Sunday, December 2, 2012

Chirality, a Primer (Updated)

    The word chirality comes from the Greek word for "handedness," as in left or right-handed.  Well it turns out molecules can also have different forms that are analogous to the idea of handedness.  For an example look at alanine.  The figure shows two versions, or what chemists call enantiomers, of the amino acid alanine.  Much like each hand has five fingers, one thumb, ect both molecules have the same number of atoms and same general chemical structure, but make no mistake these are two distinct compounds.  
     Chemists have different ways of naming the different enantiomers.  There are three different systems for naming, the S/R system is preferred by chemists and involves numbering the atoms bonded to the center of the plane of symmetry (the chiral carbon).  The +/- system is based on how each enantiomer shifts light, either in a (+) dextrorotary (clockwise), or (-) levorotary (counterclockwise) direction.  Finally there is the D/L system of naming, which has nothing to do with light and is based on the labeling of the biological molecule glyceraldehyde.  Confused yet?  Me too.  All you really need to know is that these are two distinct molecules.  
     Chirality is an important chemical concept, particularly for pharmacology and medicinal chemistry.  Most drugs work by interacting with a specific receptor, oftentimes described like a key (drug molecule) fitting into a lock (receptor).  It is not uncommon for receptors to respond to only one of the two forms, if the receptor was a left-handed glove it would fit well with a left hand but not very well with a right hand.  One of the most famous examples of different pharmacological effects due to chirality is methamphetamine.  
     Methamphetamine has two enantiomers, L-meth and D-meth.  D-methamphetamine is the good stuff, well I personally wouldn't touch the stuff as coffee gets me as stimulated as I care to be, but D-meth is what speed aficionados like.  L-meth is much weaker with little effect on the central nervous system, although it is a good decongestant and is even used in Vicks inhalers!  
    When drugs are synthesized in a laboratory, the chemical reactions often result in a 50:50 mix of the enantiomers, called a racemic mixture.  Because the two drugs have the same basic chemical structure, they are share physical properties (solubility, melting point, ect), which makes them difficult to separate.  In some cases, such as virtually all the methadone sold in the US, what people are actually getting is two different drugs with different pharmacological properties.  
     Methadone such as is dispensed at clinics across the US, is a 50:50 mix of (S)-Methadone and (R)-Methadone.  The only difference is the direction the methyl (CH3) group is facing, in the diagram to the left, in (S)-methadone the methyl is pointing forward as signified by the solid black line.  In (R)-methadone the methyl is facing away from the viewer, into the page as signified by the dashed line.  For another view of the two enantiomers see the three-dimensional methadone models in the image.  The white arrow points to the methyl group, otherwise the molecules are identical.   
   The position of that methyl has a large effect on methadone's opioid properties.  For all practical purposes, only (R)-methadone actually has any opioid effect.  One possible explanation for this has to do with the space between the nitrogen (blue in model) and the oxygen (red).  In (R)-methadone the methyl is facing away from the space between the oxygen and nitrogen, which allows a bond to form.  In (S)-methadone the methyl group is blocking this space.  

It should also be noted that not all molecules have mirror images, hence they are achiral.  Other molecules have more than one chiral center, and the number of different combinations of enantiomers (called stereoisomers) grows exponentially.  For example morphine has five chiral carbons, marked with red dots.  Theoretically at least, morphine has 32 different stereoisomers.  Fortunately plants (and animals) are masters of biochemistry and are able to produce a single specific form of morphine, as all the different stereoisomers could have different pharmacological effects.  This is also a reason why poppies are still used as the source material for all opiates currently used in medicine today.  

Update, 12/3/2012

     If you are taking methadone what does this mean for you.?  If you live in the US, and probably most of the world (there may be places where you can get enantiomerically pure (R)-methadone, I just am not aware of any) you are getting a racemic (50:50) mixture of R/S Methadone.  (R)-methadone is 10-50 times stronger than (S)-methadone, so for all practical purposes only half of your dose is actually an opioid.
    This becomes relevant clinically because the different enantiomers have different pharmacological properties.  Take peak-and-trough testing for example.  Let's say you are on a high dose of methadone but wake up every morning feeling sick.  You request an increase but since you are already on a high dose the clinic says, "Hold up there we can't take your word for it, you're a junkie and everyone knows junkies lie so we are going to confirm your feelings with a blood test."
    Peak and trough testing is a blood test that measures the level of methadone at two points in a 24 hour period.  The first is right before dosing when the methadone is lowest (the trough), then another blood test occurs about 3 hours after dosing when the methadone has reached maximum blood concentration (the peak).  Supposedly based on this test they can tell if you really need additional methadone.
     But here's the thing, the blood test does not distinguish between (S)- or (R)-methadone.  While they are similar in structure and share many pharmacological properties, they are not the same.  An individual may metabolize (R)-methadone faster than (S)-methadone, so that by the time they wake up in the morning the level of (R)-methadone is way down and they are beginning to feel withdrawal.  However their blood is still loaded with (S)-methadone, so the peak and trough test, which does not distinguish between R and S enantiomers, gives results that indicate the level of methadone is adequate.  And so the doctor with their test results can tell the patient it's all in their head, when in reality there is a clinical reason why the person wakes up every morning feeling ill.  The patient should always be trusted when it comes to their own body.
     There may be other differences in the two enantiomers.  Methadone has action on other receptors besides the endorphin receptors.  Would there be any advantages to using pure (R)-methadone?  At this point I am not sure but will revisit this issue as I learn more.

