New Psychoactive Substances (including kratom, synthetic cannabinoids, synthetic opioids, synthetic cathinones, and more).

Related Chapters:
Fentanyl
Entheogens and Psychedelics

Chapter Sections:
Overview
Ketamine
Khat
Kratom
Krokodil
Synthetic Opioids (e.g. Fentanyl)
Synthetic Cathinones (Mephedrone, Methylone)
Phenethylamines
Salvia Divinorum
Synthetic Cannabinoids
Others - New psychoactive substances are being developed at a rapid rate

Page last updated June 10, 2020 by Doug McVay, Editor/Senior Policy Analyst.

31. Analgesic and opioid-like effects of Kratom

"In Southeast Asia, kratom has long been used for the management of pain and opium withdrawal.6,9-11,14 In the West, kratom is increasingly being used by individuals for the self-management of pain or withdrawal from opioid drugs such as heroin and prescription pain relievers.20,27 It is these aspects of kratom pharmacology that have received the most scientific attention. Although to our knowledge, no well-controlled clinical studies on the effects of kratom on humans have been published, there is evidence30-38 that kratom, kratom extracts, and molecules isolated from kratom can alleviate various forms of pain in animal models. Studies have used a variety of methods including hot plate,35,37,39 tail flick,32,39 writhing,37,38 and pressure/inflammation35,38 tests in mice32,35,38,39 and rats,35,37 as well as more elaborate tests in dogs and cats.35 In addition, a variety of chemical compounds have been isolated from kratom and shown to exhibit opioid-like activity on smooth muscle systems31,33,34 and in ligand-binding studies.39,40 Most notably, many of the central nervous system and peripheral effects of these kratom-derived substances are sensitive to inhibition by opioid antagonists.31-34,39-41"

Prozialeck, WC, Jivan, JK, and Andurkar, SV. Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. Journal of the American Osteopathic Association. December 2012;112(12):792-9.
https://www.ncbi.nlm.nih.gov/p...
http://jaoa.org/article.aspx?a...

32. Toxic Effects of Kratom

"During the past 3 years, there have been an increasing number of case reports15,17,29 describing unusual adverse reactions in patients who had been using kratom or kratom-based products. The acute adverse effects of kratom experienced by many users appear to be a direct result of kratom's stimulant and opioid activities.6,9,11,30,31 Stimulant effects may manifest themselves in some individuals as anxiety, irritability, and increased aggression. Opioid-like effects include sedation, nausea, constipation, and itching. Again, these effects appear to be dose dependent and to vary markedly from one individual to another. Chronic, high-dose usage has been associated with several unusual effects. Hyperpigmentation of the cheeks, tremor, anorexia, weight loss, and psychosis have been observed in individuals with long-term addiction.9 Reports of serious toxic effects are rare and have usually involved the use of relatively high doses of kratom (>15 g).9,17,45,46 Of particular concern, there have been several recent reports of seizures occurring in individuals who have used high doses of kratom, either alone or in combination with other drugs, such as modafinil.17,22,45 Kapp et al15 recently described a case of intrahepatic cholestasis in a chronic user of kratom.
"It is important to note that in each of these case reports, the patients may have had confounding health conditions, may have been using other drugs along with kratom, or both. One of the major problems in evaluating the potential uses and safety of an herbal agent such as kratom is the lack of understanding of how substances in kratom may interact with prescription medications, drugs of abuse, or even other herbal supplements. This issue is compounded by the relative lack of regulations and standardization related to the production and sale of kratom. These potential hazards were highlighted in several case reports of deaths resulting from the use of a kratom-based product known as 'Krypton'.16,47 This agent, which was touted as a very potent form of kratom, had been marketed in Sweden. During the past 5 years, there have been reports of 9 deaths related to the use of Krypton.16 In a case series by Kronstad et al,16 subsequent forensic studies revealed that Krypton contained high amounts of the exogenous pharmaceutical agent O-desmethyltramadol, which has opioid and neuromodulator activity. Evidently, the exogenous O-desmethyltramadol had been added to the plant material. Even though mitragynine was also detected in the products, it was not determined how the 2 substances may have interacted to cause death. Another recent report48 described a fatal reaction that appeared to be associated with the use of a combination of propylhexedrine—an ? agonist and an amphetamine-like stimulant—and mitragynine. This latter case highlights the fact that extracts and tinctures containing purified mitragynine, 7-hydroxymitragynine, and 7-acetoxymitragynine have become available for purchase by means of the Internet. These sources can easily be found by conducting an Internet search using the term 'mitragynine purchase.' The possibility that these highly concentrated mitragynine alkaloid extracts could be used in conjunction with other psychoactive drugs (eg, alcohol, sedatives, opioids, stimulants, cannabinoids) raises the potential for serious drug interactions."

