In this installment we shall primarily discuss the chemistry and biochemistry of key Cannabis components. "Key" is important, because Cannabis contains dozens of known cannabanoid compounds, so only the most important will be treated. Now, before we go into those, let us think about neurotransmitters and receptors. Those of you who missed the first installment of this series may wish to review the basics here. There are two cannabanoid receptors known, called CB1 and CB2. CB1 receptors are in the brain for the most part and are the ones that have to do with the mental effects of Cannabis. CB2 receptors are mainly in the immune system and are thought to mediate the anti inflammatory effects of Cannabis.
There is also evidence that the opioid mu 1 receptors are activated are also activated, and this produces a dopamine cascade. As explained in the first installment, most drugs that have a potential for abuse have the dopamine cascade in common. So there is why Cannabis tends to be habit forming, although the consensus is that it is not physically addicting like alcohol and the opiates, along with other depressants.
Well, if there are receptors for cannabanoid materials, there has to be a natural neurotransmitter that cannabanoids mimic. Sure enough, several have been found, including N arachidonoylethanolamine and 2 arachidonoylglycerol. Here are pictures of their molecular structures:
These receptors involve more complex mechanisms that the ones that we have discussed before. First of all, these receptors operate in reverse. That is, the receptor is in the postsynaptic neuron rather than the presynaptic one. Second, these receptors stimulate an intermediary messenger, a so called G protein. Depending on the system, these G proteins have their effect. In Cannabis intoxication, it is the GABA system that is affected, and the release of GABA is inhibited. We talked about inhibition of the GABA system last time during our discussion of alcohol, here.
The main psychoactive material in Cannabis is delta 9 tetrahydrocannabanol, or THC. There is another psychoactive THC, delta 8 THC. In Cannabis, the delta 9 isomer is the prevalent one. Here are pictures of the THCs:
Note that the only difference is the double bond in the left hand top ring.
Interestingly, there is little THC in Cannabis. It predominately exists in the form of delta 9 tetrahydrocannabinolic acid (THC acid), which is essentially inert phenomenologically. Like many organic acids, upon heating it can decarboxylate (losing a carbon dioxide), which produces the THC when Cannabis is smoked or cooked. This is one reason why uncooked Cannabis has little effect. So for those of you out there using low temperature methods to extract Cannabis, unless you heat it up later in some manner you will not get much of an effect. Here is a picture of the delta 9 THC acid:
The "A" or "B" means that the COOH group can be in either place but not both places.
Whilst the tetrahydrocannabinols predominately effect the CB1 receptors, cannabinol has its primary effect on the CB2 receptor and thus has less psychoactive potency. However, activation of the CB2 receptor is thought to be responsible for several of the medical effects of Cannabis, and "medical marijuana" is bred for higher cannabinol content. It is also a degradation product of THC upon long storage, so older Cannabis may well have more medical effect than fresher material. Here is a picture of cannabinol:
Note that the only difference betwixt THC and this material is that there are two extra double bonds in the upper left ring here.
Remember, CB2 modulates the immune response, so this may be part of the key to the difference between whole Cannabis and commercially available THC (dronabinol) that is prescribed for certain medical conditions. Interestingly, dronabinol, the chief psychoactive material in Cannabis, is only a Schedule III drug, meaning that not only can it legally be prescribed, refills can be had without a new prescription. Go figure.
There are some interesting drugs coming down the pike that take advantage of the CG receptors. One that I find fascinating is the use of a CB1 antagonist (THC is a CB1 agonist) as an appetite suppressant. (An antagonist decreases the activity of a receptor, whilst an agonist increases it. Just think about agging someone on and you can remember which is which). Basically, the logic behind this is amounts to the "munchies" in reverse. Instead to increasing hunger, the antagonist decreases it.
There are several synthetic cannabanoids that should have some mention. It turns out that the sidechain on the lower right of the pictures is important for CB1 agonist activity. For example, going from the five carbon one to a branched nine carbon one increases activity significantly.
No discussion of Cannabis would be complete (and this one is far from complete) without mentioning drug testing. THC does not linger in the urine for very long, maybe a couple of hours, but it is widely distributed in fatty tissues. Over time it is metabolized to 9 carboxy THC, and that is water soluble and is excreted in the urine. If someone has a one time exposure to THC, there is not much opportunity for it to build up in fat stores, so it clears from the system in a couple of days (depending on the person). For chronic use, several weeks of abstinence may be required before the urine tests negative. Thus, a person who smoked Cannabis one time yesterday may give the same result as a regular user who quite two weeks ago. Cannabis has the longest detection time with respect to urine testing of any common drug of abuse.
Drug testing is a two step process (after collection of the specimen and delivery to the testing laboratory, that is). During collection, the urine temperature and specific gravity is normally taken. If the urine temperature is significantly different than body temperature, the sample is rejected. Likewise, if the specific gravity is too low the assumption is made that either the person being tested loaded up with water to dilute the sample or added water to it and the sample is rejected again.