Read more about Peak and Trough testing here.


  1. whoa... i think i sort of understand this, but im not sure - Andy are you saying that the whole methadone debate online is a right one afterall? the debate of clinic methadone vs prescription methadone or methadose vs methadone?

    it seems to me like thats what this is saying, but i am really not sure, i dont totally understand... It would seem to me like, there would be an interest in a methadone clinic using the one that doesnt bind or allow for binding versus the one that does.

    I may totally not be understanding this though. I mean, because I have a very poor, poor understanding of things like this.

    If I'm on the right track, citing the left hand right hand example, it would make sense, why, without further inspection, on the surface, nobody would know the difference and thus why there is no real solid explanation in the debate.

    I could totally have the wrong idea, can you explain this all a bit further??

    1. Whether you get your methadone from a clinic or as a pill prescription its all the same, at least in the United States. All the methadone is a 50:50 mix of (R)-meth and (S)-meth. There may be places in the world where you can get pure (R)-meth, but I am not aware of any.
      When Drs. Dole and Nyswander were experimenting with methadone they tried using just (S)-methadone and after a few days the patients started getting sick, though they thought it was the flu since they were still getting dosed.

      Whether you call it methadone, methadose or methadol, its all the same, a 50:50 mix of R/S methadone.

    2. Good reading man, thanks! I know I`m many years to late but I hope it`s OK. I thought they distinguished between the (S) and (R) enantiomers when it comes to the blood tests, but if they don`t it explains why the test is almost always irrelevant for me. In my country and also neighbouring countries they give out pure (R)-Methadone to people who`s experiencing prolonged QT time on the heart because the (S)-enantiomer is known to cause heart problems among others over time, especially when used in higher doses like in treating opioid addiction. (S)-Methadone really don`t have the good effects you want, it`s the one with the bad effects so stay away if you can because it will shorten your life by many years depending on dose and time of usage. So if you have the opportunity to pick take the (R)-enantiomer because that`s the one you really want.

  2. heh, i mean, as i told you Andy, I am, sadly lacking in educational credentials nevertheless I think I developed an understanding of what you were saying - however, I fear I could be wrong, even so, it would seem to explain alot if my interpretation of what youve said is close/accurate.

    I find myself getting extremely f'n pissed off at the moment, seeing as I've got to go now and get this god forsaken s-methadone when I think I really ought to be getting r-methadone. I've got a mind to print several hundred copies of this entry here and stand outside the clinic and hand them out. I am really that pissed off right now and thinking back to all the time I've spent on the s-methadone for the personal reasons I explained, it gets me even more profoundly pissed off. Thank God my tale isnt like that of so many others talking about 20 years + of s-methadone life, I know they'd scold me with my measley 1 year and a couple months, nevertheless, a day without proper opiates is a day not worth living in my opinion and having collected in excess of 365 days of them while taking this crap that someone there knows is not the proverbial left hand, and their blank fuckin' faces when you tell them so and they lie to you and play moral authority with you, hey motherfuckers im the one PAYING motherfuckin money for this pathetic shit give me the right fuckin methadone you sonofabitches !!! you know?? i think im going to go ahead and print this now, 300-400 copies should do. what do you think ???

    1. As I commented above you are getting the 50:50 mix of R/S methadone. (R)-methadone is 10-50 times stronger than (S)-methadone, so for all practical purposes only half of your dose is actually an opioid.

      Does this actually matter? Is it relevant clinically? I'm not 100% sure. There doesn't seem to be a ton of research on the difference in pharmacology, beyond stating that basically only (R)-methadone is active (at least as an opioid, S-meth has other properties which may or may not be advantagous).

      So do understand that ALL the methadone given out in the US is the 50:50 mix of R/S.

      At this point I should point out that I am not a doctor or pharmacist. For yourself or any of my other readers please don't take this or anything I write as medical advice. I am simply a man who enjoys taking opiates and cares a great deal about the human rights abuses suffered on people who use the "wrong" drugs for the "wrong" reasons. My own education involves a 4-year degree (BS) in biological chemistry. Most of what I write is culled from medical journals and research papers, but it is all my opinion. While I do strive to be as accurate as possible, it is entirely possible I do get some things wrong.