Prozialeck, WC, Jivan, JK, and Andurkar, SV. Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. Journal of the American Osteopathic Association. December 2012;112(12):792-9.
https://www.ncbi.nlm.nih.gov/p...
http://jaoa.org/article.aspx?a...

33. Reported Adverse Effects of Kratom

"In spite of the increasing use of this substance, scientific literature about the effects and toxicity of kratom alone remains very scarce.
"Kratom is a central nervous system stimulant, from which over 40 alkaloids have been isolated. In low doses it is reported to have stimulant effects (used to combat fatigue during long hours of work), while at high doses, it can have sedative-narcotic effects.87 In 1921, the major alkaloid found in this plant, ‘Mitragynine’, was first isolated. Mitragynine has an opioid agonistic activity and its derivative 7-hydroxymitragynine (7-OH-mitragynine) is reported to be more potent than mitragynine or morphine.88
"Nine fatal cases of intoxication associated with the use of ‘krypton’, a mixture of mitragynine and O-desmethyltramadol, have been described in scientific literature. However, these fatalities have been attributed to the addition of O-desmethyltramadol to the dried kratom leaves.89"

UN Office on Drugs and Crime, "The Challenge of New Psychoactive Substances: A Report from the Global SMART Programme" (Vienna, Austria: UNODC Laboratory and Scientific Section, March 2013), pp. 14-15.
http://www.unodc.org/documents...

34. The Emergence of 'Krokodil'

"In the last three to five years an increasing number of reports suggest that people who inject drugs (PWID) in Russia, Ukraine and other countries are no longer using poppies or raw opium as their starting material, but turning to over-the-counter medications that contain codeine (e.g. Solpadeine, Codterpin or Codelac). Codeine is reportedly converted into desomorphine (UNODC, 2012; Gahr et al., 2012a, 2012b, 2012c; Skowronek, Celinski, & Chowaniec, 2012). The drug is called Russian Magic, referring to its potential for short lasting opioid intoxication or, more common, to its street name, krokodil. Krokodil refers both to chlorocodide, a codeine derivate, and to the excessive harms reported, such as the scale-like and discolored (green, black) skin of its users, resulting from large area skin infections and ulcers. At this point, Russia and Ukraine seem to be the countries most affected by the use of krokodil, but Georgia (Piralishvili, Gamkrelidze, Nikolaishvili, & Chavchanidze, 2013) and Kazakhstan (Ibragimov & Latypov, 2012; Yusopov et al., 2012) have reported krokodil use and related injuries as well."

Grund, J. -P. C., et al. "Breaking worse: The emergence of krokodil and excessive injuries among people who inject drugs in Eurasia." International Journal of Drug Policy (2013), http://dx.doi.org/10.1016/j.dr...
http://www.ijdp.org/article/S0...

35. Krokodil Production

"In considering the drug krokodil, two aspects are of importance, its pharmacology and its chemistry. The short half-life, limited high after the impact effect and, in particular the need for frequent administration may narrow the attention of users on the (circular) process of acquiring, preparing and administering the drug, leaving little time for matters other than avoiding withdrawal and chasing high, as reported in several popular magazines (e.g. Shuster, 2011; Walker, 2011). However, when the layers of bootleg chemistry and attribution are peeled off, what’s left is an opioid analogue (or several ones) that, besides the variations in half-life, behaves pharmacologically not very different than heroin or Hanka (Haemmig, 2011). There are various paths to synthesize desomorphine from codeine, but the chemical process most commonly reported to be used by PWID in Russia and Ukraine is very similar to that of home-produced methamphetamine or Vint (Grund, Zábransky, Irwin, & Heimer, 2009; Zábransky, 2007) – a rudimentary version of a simple chemical reduction. The illicit production of krokodil reportedly involves the processing of codeine into the opiate analogue desomorphine (UNODC, 2012; Gahr et al., 2012a, 2012b, 2012c; Skowronek et al., 2012). Desomorphine (Dihydrodesoxymorphine-D or PermonidTM ) is an opiate analogue first synthesized by Small in 1932 (Small, Yuen, & Eilers, 1933). The analgesic effect of desomorphine is about ten times greater than that of morphine (and thus stronger than heroin), whereas its toxicity exceeds that of morphine by about three times (Weill & Weiss, 1951). The drug’s onset is described as very rapid but its action is of short duration, which may lead to rapid physical dependence and frequent administration."

