong acid usually required to catalyze the conversion of organic acids and alcohols to esters, we would end up with pleasant smells.  The alcohol, if in excess, would also inhibit the growth of bacteria. In those days I was under the false impression that butyric acid was the main culprit of armpit odor. If that was the case, ethanol and a catalyst, butyric acid would be converted into one of the sweet smells of pineapple, ethyl butyrate.

Of course, throughout the day I could not stop sneaking a peak at the current knowledge of deodorant chemistry. One of the compounds secreted by armpit sweat glands is 3-hydroxy-3-methylhexanoyl-glutamine  (C12H22N2O5). This compound has no odor; however, it’s not left intact by the most abundant armpit bacteria Corynebacterium jeikeium,  a harmless member of a genus that also includes a species responsible for diphtheria. With the help of zinc-dependent enzyme, C. jeikeium cleaves off the glutamine component and leaves behind the cheesy and rancid compound 3-hydroxy-3-methylhexanoic acid:3-hydroxy-3-methylhexanoic acid

They don’t have exclusive control over this semi-closed and moist environment— prime real estate for bacteria. Staphylococcus haemolyticus also hangs out here and converts a different precursor into 3-methyl-3 sulfanylhexan-1-ol. 3-methyl-3 sulfanylhexan-1-ol This molecule is not as repulsive as the C. jeikeium’s byproduct. It has a fruity, onion-like smell. Not surprisingly, female armpits produce more of the latter. They have, on average, lower ratios of C. jeikeium to S. haemolyticus bacteria. If you look closely at the data of the ratio of the will-turn-to-cheesy-smell to will-turn-to-onion-smell secretions, you can see a wide variety of compositions in men, but none of the women tested showed the high peaks that appear in more than half the male samples.

Most deodorants use the right strategy: their ingredients curb the growth of bacteria. Speedstick, for example, uses propylene glycol, soap(sodium stearate), salt and stearyl alcohol. Some more innovative deodorants include pleasant-smelling molecules similar in shape to the organic acids so that they compete for spots on nasal receptors. Unfortunately for women, their discriminating noses aren’t as easily fooled as those of men. Other additives in some preparations attempt to block active sites on enzymes that bacteria use to generate the offensive smells.

ratiosRegardless of the precise formulation, rub-on deodorants and anti-perspirants are often dissolved in clear, odorless silicones known as cyclomethicones. Their advantage is that these non-irritants apply smoothly, evaporate quickly, leaving the active residue as their only trace.

Cyclomethicones are also used in antiperspirants, whose active ingredient is commonly aluminum zirconium tetrachlorohydrex with glycine hydrated in its structure. Some investigators were under the impression that the compound combines with intraductal keratin fibers to temporarily block sweat pores, which starves bacteria. What’s more likely is a precipitation reaction involving the complex salt, and the insoluble solid blocks the pore.

Eventually, with a deodorant additional sweat dilutes and washes away soap and other soluble ingredients. With an antiperspirant, a pressure buildup eventually forces insoluble products out of the duct. Either way, monsters of the armpits eventually regain control.

Sources: 

M Troccaz and al. Chem Senses. 2009 Mar;34(3):203-10. Epub 2009 Jan 15. full text : 

Gautschi, Markus; Natsch, Andreas; Schröder, Fridtjof  Biochemistry of Human Axilla Malodor and Chemistry of Deodorant Ingredients  Volume 61, Numbers 1-2, February 2007 

http://cen.acs.org/articles/90/i27/Deodorants-Antiperspirants.html

http://www.colgate.com/app/Speedstick/US/EN/Products/SpeedStick.cvsp
http://www.rosehulman.edu/~devasher/CHEM470/classnotes/23The%20Dry%20Facts%20About%20Wet%20Perspiration.pdf

http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0846.2011.00532.x/full

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