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The Continuing Challenge of Designer Drugs
Marilyn A. Huestis, PhD
Senior fellow at the Institute on Emerging Health Professions, Thomas Jefferson University. Former Chief of the Chemistry and Drug Metabolism Section, IRP, National Institute on Drug Abuse (NIA). Dr. Huestis has disclosed that she has received payment as a consultant for Dynacare Laboratories, which provides lab testing.
Dr. Capurso has reviewed this article and found no evidence of bias in this educational activity.
CATR: Please tell us about your background.
Dr. Huestis: I’ve worn lots of hats over my career as a clinical chemist, toxicologist, and forensic toxicologist. I was at the National Institutes of Health for more than 23 years, where I had the pleasure of leading the Chemistry and Drug Metabolism Section, and for the last five years I’ve been running my own consulting company.
CATR: Let’s start out by having you define the term designer drug.
Dr. Huestis: Designer drugs, also known as novel psychoactive substances, are synthesized to give effects that are qualitatively similar to commonly misused drugs, meaning they bind to the same receptors in the brain and body. However, they are usually quantitatively much more potent than the drugs we’re used to seeing.
CATR: How did these come about? It feels like we’ve been talking more about designer drugs in the past few years.
Dr. Huestis: There certainly has been an explosion in their diversity and availability. The first class of designer drugs, the synthetic cannabinoids, appeared nearly 20 years ago. Scientists developed the first synthetic cannabinoids as pharmacological tools to study the endogenous cannabinoid system and published their synthetic methods in journals. Illicit manufacturers simply followed these methods to produce these products for recreational use. Of course, now, many new compounds are produced with molecule changes that can alter their pharmacological effects.
CATR: If designer drugs are simply analogs of existing compounds, why are they such a big problem? How exactly are they worse than the usual drugs we see on the streets?
Dr. Huestis: Designer drugs can be horrendously problematic in many ways. First is the sheer number of them. We used to worry about amphetamines, cannabis, cocaine, opiates, benzodiazepines, and PCP—along with a few others. But since 2004, according to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), we have over 750 new designer drugs, each with their own pharmacologic profile. Second, we lack safety studies. These compounds aren’t even tested on animals, let alone humans; the first people who experience the drugs’ effects are the people who buy them. And third is the absence of quality control. For instance, early versions of synthetic cannabinoids were sprayed onto dried plant material and sold. It was all done by hand, so there were “hot spots”—two people might take the same drug and one might die while the other one ends up OK because the concentration in different places varies wildly. In addition, drugs often contain chemical contaminants or are combined with other dangerous compounds. Finally, these drugs find their way into unexpected places. For example, highly potent designer opioids, which kill many people, are not only used to fortify heroin, but can be found in cocaine, benzodiazepines, counterfeit opioid pills, and even cannabis.
CATR: The danger of fentanyl derivatives has been widely reported. What other classes of designer drugs are there?
Dr. Huestis: Yes, there are many fentanyl derivatives, with the most worrying being carfentanil, which is hundreds of times more potent than fentanyl itself. Among the other classes, synthetic cannabinoids are the most common. There is also the class of designer stimulants as well. We are all familiar with the effects of stimulants like amphetamines and methamphetamine. These designer drug analogs are a class called synthetic cathinones, commonly referred to as “bath salts,” which are structurally based off the natural drug khat. They are stimulants, just like amphetamines, and have similar physiologic effects. Designer benzodiazepines are a popular new type of designer drug, as are hallucinogens that mimic LSD, PCP, and others.
CATR: How does the legal system deal with these drugs?
Dr. Huestis: It depends what part of the world you’re in. In many European countries, a drug is prohibited only if it is specifically listed by the government or their Drug Enforcement Administration (DEA) equivalent. In the US, the DEA also maintains a list of prohibited compounds. The difference is that the US has the Federal Analogue Act, which says compounds with a similar molecular structure or pharmacologic effect to a prohibited compound are also prohibited (www.law.cornell.edu/uscode/text/21/813).
CATR: That seems like a good idea.
Dr. Huestis: It is in theory. But there’s hesitancy to define what an analog is because then manufacturers can try to find ways around the law. And this ambiguity can create a legal mess.
CATR: Can you give an example?
