New Psychoactive Substances

New Psychoactive substances (NPS) are creating a nightmare for physicians, law-enforcement, and public safety. A variety of new synthetic agents, many with opioid-drug similarities have been leeching into the public domain, wreaking havoc and death  among naive users who are not even aware of what drug they are taking

Named examples include AH-7921, U-47700, MT-45, Butyrfentanyl, 4F-butyrfentanyl, acetylfentanyl, 4-MeO butyrfentantl, Furanylfentanyl, and acrylfentanyl.  These have been labeled as ‘not for human consumption’ or ‘research chemical’ thereby circumventing legislative control. Even after illegality is established, other countries may still allow their use and even internet trade. Problems with these chemicals include poor quality control, debasement with other chemicals, and unknown or unintended secondary medical consequences from unknown pharmacodynamics. Fatalities have been documented form unintended or intentional use.

The Swedish STRIDA project, initiated in 2010 by the Karolinska Institute and University Laboratory monitors the occurrence and health hazards of NPS in Sweden, and has documented structurally diverse agents, such as MT-45, which have resulted in a number of unintended toxic effects such as hearing loss, cataracts, and sever skin problems due to use of NPS. Of note, many individuals will mix drugs and create even more risk for side effects or death. Even in spite of public knowledge of medical complications of NPS use, including death, the use of NPS has continued to rise quickly in numerous countries.  NPS distribution has largely been driven by the internet, with countries such as China and India playing significant roles in their manufacture. The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) identified over 650 diff erent websites selling so-called legal highs on the surface web in 2013; European monitoring center for drugs and drug addiction  More recently, “cryptomarkets”, which are anonymous marketplaces operating on the so-called darknet, and accessible only via specially configured browsers, have played an increasing role in NPS distribution. Multiple agents of varying classes are sold, including hallucinogens and amphetamine-type stimulants. For example, the 2C-x class of empathogens (substances in the 2C-x class, despite often being sold as substitutes for MDMA have other hallucinogenic qualities) , the psychedelic tryptamine DMT, and substituted 2C-x variants of the NBOMe class are sold by the highest number of vendors across markets. α-PVP is also available on cryptomarkets and is sold by around 5% of NPS vendors. In these communities, online vendors depend on consumer feedback to maintain trust with the community, and are thus accountable for the products they sell. People using cryptomarkets to obtain drugs report fewer concerns about drug purity, lower levels of exposure to physical violence, and fewer law enforcement consequences compared with obtaining drugs from other sources.

Death from NPS has been documented throughly: For eample, the fentanyl analogue acetylfentanyl, for example, has been associated with multiple cases of life-threatening intoxication and death.  http://www.emcdda.europa.eu/publications/insights/internet-drug-markets

The internet and Drug Markets – PDF

Drugs and the Internet – Australia

DRUGS AND THE INTERNET – Australia 2016 PDF

https://www.cryptocoinsnews.com/%20%20darknet-marketplace-issues-complete-ban-drug/

Hidden wholesale The drug diffusing capacity of online drug cryptomarkets   The cryptomarket: an ‘anonymous open’ drug market that transcends locale

Novel Synthetic Opioids An Opioid Epidemic Within an Opioid Epidemic   Prescriptions for opioid analgesics paralleled an
increase in opioid abuse and fatalities between 2002 and
2010, leveling off from 2011 to 2013.3 However, drug
overdose deaths involving natural and semisynthetic opioids,
including the most commonly prescribed opioid pain
relievers, oxycodone and hydrocodone, increased by 9%
between 2013 and 2014. However, as
the availability of prescription opioids has decreased, the use
and availability of other opioids has increased. Heroin overdose death rates increased 26% from 2013 and 2014 and have more than tripled since 2010. Even more concerning, between 2013 and 2014
the death rates for synthetic opioids, excluding methadone
(eg, fentanyl), increased by 80%, largely because of increased
use and abuse of nonpharmaceutical fentanyl. There have been spikes in overdose deaths related to fentanyl and its analog, acetylfentanyl.  National Heroin Threat Assessment Summary