Grund, J. -P. C., et al. "Breaking worse: The emergence of krokodil and excessive injuries among people who inject drugs in Eurasia." International Journal of Drug Policy (2013), http://dx.doi.org/10.1016/j.dr...
http://www.ijdp.org/article/S0...

36. Harms Associated with Krokodil Use

"In recent years, harm reduction and drug treatment services from Russia, Ukraine, Georgia and Kazakhstan began reporting severe health consequences associated with krokodil injecting. Although serious localized and systemic harms have previously been associated with injecting homemade opiates and stimulants in the region (Grund, 2002; Volik, 2008), the harms associated with krokodil injecting are extreme and unprecedented. The most common complications of krokodil appear to be serious venous damage and skin and soft tissue infections, rapidly followed by necrosis and gangrene (Gahr et al., 2012a, 2012b, 2012c; Skowronek et al., 2012). Our research further identified an impressive, undoubtedly incomplete, list of injuries and symptoms (Table 1), reported in the media (e.g. Shuster, 2011; Walker, 2011) and identified in YouTube clips and photographs on the internet. Importantly, this list includes several parts of the body that are not typically used as sites for injecting drugs. This suggests that the ill effects of krokodil are not limited to localized injuries, but spread throughout the body (Shuster, 2011; UNODC, 2012), with neurological, endocrine and organ damage associated with chemicals and heavy metals common to krokodil production (Lisitsyn, 2010).
"It is important to note that the described harms seem to become manifest relatively shortly after krokodil injecting is initiated. Present accounts of krokodil related harms often concern young people presenting in emergency rooms and surgeries with extreme and advanced complications. According to NGOs that work with people who inject krokodil, these young people have relatively short histories of using the drug. Mortality rates among young krokodil users are reportedly high (Akhmedova, 2012; Shuster, 2011; Walker, 2011), with official reports associating krokodil use with half of all drug-related deaths in at least two Oblasts (Walker, 2011)."

Grund, J. -P. C., et al. "Breaking worse: The emergence of krokodil and excessive injuries among people who inject drugs in Eurasia." International Journal of Drug Policy (2013), http://dx.doi.org/10.1016/j.dr...
http://www.ijdp.org/article/S0...

37. Prevalence of Krokodile Use

"The estimated number of PWID in Russia was close to 2 million in 2008 (Mathers et al., 2008). 2.3% of the Russian population uses opioids annually and 1.4% heroin, compared to an annual prevalence of 0.4% opioid use in Western and Central Europe (UNODC, 2012). While actual epidemiological data is not available, a number of academic and media reports suggest that 5% or more of Russian drug users (approximately 100,000 PWID) may be injecting krokodil (Walker, 2011), while 'various official estimates' place the numbers of Russian PWID using krokodil as high as one million (Shuster, 2011). Epidemiological data is critical to evaluating claims that the use of krokodil is reaching epidemic proportions in Russia (Walker, 2011), and potentially, the Ukraine. There are an estimated 290,000 to 375,000 PWID in Ukraine (Mathers et al., 2008). A recent national survey found that 7% of PWID have used krokodil in 2011 (Balakireva, 2012), suggesting that around 20,000 PWID in Ukraine may have used krokodil that year. Balakireva and colleagues furthermore found statistically significant differences in krokodil use between the cities in the study, with most krokodil use reported in Uzhhorod (35.6%), Simferopol (26.9%), Kyiv (21.7%), Chernivtsi (15.5%) and Donetsk (12.6%). Estimates from other countries are not available. Outside of the former Soviet region, krokodil has been reported in Germany (Der Spiegel, 2011) and in Tromsø in northern Norway (Lindblad, 2012)."

Grund, J. -P. C., et al. "Breaking worse: The emergence of krokodil and excessive injuries among people who inject drugs in Eurasia." International Journal of Drug Policy (2013), http://dx.doi.org/10.1016/j.dr...
http://www.ijdp.org/article/S0...