Dr. Huestis: For example, the primary psychoactive compound in cannabis is delta-9 THC. Manufacturers have created delta-8 THC, which has similar psychoactive effects, and they claim it’s legal based on the 2018 Farm Bill, which legalizes all hemp products that contain a negligible amount of delta-9 THC (www.tinyurl.com/sth48z). The DEA says no, it’s an analog, so it’s illegal. This hasn’t been court tested, and the result is a patchwork of areas where delta-8 THC is and isn’t legal—which is confusing for users, providers, and law enforcement (Chan-Hosokawa A et al, J Anal Toxicol 2021:bkab029). Another issue is that when the DEA sees a drug is associated with high morbidity and mortality, they issue an Intent to Schedule, which means the drug can be restricted, but only after six months. The response is a huge boost in sales of that compound on illicit websites. Internet vendors reduce prices, and the substance can be sold out literally within a day, put out onto the streets, and then replaced with something new. It’s a never-ending cycle.
CATR: Are most designer drugs now primarily bought and sold through the internet?
Dr. Huestis: Initially they were available at head shops, gas stations, places like that. Some are still available that way depending on legality. But the most popular route by far is for drugs to be purchased over the internet and sent through the mail—they arrive in a few days at your doorstep in plain packaging. There are very few seizures by customs because drugs are often sent in very small, sealed vials containing concentrates. The vials can be small and difficult to detect because the drugs they contain are so potent.
CATR: What are some of the side effects that clinicians should be aware of?
Dr. Huestis: Remember, designer drugs have qualitatively similar but quantitatively more potent effects. For instance, people have increased heart rate when they smoke cannabis; however, synthetic cannabinoids can cause heart attacks and strokes. In fact, there was an instance of three 16-year-olds who all had heart attacks after using synthetic cannabinoids together (www.tinyurl.com/28b864ty). Cannabis can cause paranoia and psychosis, but when caused by synthetic cannabinoids, these effects can be prolonged, severe, and associated with violence. In fact, there are multiple instances of murder and attempted murder where synthetic cannabinoid use is implicated. Synthetic cathinones are similar; they can affect your cardiovascular and central nervous systems much more severely than amphetamines or methamphetamines. Designer benzodiazepines can cause somnolence and sedation resulting in death, even at small doses. And, of course, we’ve already talked about the dangers of designer opioids.
CATR: What can providers do to treat intoxicated patients who present with these extreme effects?
Dr. Huestis: The fact that we don’t have antidotes to many of these drugs is a big problem. For designer opioids, of course, we have naloxone. For designer benzodiazepines, we have flumazenil. But that’s about it. For the most part, all physicians can do is supportive therapy—keep the airway clear, regulate heart rate, and aggressively control body temperature. Many of the synthetic cathinones can cause dangerous hyperthermia (Zaami S et al, Eur Rev Med Pharmacol Sci 2018;22(1):268–274). Antipsychotics and benzodiazepines can be used to control behavioral agitation. As an aside, I’ve been a proponent of making available the CB1 cannabinoid receptor antagonist rimonabant (Huestis MA et al, Psychopharmacology (Berl) 2007;194(4):505–515). It was used for weight loss overseas but was pulled from the market because of associations with depression and suicidal ideation. But wouldn’t it be wonderful if it was available for one-time use in emergency rooms for synthetic cannabinoid overdoses? It could be lifesaving.
CATR: A treater must know what was ingested to provide a proper antidote if one is available. You’ve done a lot of work in identification of designer drugs through urinalysis.
Dr. Huestis: I have. Because many of these compounds are so potent, and we know so little about them, we often don’t even know how to identify the agents a patient has used. Typical urine drug tests are done with immunoassays that are widely available for commonly misused substances. More accurate confirmation testing is done with mass spectrometry, which takes some time but is also generally available. However, we don’t have immunoassays for most designer drugs, and mass spectrometry may not be useful because we don’t know what metabolites to look for in the first place.
CATR: Does that mean it’s not worth testing for designer drugs at all?
Dr. Huestis: I always encourage providers to send urine out for testing. Most small laboratories can’t handle testing for all the known 700+ designer drugs; it’s too expensive. But large hospital systems and reference labs with high-resolution mass spectrometry can screen for many compounds. The data might help not only your patient, but also public health. There are instances of highly potent drug batches causing mass overdose events with dozens or hundreds of people affected in a short time. Over 600 people became critically ill from a single batch of synthetic cannabinoids in Mississippi, for instance. In cases like these, urine toxicology information is very important for public health departments and medical examiners trying to respond to the situation in real time. There can also be third-party payment issues for send-out urine drug testing. Hospitals may be reluctant to identify specific drugs because it may compromise insurance company payment. Providers should figure out how to deal with this issue within their hospital system; think of the lives you may save!
