Hello, this is Michael Peat and in this presentation I'm going to talk about the toxicology of some of the drugs included in the DOT program and some in other programs. This is really an overview of the toxicology related to the detection in urine. Obviously much more is known about each of the drugs and each of the drug classes and several of them have therapeutic benefits. Our first two slides are going to comment on general interpretation issues associated with these programs. This slide deals with the interpretation of negative results. This really is a reminder to you of some points that I raised in my lab testing presentation and is straightforward. Obviously in the large majority of cases greater than 95% indicates no drug use. It could indicate a no drug use recently situation or a negative result could be due to dilution, substitution, adulteration or the drug being present but below the pre-established cutoff. This is really straightforward. There is no need to emphasize anything on this slide and I will move on to the interpretation of positive results. This slide deals with the interpretation of positive results. I cannot emphasize enough the first bullet. A positive result indicates that that donor had used a drug, multiple drugs only. It does not correlate to impairment. The only drug for which the impairment information is available is ethanol or alcohol and alcohol does correlate, impairment from alcohol does correlate to blood concentrations and breath concentrations but that is the only drug for which that information is available. A positive result does not indicate the route of administration. It may be able to give you some idea of the time of use but it does not tell you exactly what time that drug was used or the amount of that drug that was used. I cannot emphasize that you should not over interpret positive results. That has caused issues in the past, distance past, but nevertheless it has caused issues to medical review offices in the past. I am going to move now to the cannabinoids. What is this? This is a marijuana bush and it is at the University of Mississippi in Oxford. The University of Mississippi has the only legal marijuana farm in the country and they grow marijuana and isolate THC etc. for government researchers. They have been doing that for almost 50 years at this point, if not longer. The THC potency in these bushes is somewhere between 8 and 10% and the plants that are growing hydroponically in ideal conditions can produce marijuana of 15 to 20% potency. There is a great difference between these bushes which is approximately 8 foot high and 10 foot wide compared to those plants that are growing under hydroponic conditions. So we are going to talk about cannabinoids. There are actually 61 chemicals known as cannabinoids in marijuana and there is a lot known about these cannabinoids at this point. We are going to focus on delta 9 tetrahydrocannabinol, THC, which is the psychoactive constituent of marijuana. A point worth making here is that the US refers to the material from the plant etc. as marijuana. In Europe and parts of Asia, it is more common to find THC in hashish, which is a resin or a pad of resin from the fruiting tops of the marijuana bushes. And if you have seen that, it can be gold, it can be black almost, but it is definitely a resinous material and that is found most commonly in Europe and Asia. There are two major metabolites of THC. The first one is hydroxy-THC, short term for it, and that is equipotent to THC but it is short lived and THC and hydroxy-THC are difficult to detect in urine. The major metabolite that we detect in urine is 11-nor-delta-9-THC-9-carboxylic acid. This is referred to as THC-acid, THC-a, carboxy-THC, THC-carboxy, and unfortunately some people refer to it as THC when they talk about detection in urine, it is obviously not THC. This metabolite is approximately a third of the total metabolites excreted in urine and I say approximately, I really should emphasize that in bold and italics because it is approximately. There are 20 other oxygenated metabolites and I've listed the types of metabolites here and certainly they can be detected in urine and some of these contribute to the immunoassay response but they are not routinely detected at all in these programs, either HHS-DOT or other workplace programs. We are going to continue on the next slide to talk some more about cannabinoids. Let's talk about some other issues with cannabinoids. The receptor sites have been identified for a number of years now and the ligands for those receptor sites have also been identified. They are related to a fatty acid in chemical structure. These receptor sites are undoubtedly therapeutically useful. Pharmaceutical companies are developing drugs that bind to the receptor sites and have therapeutic benefit without the side effects of THC. I believe you will hear a lot more about this in the near future. The big point on this slide is the detection time frame. There are a couple of myths in toxicology. One is that two beers can get you to a 0.08% and the second myth is that if you smoke marijuana