Heroin Trafficking in the United States 2016

Concepts of illicit drug quality among darknet market users Purity, embodied experience, craft and chemical knowledge

The internet and Drug Markets

Trends in new psychoactive substances from surface and “dark” net monitoring

New psychoactive substances in prisons high and getting higher

Who sells what Country specific differences in substance availability on the Agora cryptomarket

Everything you always wanted to know about drug cryptomarkets

Safer scoring Cryptomarkets, social supply and drug market violence

Going international Risk taking by cryptomarket drug vendors

The transparency paradox. Building trust, resolving disputes and optimising logistics on conventional and online drugs markets

Results of an international drug testing service for cryptomarket users

Drug use harm trajectories before, during and after the emergence of Silk Road§

In addition to nonpharmaceutical fentanyl, there are myriad other novel synthetic opioids that continue to emerge on the illicit drug market.1 Many of these drugs were initially developed in research laboratories as opioid agonists for analgesic use but were never brought to market for use in human beings. As such, most of the novel synthetic opioids do not have any human pharmacokinetic or pharmacodynamic data available. One such example is the W-series research opioids (W1 to W32), specifically, W-18, developed in 1981 at a Canadian university. Although early reports suggest that W-18 has 100 times the potency of fentanyl, true pharmacologic and potency data are lacking. Recently, in Ohio, multiple overdoses and deaths of patients who believed they were purchasing heroin were attributed to the ultrapotent fentanyl derivative carfentanil.  (elephant-sedative-carfentanil-threat) The synthetic opioids MT-45 and AH-7921 were first reported to the National Forensic Laboratory Information System in 2013. Opiates and Related Drugs 2009-2014 NFLS MT-45 has been associated with 28 deaths reported to the European Monitoring Centre for Drugs and Drug Addiction since 2013 and 2 reported deaths in the United States. MT-45 – opioid dataset  The abuse potential of AH-7921 was identified in 2012, when it was isolated in a seized sample purchased on the Internet, and it has been increasingly used in Japan, the United States, and Europe. Lethal poisonings with AH-7921 in combination with other substances [

Abstract 

J Anal Toxicol. 2014 Oct;38(8):599-604. doi: 10.1093/jat/bku057.

Fatal intoxications associated with the designer opioid AH-7921

AH-7921 (3,4-dichloro-N-[(1-dimethylamino)cyclohexylmethyl]benzamide) is a designer opioid with ∼80% of morphine’s µ-agonist activity. Over a 6-month period, we encountered nine deaths where AH-7921 was involved and detected in blood from the deceased. Shortly after the last death, on August 1 2013, AH-7921 was scheduled as a narcotic and largely disappeared from the illicit market in Sweden. AH-7921 was measured by a selective liquid chromatography-MS-MS method and the concentrations of AH-7921 ranged from 0.03 to 0.99 µg/g blood. Six of our cases had other drugs of abuse on board and most had other medications such as benzodiazepines, antidepressants and analgesics. However, the other medicinal drugs encountered were present in postmortem therapeutic concentrations and unlikely to have contributed to death. In addition to the parent compound, we identified six possible metabolites where two N-demethylated dominated and four mono-hydroxylated were found in trace amounts in the blood. In conclusion, deaths with AH-7921 seem to occur both at low and high concentrations, probably a result of different tolerance to the drug. Hence, it is reasonable to assume that no sharp dividing line exists between lethal and non-lethal concentrations. Further, poly-drug use did not seem to be a major contributing factor for the fatal outcome.]