CATR: Are there any other issues providers should be aware of in the management of acute intoxication?
Dr. Huestis: All patients presenting with intoxication by designer drugs should at the very least receive a psychiatry consult. It is important to determine whether the patient has developed a substance use disorder that needs further treatment. We also know there is a very high comorbidity of substance use and mental illness. So, it’s not good enough to just support a patient through the intoxication and send them out the door.
CATR: And what about long-term treatment?
Dr. Huestis: We know that individuals can become both physiologically and psychologically dependent on designer drugs, except for hallucinogens, just like their more common counterparts. Unfortunately, we don’t have data about how to treat designer drug addiction. The general practice has been to let the drug class guide the treatment (Klega AE and Keehbauch JT, Am Fam Physician 2018;98(2):85–92). The most common example is use of methadone or buprenorphine for patients using designer opioids. Designer opioids are now frequent contaminants in the illicit opioid supply. No one would recommend changing opioid use disorder treatment based upon whether a patient used designer opioids. Cognitive behavioral approaches, contingency management, and the limited pharmacologic options that we have for cannabis, stimulants, and benzos are probably similarly useful for the designer drugs with similar mechanisms of action, though we don’t know for sure.
CATR: Given that the landscape of designer drugs is evolving so quickly, how can clinicians stay informed?
Dr. Huestis: I recommend starting with review articles accessible through PubMed. We published a thorough review in 2017 that is a good summary of the field, at least where things stood several years ago (Logan BK et al, J Anal Toxicol 2017;41(7):573–610). Our 2021 update is set to be published in the next few months. I contributed to a recent review of designer benzodiazepines that I would recommend as well (Brunetti P et al, Pharmaceuticals (Basel) 2021;14(6):560).
CATR: Any good internet sites that you’d recommend?
Dr. Huestis: Yes. The EMCDDA has a website with in-depth information that I highly recommend (www.emcdda.europa.eu/emcdda-home-page_en). It focuses on Europe, where the pattern of available drugs can be a bit different, but the information there is very useful. The Center for Forensic Science Research in Education (www.cfsre.org) is another good resource that provides up-to-date information for the US. In addition, the American College of Medical Toxicologists (www.acmt.net) is a good resource and they host informative webinars as well. Geographical differences make it especially difficult to stay current, so I also recommend getting comfortable working with the local poison control center and forensic laboratories, especially for clinicians who work in an emergency setting. These are the people who will be the first to know about the influx of new drugs.
CATR: Thank you for your time, Dr. Huestis.
Addiction TreatmentDr. Huestis: I’ve worn lots of hats over my career as a clinical chemist, toxicologist, and forensic toxicologist. I was at the National Institutes of Health for more than 23 years, where I had the pleasure of leading the Chemistry and Drug Metabolism Section, and for the last five years I’ve been running my own consulting company.
CATR: Let’s start out by having you define the term designer drug.
Dr. Huestis: Designer drugs, also known as novel psychoactive substances, are synthesized to give effects that are qualitatively similar to commonly misused drugs, meaning they bind to the same receptors in the brain and body. However, they are usually quantitatively much more potent than the drugs we’re used to seeing.
CATR: How did these come about? It feels like we’ve been talking more about designer drugs in the past few years.
Dr. Huestis: There certainly has been an explosion in their diversity and availability. The first class of designer drugs, the synthetic cannabinoids, appeared nearly 20 years ago. Scientists developed the first synthetic cannabinoids as pharmacological tools to study the endogenous cannabinoid system and published their synthetic methods in journals. Illicit manufacturers simply followed these methods to produce these products for recreational use. Of course, now, many new compounds are produced with molecule changes that can alter their pharmacological effects.
CATR: If designer drugs are simply analogs of existing compounds, why are they such a big problem? How exactly are they worse than the usual drugs we see on the streets?
Dr. Huestis: Designer drugs can be horrendously problematic in many ways. First is the sheer number of them. We used to worry about amphetamines, cannabis, cocaine, opiates, benzodiazepines, and PCP—along with a few others. But since 2004, according to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), we have over 750 new designer drugs, each with their own pharmacologic profile. Second, we lack safety studies. These compounds aren’t even tested on animals, let alone humans; the first people who experience the drugs’ effects are the people who buy them. And third is the absence of quality control. For instance, early versions of synthetic cannabinoids were sprayed onto dried plant material and sold. It was all done by hand, so there were “hot spots”—two people might take the same drug and one might die while the other one ends up OK because the concentration in different places varies wildly. In addition, drugs often contain chemical contaminants or are combined with other dangerous compounds. Finally, these drugs find their way into unexpected places. For example, highly potent designer opioids, which kill many people, are not only used to fortify heroin, but can be found in cocaine, benzodiazepines, counterfeit opioid pills, and even cannabis.