you'll be positive for 30 days or more. If you smoke marijuana socially, for example on a Friday night and then have a drug test on a Monday or Tuesday and you do that twice a month or twice every six months, then you are probably going to test negative on Monday or Tuesday. If you smoke more regularly than that or if you smoke daily, the marijuana THC will build up in your system because it's fat soluble and you will test positive for longer periods of time. If you come off marijuana after several months or years of use, there are data to say that you will test positive for 50, 60 or more days. So the more frequently you use marijuana, the longer you use it for, then the longer the time frame of detection is. That obviously depends on the cut off of the kits that are used in the initial test and on the specificity of that antibody, but in general that's a good rule. The more you use, the longer you've used, the longer you will test positive for. The bottom bullet includes therapeutic agents, marijuana which is for treatment of nausea and side effects for treatment of muscle spasticity. Obviously in those situations you would expect a prescription and you would take a lab test positive for THC acid and call it a negative and report that to the drug, to the DER or the company. So we're going to now move on to some issues or points associated with cannabinoids and THC. I've talked about time since last use, degradation post-collection in my lab testing talk, cannabinoid mimetics in my lab testing talk. So let me cover the other bullets going up from the bottom. Medicinal marijuana obviously has been approved in many, many states today. The federal government has not approved it and still considers THC marijuana to be a Schedule 1 drug. So medicinal marijuana under DOT is not considered to be a reasonable excuse, I can use that term, and you would confirm a positive lab result as positive in those situations. The second point, release from lipid depots, there used to be an affidavit available that potentially showed that if a donor who is maybe a little bit obese, certainly a little overweight, came off marijuana, went into an exercise program, would release THC from the lipid depots, that would be converted to the metabolite and then you get a positive result because that individual went into an exercise program. That's not the case. There are no studies to support that. And in fact, THC is stored in lipid depots, but it's stored as fatty acid conjugates in those depots. So when it's released, it's released as fatty acid conjugates. So that is not a valid reason for a positive, even if it was, DOT, HHS would not care. The time since last use we talked about, unknowing ingestion, if you eat a marijuana brownie or salad dressing or whatever that contains marijuana, you will excrete THC acid in urine and test positive. DOT does not care about that. Some company programs address that. That's a very difficult question, as is medicinal marijuana in those states that don't allow it in non-DOT programs. And you may well be asked to advise companies on how to handle those situations. Top bullet refers to passive inhalation. Yes, there are studies published that show if I put a volunteer in a small room and expose them to marijuana smoke for four days, they have to wear goggles, they may feel the psychological effects of marijuana, THC, you will have positive urines. But those are not reasonable circumstances. In the reasonable circumstances, for example, if I put you in a house where there's a party and the doors open, et cetera, and several people are smoking marijuana in that house and you're exposed to that marijuana smoke. Similarly, if I put you in a small car going down the freeway and people are smoking in that car, you will not test positive in those situations. The concentrations of THC acid in urine do not reach the cutoffs under those situations. So passive inhalation in extreme conditions, very extreme conditions in my view, may give you a positive, but normal exposure to marijuana smoke socially will not do so. So I'm going to move on now to some other issues related to cannabinoids. I want to briefly talk about hemp. Hemp has gained a lot of publicity in the last few years and is a useful agricultural product, and that's been recognized recently in that the government has approved its growth for agricultural and industrial uses. There are DEA regulations that define hemp when compared to marijuana. I'm not going to go through those, but if you're interested in those, they're available on the DEA website. In the past, people have done study with hemp flour, and you can see from the first bullet that none of the urines collected in that study showed a positive result. However, in the case of hemp oil, and what is hemp oil? Hemp oil is simply hemp that's been, the THC in it essentially has been extracted by developing an oily product with organic solvents, etc., and that's concentrated the THC. There is a hashish oil in the Middle East that the same principle applies to, and that can have actually 35% or so of THC in it. In any case, the second