38. Krokodil - Reasons and Risks

"In sum, these observations suggest that the relatively limited availability of black market opiates and stimulants and the relative ease of harvesting legal precursors to powerful analogues from the countryside and pharmacies inspired and sustained a Soviet-style homemade drug culture in the Eastern European region that remains radically different from those observed in countries where narco-traffickers dominate the production and distribution of drugs (Booth, Kennedy, Brewster, & Semerik, 2003; Grund et al., 2009; Grund, 2005; Subata & Tsukanov, 1999; Zábransky, 2007).
"The physical and logistical exigencies of home production; its locus in networks of drug injecting friends and the high degree of cooperative action involved (in foraging for, producing and using the drugs); the multiple roles and ambiguous status of injecting paraphernalia; the routine occurrence of well-known risk behaviours (e.g. syringe sharing, frontloading) and those currently less well understood, such as the slapdash nature of the bootleg drug synthesis and its unpredictable outcomes in terms of actual drug product, purity and pollution— indeed all of these factors contribute to and interact within the vastly complex high risk environment of home drug production in the region."

Grund, J. -P. C., et al. "Breaking worse: The emergence of krokodil and excessive injuries among people who inject drugs in Eurasia." International Journal of Drug Policy (2013), http://dx.doi.org/10.1016/j.dr...
http://www.ijdp.org/article/S0...

39. Stigmatization and Inhumane Treatment of Krokodil Users

"In Russia and many other post-Soviet countries, the old ideology lingers on in narcological institutes, out of sync with modern public and mental health concepts (Grund et al., 2009). Many narcologists continue to view addiction as criminal or moral deviance and not as a disease. Narcological dispensaries continue to share information with law enforcement (Mendelevich, 2011). The threat of removal of child custody rights may impede women’s access to health care in particular (Shields, 2009). Stigma and discrimination, hostile treatment and lack of confidentiality are persistent in the treatment of PWID and must be viewed as important barriers to timely seeking medical care (Beardsley & Latypov, 2012; Mendelevich, 2011; Wolfe et al., 2010). PWID have therefore strong incentives to avoid narcological facilities and, by association, other state health services. In their personal 'hierarchy of risk,' seeking help for significant health problems is subordinated by the need to stay under the radar of the authorities (Connors, 1992). Several of the YouTube clips on the internet furthermore document not only the gravity of harms among krokodil users, but also poor and inhumane treatment of those hospitalized with krokodil related injuries. In one video a man’s leg is sawn off under the knee with a lint saw in what seems not to be a surgical unit, but perhaps a common hospital ward. The man sits wide-awake in an ordinary wheelchair and holds his leg himself above a bucket, which was lined with a garbage bag just before. These videos and case reports (Asaeva et al., 2011; Daria Ocheret, personal communication, 2012; Sarah Evans, personal communication, 2012) suggest that the care provided to those with krokodil related injuries may be (grossly) substandard, sometimes exacerbated by improper diagnosis and faulty clinical decisions."

Grund, J. -P. C., et al. "Breaking worse: The emergence of krokodil and excessive injuries among people who inject drugs in Eurasia." International Journal of Drug Policy (2013), http://dx.doi.org/10.1016/j.dr...
http://www.ijdp.org/article/S0...

40. Synthetic Cathinones

"Synthetic cathinones are related to the parent compound cathinone (Figure 1), one of the psychoactive principals in khat (Catha edulis Forsk). Cathinone derivatives are the β-keto (βk) analogues of a corresponding phenethylamine. The group includes several substances that have been used as active pharmaceutical ingredients (API) of medicinal products, e.g. amfepramone (diethylpropion; Figure 2). Since the mid-2000s, unregulated ring-substituted cathinone derivatives have appeared in the European recreational drugs market. The most commonly available cathinones sold on the recreational market in the period up to 2010 appear to be mephedrone (Figure 3) and methylone (Figure 4). These products are usually encountered as highly pure white or brown powders. Ring-substituted cathinone derivatives are claimed to have effects similar to those of cocaine, amphetamine or MDMA (ecstasy), but little is known of their detailed pharmacology. Apart from cathinone (Figure 1), methcathinone (Figure 5) and two API’s amfepramone (Figure 2) and pyrovalerone, cathinone derivatives are not under international control."

Synthetic Cathinones Drug Profile. European Monitoring Centre on Drugs and Drug Addiction. Lisbon, Portugal. On the web at http://www.emcdda.europa.eu/pu... , last accessed September 21, 2018.

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