Abuse of AH-7921 has accounted for at least 16 deaths between 2012 and 2013,16 including one in the United States. AH-7921 PDF  and AH-7921 the list of new psychoactive opioids is expanded An isomer of AH-7921, U-47700, is the new compound reported and is now present in the illicit drug marketplace; it already has one recent report of death related to its use. Legislators are seeking to gain control over the spread of this dangerous drug, and recently the Kansas Bureau of Investigation released a public health warning after a number of unintentional drug overdose deaths in Kansas during the past month related to the use of U-47700.  Several states, including Ohio, Wyoming, Georgia, and Kansas, are taking steps to have U-47700 placed under emergency scheduling to make consumption, possession, and distribution illegal. In addition, anecdotally, many medical toxicology program directors from across Canada and the United States have reported presumed cases of U-47700 exposures and deaths; analytical studies are sorely missing. < Of note as of January 2017 the drug is schedule 1::

AH-7921 is a structurally unique synthetic opioid analgesic that has recently entered the drug arena in Europe, the USA, and Japan. Although it was synthesized and patented in the mid-1970s, it was first identified in a seized sample purchased via the Internet in July 2012 and formally brought to the attention of the European Union early warning system in August 2012 by the United Kingdom. Several in vitro experiments and animal model studies established the morphine-like analgesic action of AH-7921 as a l-opioid receptor agonist that has been found to be several times more potent than codeine and at least as potent as morphine. This novel psychoactive substance has already led to eight non-fatal intoxications and 16 deaths in Sweden, the United Kingdom, Norway, and the USA. AH-7921 is a new, structurally atypical synthetic opioid analgesic that appears to be sold as a ‘‘research chemical’’ or ‘‘legal opioid’’ on the Internet since 2012. It was synthesized in the 1970s by Allen and Hanburys Ltd. as a potential analgesic medicine; however, its development was abandoned due to its addictive properties. It has never been marketed as a medicine, nor used as pharmaceutical or medicinal product; it has also no industrial use [6]. There are very few references available on this compound [7]. In vivo studies in animals indicated its l-opioid receptor agonistic activities, although no studies have evaluated its pharmacological and toxicological properties in humans. Its activities are similar to those of morphine and include analgesia, hypothermia, respiratory depression, and addictive behavior [7–9]. The abuse of AH-7921 has been reported in eight member states of the European Union as well as in Norway, leading to severe toxicity (non-fatal) cases and 16 reported deaths within a limited period of time (December 2012–September 2013).

U-47700:

https://psychonautwiki.org/wiki/U-47700

 

U-47700 (3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]- N-methylbenzamide) is a novel compound with opioid properties, developed by Upjohn in the 1970s and derived from the earlier opioid analgesic AH-7921 (3,4-dichloro-N- {[1-(dimethylamino)-cyclohexyl]methyl}benzamide) . U-47700 is a structural isomer of AH-7921. AH-7921, which possesses the same potency as morphine, was first identified in 2012 in a seizure purchased over the internet and recently entered the recreational and illicit drug market as new psychotropic substance in Japan, the USA, and Europe . U-47700 was never studied in humans and is not registered for medical use in humans. Very little, if any, information on it is available in scientific literature. U-47700 is an opioid analgesic drug, considered to have a potency of approximately 7.5 times that of morphine.

Tolerance and addiction potential -psychwiki

As with other opioids, the chronic use of U-47700 can be considered moderately addictive with a high potential for abuse and is capable of causing psychological dependence among certain users. When addiction has developed, cravings and withdrawal symptoms may occur if a person suddenly stops their usage.

Tolerance to many of the effects of U-47700 develops with prolonged and repeated use. The rate at which this occurs develops at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance. This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about 3 – 7 days for the tolerance to be reduced to half and 1 – 2 weeks to be back at baseline (in the absence of further consumption). U-47700 presents cross-tolerance with all other opioids, meaning that after the consumption of U-47700 all opioids will have a reduced effect.

The risk of fatal opioid overdoses rise sharply after a period of cessation and relapse, largely because of reduced tolerance.[21] To account for this lack of tolerance, it is safer to only dose a fraction of one’s usual dosage if relapsing. It has also been found that the environment one is in can play a role in opioid tolerance. In one scientific study, rats with the same history of heroin administration were significantly more likely to die after receiving their dose in an environment not associated with the drug in contrast to a familiar environment

U-47700 has a high toxicity relative to its dose due to its extreme potency. As with all opioids, long-term effects can vary but can include diminished libido, apathy and memory loss. It is also potentially lethal when mixed with depressants like alcohol or benzodiazepines.