bullet shows that with hemp liquid gold, which is a hemp oil, you can see some positive results were obtained with that product. Does TOT care? No, this is not a therapeutic use, this is not an approved use. TOT does not care. So, even if this had happened to somebody, and they had deliberately done it, this would be a positive result from your perspective, if it was reported positive by the lab. So, we're now going to move on to cocaine. Let's talk a little bit about cocaine. Benzolecanine and ethylene methyl ester are its major metabolites in urine. This program detects benzolecanine, which has a fairly long urine half-life in the days, three to four days. However, cocaine's plasma half-life is very short, 45 minutes to an hour. So, there's a great difference between those two, but in terms of detection time frame, benzolecanine can be detected for a number of days after cocaine use. It's water-soluble, and the urine concentrations can be extremely high. Generally, the labs report these to you as greater than 5,000 or 10,000 nanograms per mil, which is their upper limit of linearity. I see no reason for you to have exact concentrations if they're above that, simply because this is a detection program. For your interest, I have seen millions of nanograms per mil reported. One case I was involved in was a bush pilot in Alaska who had several millions of nanograms per mil in his urine, and he managed to take off, but did not land successfully on his destination lake. The preferred routes of administration I've listed on this slide, but obviously the Inca Indians use it orally, primarily as an appetite depressant. There are therapeutic uses, ear, nose, and throat work being the most favored. It's a very, very efficient vasoconstrictor, and is used extensively in nasal surgery. TAC is tetrakane, adrenaline, and cocaine, which is a topical liquid used as a vasoconstrictor by EMTs. It's not used very frequently today, but it obviously may still be so, and it would be logged in the medical records if that was the case. So I want to talk about cocaine issues, but before I do, I want to emphasize that the other canes, lidocaine, benzocaine, mipipacaine, etc., do not give positive benzolecine results in urine. So let's move on to other issues with cocaine. Let's talk a little bit about these issues, and let's go from the bottom up. Herbal teas are decoconized teas, that is, just like decaffeinated coffee, they've been treated to remove the cocaine. And just like decaffeinated coffee, which contains traces of coffee or caffeine, then the herbal teas contain traces of cocaine. So if an individual uses these repeatedly, the cocaine will build up in the system and can give positive results in the urine, primarily in the low 1000s or 100s of nanograms per ml of benzolecine. These teas are actually used frequently by the Latino communities in this country. Either they bring them back if they visited relatives, or the relatives bring the teas with them. The FDA has banned their importation, but they are available, and if a donor uses them, then that can result in a positive benzolecine. DOT, in fact, does not care about that, and you are required to call them positives. But if you work with a company that has a significant Latino workforce, I do suggest that you talk to them about these issues. Degradation post-collection is not really an issue. It can occur if the urine is alkali, but in this program, it's not an issue because of the time from the first test to a possible retest is very short, and also most of the urines are either neutralish or acid, slightly acid. Unknowing ingestion, yes. You will hear all sorts of stories about an unknowing ingestion of cocaine. They all have some dealings with, in my experience, seminal fluid, and I'm not going to go into any more details than that. Passive inhalation. If you expose a person passively to cocaine under controlled conditions, then they give negative results. There is some evidence that people who live in crack houses, particularly children, that they're exposed to cocaine, obviously, and they can test positive in hair and urine for cocaine and benzolecanine. Whether that's from passive inhalation of the smoke or whether that's by the children's habits of licking their fingers in the dust and sucking on their fingers is difficult to determine, but there is some evidence. Again, of course, DOT would not allow that to be a legitimate excuse, and you would report it as positive. So we're now going to change drugs and go to the opiates and talk about the opiates metabolism. This is a definition of opiates and opioids. These terms are often used interchangeably, and I believe that we will move in the next year or two to just defining this group of drugs as opioids and dropping the term opiates. But an opiate is a drug, morphine, heroin and codeine, that has been contained in heroin or derived from, sorry, contained in opium or derived from opium. So morphine and codeine can be found in opium, heroin is obviously synthesized from morphine and these compounds are called opiates. There are other drugs, paparavine, thebane