When the sample gets to the laboratory, it is opened, following chain of custody procedures, and a screen for drugs is made. Usually Cannabis, opiates, barbiturates, amphetamines, and cocaine are screened, but other drugs can be added to the panel. This screening is fast and relatively cheap, using technology almost identical to home pregnancy tests. If this screening test is negative, the person being tested is presumed to be below detection levels for all materials tested for and "clean" results are reported.
If the screening test tests positive for one or more drugs, an extensive and expensive confirmatory test is done. The urine sample is extracted with an organic solvent, the sample volume reduced to increase sensitivity, and the sample is typically analyzed by gas chromatography mass spectrometry (GCMS), an exquisitely sensitive and selective chemical analysis instrument. Sometimes the screening test cross reacts with something in urine that is not a drug, but GCMS does not make that mistake. I have run literally thousands of GCMS analyses, and have the utmost confidence that if a material was there that I would see it, and if it were not I would not. If that test comes back positive, the result is airtight unless some defect in sample custody has arisen.
Now comes the problem: having worked in advanced analytical laboratories, I know for a fact that samples sometimes get switched or mislabeled. This is just a fact. Modern quality assurance and chain of custody procedures are supposed to prevent this, but sometimes things happen. What are the chances? Probably less than one in ten thousand or more, but if you the guy who loses a job over it, the probability does not matter. The only defense against this is to insist that your sample be split at the point of collection and a new chain of custody be made for the second sample and that it be stored in the custody of those who took it until the results from the first one come back. Using the one in ten thousand guesstimate, the probability of getting two of yours samples wrong in any way become one in one hundred million, and to get them wrong the same way are vanishingly small.
I intentionally refrained from discussing legal issues surrounding Cannabis except incidentally to other points. Readers are welcome to discuss these issues in comments, but I choose not to express my opinion in this matter, preferring to keep with the scientific topics.
UPDATE: Our friend Im NORML R U suggested an interesting article from the UK. The link for it is here.
UPDATE the second: if you look at the structural formula for the THC acid, you will, if you count carbons, that the lower right chain is a carbon short. I apologize for the error. I should draw my own structural formulae rather copy them elsewhere.
Update the third: boy, did I hit a nerve. Coffee drinkers, cigarette smokers, and alcohol drinkers, to the person, never objected to the label of using a drug of abuse, but the Cannabis users are coming with pitchforks. Let us get this understood right now: I have no problem with folks who use Cannabis. I do have a problem with folks who are so emotionally attached to an issue that they can not read scientific information without being insulted. Cannabis IS a drug of abuse, just like caffeine. I will also say this: Cannabis does interfere with cognition in the acute phase of intoxication. Caffeine and nicotine seem to help with cognition, or are pretty neutral.
I would rather encounter a Cannabis smoker operating a motor vehicle on the road than a drunk, but I would rather by far have an encounter with a coffee drinker or nicotine user. Does that make Cannabis users evil? No. Does that mean that those who use it are not impaired during the acute phase. No. Without giving away personal information, I identify with Cannabis users. But that does not change the fact that it is a psychoactive substance that can impair cognition and motor skills during the acute intoxication phase. One further note, if it did not get you off, why bother with it? I do not condemn folks who imbibe. I do have a problem with soreheads that are so emotionally attached that reason flies out the windows. Several commentors are in that latter category.
I have been castigated because I called Cannabis a drug of abuse. Well, castigate away, because it IS. Does that make it, or the ones who use it, bad people? No. I have no fundamental problem with drug use (note that I use the term abuse in the title because it is the accepted term, not because I agree with it). Hell, if I called the series Drugs of Use, we could start with aspirin and end with Zyloprim and NO ONE would read it.
Update the forth: here is a better link to the original literature provided by our friend Im NORML R U. You have to subscribe, but it is free. The Lancet is the premier UK medical journal, so a free subscription is a really good deal. I am going to subscribe after I pull the pitchforks out of my back.
Update the fifth: it looks like amphetamines are the biggest vote getters (other than pie) on the survey. I will check again tomorrow to verify, and to answer any hanging comments. Thanks to everyone for their input. I think that a few went away mad because I challenged their root beliefs, but I know that at least a couple of others, who were originally offended, realized that we are having a discussion, not a finger pointing session. For the former, I hope that you revisit and realize that you are welcome. For the latter, thanks for hanging in long enough to get the whole story.
I have not said anything about my cigarette smoking. I had five hand rolled Prince Alberts and one Camel today, and am fininishing up the last Prince Albert one now. This is quite the transition. Three months ago, I smoked 30 or more Camel cigarettes a day. I well know about drugs of abuse. But with resolve and no intention to pay taxes for those little rolled cylinders, I am just about free of them, except for the ones that I roll.
Update the last at 01:56 AM Eastern. I have enjoyed the comments. I will check back before the deadline tomorrow evening to answer any stray ones. Thanks for reading, thinking, and for those of you who were hesitant, to comment. We do not have to agree on all points, but I think that it is important for us to agree to discuss things. A new warmest regards from Doc
Well now you have done it. You wasted a perfectly good batch of electrons reading this pitiful excuse for a post. And though I know that it resembles a cat excreting razor blades when I say this, I learn much more from you than I could possibly teach writing this series, so questions, comments, tips, and flames are welcome.
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