      Would there be real advantages to using pure (R)-methadone? I don't know if it has been adequately investigated. One thing it would do is effectively double the potency of methadone, so dosages would be cut in half.

  3. Greetings & Hallucinations!

    I finally found your blog. (Technical difficulties prevented further fact-finding missions on HH)

    I am SO glad that you're out there reporting on these things. As you stated, everyone know that "junkies" are liars and can't be trusted.....especially with their own bodies. The nation (in particular) is so full of doo-doo-poopy-cocka it's not only NOT's DANGEROUS. I am so sick and tired of hearing all these references to "the literature" as being so authoritative.....particularly when the good folks doing the research are either completely ignorant of such facts or chose to leave them out and hide them from the public at large. Our jails, hospitals, and clinics are full of folks being screwed by the system because of the lack of knowledge/understanding of these very real technical and biochemical realities.

    Keep up the good work!


    1. I neglected to mention all of the unecessary physical and emotional suffering....and even deaths....caused by such unecessary ignorance and willful neglect.


    2. Hey there glad you found the site.

      Indeed our drug policy in brutal, arbitrary, archaic, heartless, discriminatory and a host of other adjectives. Methadone is over-regulated, the individuals have very little control over their own care. Recently there have been a few papers published on how heroin is superior to methadone and more cost effective. You think this would guide policy in the US? No way!

      I read recently the mortality rate of opiate addicts is 1% per year, far higher than the average. Our policies are killing people, to say nothing of the disease, loss of opportunity and suffering. I find it shocking the treatment industry does not do more to change drug policy, it speaks volumes about where their ideology lies.

      Thanks for visiting, stop by again anytime.

  4. Hi,part of what you are missing is that the (S)-enantiomer is an NMDA antagonist, like Ketamine or PCP. This means that the 50:50 ration is REALLY good for analgesia, but not so good for opioid replacement.

    1. That's true, though a bit beyond the scope of this post.

      Methadone also affects serotonin, so there are a panoply of effects unique to methadone. These effects may very well explain why some people just don't do well on methadone, but respond very well to heroin or hydromorphone "treatment".

    2. > the 50:50 ration is REALLY good for analgesia

      hmm, it really depends on the type of pain to which you are referring. NMDA receptor antagonists have been shown effective in certain categories of neurological pain, but not necessarily in the treatment of all pain. Furthermore, there is also evidence that the action of this particular enantiomer, being an NMDA receptor antagonist, does mitigate some physical withdrawal symptoms ( ). So, an argument for using the racemate of the methadone molecule for withdrawal management could certainly be made.

      Incidentally, I did have occasion to try an enantiomerically pure formulation of l-methadone when I was living abroad in 2004. I had been taking an 80mg dose (q.d.) of the racemate prior to this and had purchased this new product, unaware that it was pure l-meth. With regard to the racemate I had been taking, I had been compounding it myself from the hydrochloride salt every few days. I stumbled across the new product while speaking to a pharmacist while out on one of my narcotic exploration forays to another area of the city. It was in pill form, came in 5mg and 10mg doses and was of German provenance. The price was reasonable and it saved me the hassle of compounding every few days. (The hot, tropical climate and issues with storage prevented me from compounding larger quantities a couple of times a month.) Pills are also so much more convenient, discreet and portable, so it offset the additional cost and seemed a no brainer. Next morning I wake up, promptly scarf down 8 of the 10mg tablets with my coffee and then head off to work. Within 30-45 minutes, the dose was coming on like gangbusters. By 60 minutes I knew that I had taken much more than my usual 80mg dose for the day. I returned home and after poking through the package insert I quickly ascertained that I was a victim of chiral carbon and my own lack of research. Needless to say I was a bit nervous that morning and the heat didn't help as I was gripped by a severe case of the methadone sweats... There is a moral in here somewhere. :)

  5. The Toll like receptors (TLR) receptors detect alien proteins.
    Toll is a germanic word that literally translates into English as “cool”. Germans like to say, “Toll Mensch” (Cool man!) because it just sounds cool. German does not normally sound cool but that is another story.
    So if a piece of bubonic plague is floating around in your bloodstream, TLR calls the pollution police (innate immune system) which mobilizes specialized cells and molecules.
    Cutting to the bottom line, opioid receptors (OR) are stereoselective so the good stuff attaches to the OR and the bad stuff is picked up by the TLR as alien crappola and ignites a reaction in the brain called Central Immune Signalling. This causes allodynia. Allodynia is more brain pain which is the exact opposite of why you took the opium.
    Isaac newton’s 3rd law is the law of symmetry (each action produces a symmetrical reaction). The metabolic symphony orchestra preserves symmetry and cadence. Bottom line: TLR4 and other receptors are fighting back against racemic methadone (RM) et al. Racemic methadone is controlled by SAMHSA which has 57,000 employees and a 3.7B budget. Leviathan and Beavis fear change.