CATR: The danger of fentanyl derivatives has been widely reported. What other classes of designer drugs are there?
Dr. Huestis: Yes, there are many fentanyl derivatives, with the most worrying being carfentanil, which is hundreds of times more potent than fentanyl itself. Among the other classes, synthetic cannabinoids are the most common. There is also the class of designer stimulants as well. We are all familiar with the effects of stimulants like amphetamines and methamphetamine. These designer drug analogs are a class called synthetic cathinones, commonly referred to as “bath salts,” which are structurally based off the natural drug khat. They are stimulants, just like amphetamines, and have similar physiologic effects. Designer benzodiazepines are a popular new type of designer drug, as are hallucinogens that mimic LSD, PCP, and others.
CATR: How does the legal system deal with these drugs?
Dr. Huestis: It depends what part of the world you’re in. In many European countries, a drug is prohibited only if it is specifically listed by the government or their Drug Enforcement Administration (DEA) equivalent. In the US, the DEA also maintains a list of prohibited compounds. The difference is that the US has the Federal Analogue Act, which says compounds with a similar molecular structure or pharmacologic effect to a prohibited compound are also prohibited (www.law.cornell.edu/uscode/text/21/813).
CATR: That seems like a good idea.
Dr. Huestis: It is in theory. But there’s hesitancy to define what an analog is because then manufacturers can try to find ways around the law. And this ambiguity can create a legal mess.
CATR: Can you give an example?
Dr. Huestis: For example, the primary psychoactive compound in cannabis is delta-9 THC. Manufacturers have created delta-8 THC, which has similar psychoactive effects, and they claim it’s legal based on the 2018 Farm Bill, which legalizes all hemp products that contain a negligible amount of delta-9 THC (www.tinyurl.com/sth48z). The DEA says no, it’s an analog, so it’s illegal. This hasn’t been court tested, and the result is a patchwork of areas where delta-8 THC is and isn’t legal—which is confusing for users, providers, and law enforcement (Chan-Hosokawa A et al, J Anal Toxicol 2021:bkab029). Another issue is that when the DEA sees a drug is associated with high morbidity and mortality, they issue an Intent to Schedule, which means the drug can be restricted, but only after six months. The response is a huge boost in sales of that compound on illicit websites. Internet vendors reduce prices, and the substance can be sold out literally within a day, put out onto the streets, and then replaced with something new. It’s a never-ending cycle.
CATR: Are most designer drugs now primarily bought and sold through the internet?
Dr. Huestis: Initially they were available at head shops, gas stations, places like that. Some are still available that way depending on legality. But the most popular route by far is for drugs to be purchased over the internet and sent through the mail—they arrive in a few days at your doorstep in plain packaging. There are very few seizures by customs because drugs are often sent in very small, sealed vials containing concentrates. The vials can be small and difficult to detect because the drugs they contain are so potent.
CATR: What are some of the side effects that clinicians should be aware of?
Dr. Huestis: Remember, designer drugs have qualitatively similar but quantitatively more potent effects. For instance, people have increased heart rate when they smoke cannabis; however, synthetic cannabinoids can cause heart attacks and strokes. In fact, there was an instance of three 16-year-olds who all had heart attacks after using synthetic cannabinoids together (www.tinyurl.com/28b864ty). Cannabis can cause paranoia and psychosis, but when caused by synthetic cannabinoids, these effects can be prolonged, severe, and associated with violence. In fact, there are multiple instances of murder and attempted murder where synthetic cannabinoid use is implicated. Synthetic cathinones are similar; they can affect your cardiovascular and central nervous systems much more severely than amphetamines or methamphetamines. Designer benzodiazepines can cause somnolence and sedation resulting in death, even at small doses. And, of course, we’ve already talked about the dangers of designer opioids.
CATR: What can providers do to treat intoxicated patients who present with these extreme effects?