that are opiates but no drug testing program looks at those drugs. And then there's a term opioid which is a synthetic drug possessing narcotic properties similar to opiates but not derived from opium. And the four that are included in the DOT program are hydrocodone, hydromorphone, oxycodone and oxymorphone. These bind to mu-opiate receptors and that's how they express their therapeutic benefits. And as I said, these terms are often used interchangeably. My next slide is a simplified chart of opiate metabolism. This slide shows the metabolism of opiates, heroin, codeine and morphine and these are the ones that we're going to concentrate on in this program. Heroin, diacetylmorphine is metabolized to 6-acetylmorphine or 6-monoacetylmorphine. As I've said before, 6M is only present if that donor has used heroin. 6M is metabolized to morphine which has further metabolites and codeine is metabolized to morphine. There is no metabolism of morphine to codeine although there are reports in the literature that those studies were done with impure morphine. So there is no metabolism of morphine to codeine. Morphine is approximately a third of the codeine concentration in urine of donors who have used codeine but there are fast and slow metabolizers of codeine so that is not a hard rule and one should be careful in interpreting it. So this is the opiate metabolism and now I'm going to move on to another picture. These are opium poppies and again they're not in my backyard but it is a prettier picture than the marijuana tree. You can see the resinous pods of opium in this picture. They cut those pods open, collect the resin and that opium resin contains morphine, codeine and other opiate alkaloids, paparavine, thebane, etc. So it's a pretty picture but poppy seeds which also can be collected from these plants is an issue in the DOT and drug testing program Next slide is we're going to talk about poppy seeds. As I said, morphine is present in poppy seeds. The amount depends obviously on the geographical origin of those poppy seeds because the presence or the concentration of morphine varies by geographical origin. After poppy seed use either in a muffin, a piece of cake or a bagel, morphine concentrations are generally in the hundreds but they're present in the hundreds of nanograms per mil. Prior to 1998, which is obviously a long time ago, the cutoff in the DOT program was 300 nanograms per mil for both morphine and for codeine. That cutoff triggered a lot of positives due to poppy seed use. So in 1998, it was increased from 300 to 2000 and then that has become, the number of positives has become much lower. However, poppy seed use daily, for example, if your habit is to have a poppy seed bagel for breakfast, then that poppy seed concentration in the urine and the body will build up and it will not probably get to 15,000 but it can certainly get to concentrations above 2000. And we'll talk a little bit about that in a few seconds because I want to mention that there are studies in the literature from poppy seed paste, cakes made with poppy seed paste or streusels and that's common in the Hungarian-German communities, it's common in the Asian-Pacific communities. There are studies that show you can get to close to 15,000 nanograms per mil, maybe 11,000 or 12,000 nanograms per mil by ingestion of those products. So in fact, there are two decision points in a morphine positive. One obviously is the lab 2000 and if that's below 2000, you will not know that, that will be reported to you as negative. And then there's a range from 2000 to 15,000 where you could expect some donors who have poppy seed bagels for breakfast, you could expect them to reach a concentration in that range where if the donor says, I have no idea how this morphine was in my urine, you have to report that as negative. Your responsibility is MRO to prove that that's illegal use of morphine. Above 15,000, it becomes the donor's responsibility to show where the morphine came from. And Dr. Peterson will go through this in greater detail in his MRO practice slide. So I'm just laying the framework for that discussion in that presentation. In poppy seed juice, the codeine concentrations are often very low. So I'm going to move on now to some properties of morphine and codeine. There's nothing new in this slide. I've talked about this in other slides. I just want to mention the fourth bullet, which is the therapeutic uses of morphine and codeine are many, and all the opioids have therapeutic benefits. There's no denying that. Unfortunately, they've all become heavily abused also. But this is just a reminder of other points that I've made. This is some bullets about 6-acetylmorphine or 6-monoacetylmorphine. It's obviously a marker of heroin use. The concentrations are generally very low. It was infrequently detected in the workplace programs. It's become more frequently detected since HHS required the labs to screen for it as well as to confirm for it. But this is now a routine drug. It's done routinely. It's confirmed routinely. And of an interest, the higher frequency of 6M in all fluids than there