Dr. Huestis: The fact that we don’t have antidotes to many of these drugs is a big problem. For designer opioids, of course, we have naloxone. For designer benzodiazepines, we have flumazenil. But that’s about it. For the most part, all physicians can do is supportive therapy—keep the airway clear, regulate heart rate, and aggressively control body temperature. Many of the synthetic cathinones can cause dangerous hyperthermia (Zaami S et al, Eur Rev Med Pharmacol Sci 2018;22(1):268–274). Antipsychotics and benzodiazepines can be used to control behavioral agitation. As an aside, I’ve been a proponent of making available the CB1 cannabinoid receptor antagonist rimonabant (Huestis MA et al, Psychopharmacology (Berl) 2007;194(4):505–515). It was used for weight loss overseas but was pulled from the market because of associations with depression and suicidal ideation. But wouldn’t it be wonderful if it was available for one-time use in emergency rooms for synthetic cannabinoid overdoses? It could be lifesaving.
CATR: A treater must know what was ingested to provide a proper antidote if one is available. You’ve done a lot of work in identification of designer drugs through urinalysis.
Dr. Huestis: I have. Because many of these compounds are so potent, and we know so little about them, we often don’t even know how to identify the agents a patient has used. Typical urine drug tests are done with immunoassays that are widely available for commonly misused substances. More accurate confirmation testing is done with mass spectrometry, which takes some time but is also generally available. However, we don’t have immunoassays for most designer drugs, and mass spectrometry may not be useful because we don’t know what metabolites to look for in the first place.
CATR: Does that mean it’s not worth testing for designer drugs at all?
Dr. Huestis: I always encourage providers to send urine out for testing. Most small laboratories can’t handle testing for all the known 700+ designer drugs; it’s too expensive. But large hospital systems and reference labs with high-resolution mass spectrometry can screen for many compounds. The data might help not only your patient, but also public health. There are instances of highly potent drug batches causing mass overdose events with dozens or hundreds of people affected in a short time. Over 600 people became critically ill from a single batch of synthetic cannabinoids in Mississippi, for instance. In cases like these, urine toxicology information is very important for public health departments and medical examiners trying to respond to the situation in real time. There can also be third-party payment issues for send-out urine drug testing. Hospitals may be reluctant to identify specific drugs because it may compromise insurance company payment. Providers should figure out how to deal with this issue within their hospital system; think of the lives you may save!
CATR: Are there any other issues providers should be aware of in the management of acute intoxication?
Dr. Huestis: All patients presenting with intoxication by designer drugs should at the very least receive a psychiatry consult. It is important to determine whether the patient has developed a substance use disorder that needs further treatment. We also know there is a very high comorbidity of substance use and mental illness. So, it’s not good enough to just support a patient through the intoxication and send them out the door.
CATR: And what about long-term treatment?
Dr. Huestis: We know that individuals can become both physiologically and psychologically dependent on designer drugs, except for hallucinogens, just like their more common counterparts. Unfortunately, we don’t have data about how to treat designer drug addiction. The general practice has been to let the drug class guide the treatment (Klega AE and Keehbauch JT, Am Fam Physician 2018;98(2):85–92). The most common example is use of methadone or buprenorphine for patients using designer opioids. Designer opioids are now frequent contaminants in the illicit opioid supply. No one would recommend changing opioid use disorder treatment based upon whether a patient used designer opioids. Cognitive behavioral approaches, contingency management, and the limited pharmacologic options that we have for cannabis, stimulants, and benzos are probably similarly useful for the designer drugs with similar mechanisms of action, though we don’t know for sure.
CATR: Given that the landscape of designer drugs is evolving so quickly, how can clinicians stay informed?
Dr. Huestis: I recommend starting with review articles accessible through PubMed. We published a thorough review in 2017 that is a good summary of the field, at least where things stood several years ago (Logan BK et al, J Anal Toxicol 2017;41(7):573–610). Our 2021 update is set to be published in the next few months. I contributed to a recent review of designer benzodiazepines that I would recommend as well (Brunetti P et al, Pharmaceuticals (Basel) 2021;14(6):560).
CATR: Any good internet sites that you’d recommend?
Dr. Huestis: Yes. The EMCDDA has a website with in-depth information that I highly recommend (www.emcdda.europa.eu/emcdda-home-page_en). It focuses on Europe, where the pattern of available drugs can be a bit different, but the information there is very useful. The Center for Forensic Science Research in Education (www.cfsre.org) is another good resource that provides up-to-date information for the US. In addition, the American College of Medical Toxicologists (www.acmt.net) is a good resource and they host informative webinars as well. Geographical differences make it especially difficult to stay current, so I also recommend getting comfortable working with the local poison control center and forensic laboratories, especially for clinicians who work in an emergency setting. These are the people who will be the first to know about the influx of new drugs.
CATR: Thank you for your time, Dr. Huestis.
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