is in urine. And I'm not sure why that is, but there are more 6M positives in all fluid programs than there are in urine testing programs. So I'm going to move on now to the opioids. The opioids include the four drugs in the first bullet, hydrocodone, hydromorphone, oxycodone, and oxymorphone. The morphones are metabolites of the codones. They're all available in the U.S. as multiple prescription drugs, often with other drugs. For example, acetaminophen. And you can isolate the opioids from the pharmaceutical formulations pretty simply. If you watch the YouTube video that I've included on this slide, you will see how simple that is. And that's obviously why these drugs become heavily abused. You can remove the opioids from the pharmaceutical preparation really simply. So I'm going to talk in the next two slides about some metabolism of these drugs. In the first slide, it's very simplified. And in the second slide of this too, it's the more complete picture. This is the simplified slide. And this is something that I mentioned on the last slide. Hydrocodone is metabolized to hydromorphone, and oxycodone is metabolized to oxymorphone. This is a more complete picture of opioid and opiate metabolism. I think I've talked about all of these in various parts of my presentation. But just let me go through quickly. The red boxes are heroin to 6-acetylmorphine. The yellow boxes are associated with metabolism of morphine, the blue with metabolism of codeine, the pinkish with metabolism of hydrocodone, and then the green with oxycodone. You can see it's a complex picture. And some of these products, metabolism products, are also very available therapeutically in other parts of the world. For example, dihydrocodine is fairly common in Europe. So it's a more complete picture, but it summarizes what we've talked about in other slides. I'm going to move on to some issues associated with opioids. Let's talk about the parent opioid compound being eliminated more quickly than the metabolites. The oxycodone could have a drug test positive only for the oxymorphone and hydrocodone only for hydromorphone. That is because the half-life of the morphones is longer than the codones. Therefore, the morphones could be present in urine only, according to the drug testing lab, and the codones would be present probably below the cutoff. You could reach out to the certifying scientist in the lab and ask them that question. If you have an oxymorphone reported positive, the donor claims to have taken oxycodone, you could reach out to the lab and ask the certifying scientist to look at that data to see if oxycodone is present, but below the cutoff. DOT, HHS allow that, and in fact, they encourage you to do that. So again, a friendly use of your friendly certifying scientist in the lab. This was the case many, many years back with codeine and morphine also, and in those situations, it disappeared when we increased the cutoff from 300 to 2000. So now I'm going to move on to some other opioid issues. Let's talk about one last opioid issue. In general, it's not reliable to rely on parent metabolite ratios, which can change throughout a metabolic cycle. There is one situation, however, that's important, and that is that both codeine and more commonly morphine may produce minor metabolites, and the minor metabolites are actually opioids. In a large amount of morphine being present, hydromorphone may be present in a quantity of up to 15% of the total morphine. That total amount of morphine, the large amount mentioned in this bullet, certainly has to be in the thousands, 10,000 nanograms per mil, if not greater, for this to happen. And the same situation happens with codeine when hydrocodone can also be reported. This was unexpected given that the structure of morphine and hydromorphone are considerably different, but it has proven to be so. So certainly, you should bear that in mind, and if you were taking an exam, you could imagine a question around this. So that's the final opioid issue. As you can see, they're probably the most difficult group that you'll come across for interpretation, and Dr. Peterson will emphasize this when he gives his talk on interpretation. So I'm going to move on to the amphetamines. Amphetamines, and these are the ones that can be reported today, methamphetamine, amphetamine, methylenedioxymethamphetamine, ecstasy, and obviously, it's metabolite MDA. Amphetamine is a metabolite of methamphetamine. Excretion is pH dependent. Acidic urine enhances excretion. The users of the amphetamines know this, and they acidify their urine as best they can to improve the excretion of the drugs. Methamphetamine, routes of administration, injection, snorting, smoking, ice, commonly known as ice, and oral. Methamphetamine is extremely toxic. Ice or smoking of methamphetamine has been shown to have more impact on the central nervous system or the brain function than the other routes, but methamphetamine in heavy doses, continued use, will destroy both the dopaminergic and the serotonergic central nervous systems. So it's a very, very toxic drug. Amphetamine is obviously still used therapeutically as Adderall, and methamphetamine can be in certain states used therapeutically, but I don't know. It's been years since I've seen a therapeutic methamphetamine. No therapeutic use for MDMA, or MDA for that matter, but MDMA is gathering some interest in the treatment of PTSD. These psychoactive drugs, MDMA, ecstasy, salicybins, etc., are gathering more interest in the treatment of disorders than they have for many, many years. And my suspicion is that one of them will be approved in the next 10 years or so for treatment of some of those diseases. So my next slide deals with DNL methamphetamine. In the past, Vicks Inhaler contained a compound called L-desoxyephedrine, which in fact is Levo or L-methamphetamine. That product now contains propylhexadrine, but obviously people store materials, and I'm sure there's Vicks Inhaler containers throughout the country that still contain L-desoxyephedrine or L-methamphetamine. The psychoactive or the more psychoactive product for methamphetamine is the dextro, the D form, and that can be separated from the L form with chiral GC-MASPEC. Fairly common procedure. Most labs will do it. Certainly the big labs will do it. And it's, in my view, a good test to get done reflexively. That is, if you have a methamphetamine positive in urine and you have the lab reflex it to this DNL separation, you will have information that could be of value in your interview. If you come back to it and want it later, the lab's going to charge you more, because they're going to have to go dig up the urine specimen from the freezer, etc. So there's a greater charge if you don't do it as a reflex. DOT has said that if it's greater than 80% of the L isomer, it's considered to be Vicks Inhaler. There are reasons for differing ratios of DNL. Obviously, impure synthesis of illicit methamphetamine would be one, and an attempt by the donor to hide methamphetamine use. I've actually had situations where people have taken a Vicks Inhaler, opened it somehow, made tea from the contents, which obviously will result in a significant L methamphetamine concentration in urine, and then that will hide the methamphetamine use. How they get that Vicks Inhaler tea, how they drink it, is beyond me, given the amount of camphor in Vicks Inhaler. But they do, and that will certainly hide the use. I'm going to move on. Let's talk about other amphetamine issues. They do result from other preparations. A positive amphetamine and methamphetamine report can be caused, for example, by Didrex benzphetamine. And paraclorobenzphetamine from Mexico and other products from outside the U.S. will metabolize to both these drugs. Selegiline metabolizes to the L isomers, which we talked about on the last slide. Other sympathomimetics will often react positively to the immunoassay at very high concentrations, but they can be differentiated by the confirmation techniques. And we talked about basalts in the lab testing part of the presentation. So I'm now going to move to PCP. PCP, there's no legitimate use for PCP. Excretion is pH dependent. There are some regional use patterns, but less so now than there used to be. And obviously there's PCP-laced marijuana joints, which they call WEPs or embalming fluid. PCP is a dissociative anesthetic. It's very toxic. It certainly produces some really strange reactions. There is a drug on the market today, or in use today, that is a dissociative anesthetic, and that's ketamine. And that's getting some increased focus because of its potential to treat depression. But ketamine is not included in these programs. So I'm now going to move forward to some other drugs and go through these briefly, as they're not included in the DOT program, but you might encounter them elsewhere. The most common of the other drugs that are included in testing programs is the benzodiazepines. There are a large number of benzodiazepines available in this country. There are also synthetic benzodiazepines. This is a very complicated field, and I certainly would advise you to have a conversation with your lab as to exactly what they can detect if you have benzodiazepines included in other programs. The other opioids I mentioned on this slide are not routinely included in workplace testing programs or included at all, but they certainly may be in rehab or medical professional programs. Barbiturates are included occasionally, but not as common as they used to be. So let's go through a few other of these. Other drugs, I just want to make a comment here. You know, specific workplaces have their own issues. Athletics, anabolic steroids, erythroprotein, etc. Anesthesiologists, safentanils, it could be nurses and miparidine. And pain management, obviously, is a whole new business. So what we do as toxicologists and what you might do as medical professionals, and what you might do as medical review officers, is far broader than the DOT program. So I want to thank you all for your attention, and I wish you the best of luck when you take the exam.

toxicology

drug test results

THC

metabolites

cocaine testing

opiate metabolism

amphetamines

workplace drug issues