It is worth noting that U-47700 crystals are particularly corrosive and somewhat caustic to mucous membranes. Careless use may deteriorate the chosen routes of administration so it is important to practice routine maintenance such as soaking the sinus cavity with water prior to and following insufflation. It is unwise to vaporise the substance as it can damage the lungs. Sublingual administration is likely to damage the skin in the mouth.

Combined consumption of U-47700 and fentanyl caused one fatality in Belgium.[19] At least 17 opioid overdoses and several deaths in the USA have also been connected with the use of U-47700.[20]

It is strongly recommended that one use harm reduction practices, and take extreme caution when using this substance.

Erowid links for U47700

Why relapse ends in death

Comparing fatal cases involving U-47700

Fentanyl and a Novel Synthetic Opioid U-47700 masquerading as street Norco in Central California

A case of acute intoxication due to combined use of fentanyl and U-47700

Use of synthetic opioid “U-47700” poses risk to Kansas citizens

Ocfentanil overdose fatality in the recreational drug scene

The hidden web and the fentanyl problem Detection of ocfentanil as an adulterant in heroin

The interest in eight new psychoactive substances before and after scheduling

Next generation of novel psychoactive substances on the horizon – A complex problem to face

The introduction of novel synthetic compounds poses several issues, including limited analytical methods for detecting and monitoring these substances. As shown in the related case report,2 suspicion for the presence of a novel drug is often initiated by experienced recreational drug users who concede that their drug experience was somehow different from normal. Additionally, a significant increase in opioid overdoses, particularly in patients with routine urine drug screens that are negative for opioids, suggests that fentanyl or another novel synthetic opioid is present. Unique toxicities have indeed been reported, including alveolar hemorrhage with butyrfentanyl and ototoxicity with MT-45.  Opioid intoxications involving butyrfentanyl, 4-fluorobutyrfentanyl, and fentanyl from the Swedish STRIDA project b

Tightrope or SlacklineThe Neuroscience of Psychoactive Substances

25B-NBOMe

Case series toxicity from 25B-NBOMe – a cluster of N-bomb cases

SYNTHETIC CANNABINOIDS

A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment

How toxic is ibogaine

METHOXETAMINE

A polydrug intoxication involving methoxetamine in a drugs and driving case.

Methoxetamine (MXE) – A Phenomenological Study of Experiences Induced by a Legal High from the Internet

Acute toxicity associated with the recreational use of the ketamine derivative methoxetamine

MDPV  BATH SALTS

Intoxications involving MDPV in Sweden during 2010–2014

Death following recreational use of designer drug bath salts containing 3,4-Methylenedioxypyrovalerone (MDPV)

NATURE: The Psychoactive Designer Drug and Bath Salt Constituent MDPV Causes Widespread Disruption of Brain Functional Connectivity.

PCP derivatives

Phencyclidine analog use in Sweden—intoxication cases involving 3-MeO-PCP and 4-MeO-PCP from the STRIDA project

FENTANYL-LIKE drugs

Opioid intoxications involving butyrfentanyl, 4-fluorobutyrfentanyl, and fentanyl from the Swedish STRIDA project

Death following intentional ingestion of e-liquid

I like the old stuff better than the new stuff – Subjective experiences of new psychoactive substances

Flubromazolam – A new life-threatening designer benzodiazepine

TRYPTAMINES

Recreational use, analysis and toxicity of tryptamines.

There are many categories of NPS, such as synthetic cannabinoids, synthetic cathinones, phenylethylamines, piperazines, ketamine derivatives and tryptamines. Tryptamines are naturally occurring compounds, which can derive from the amino acid tryptophan by several biosynthetic pathways: their structure is a combination of a benzene ring and a pyrrole ring, with the addition of a 2-carbon side chain. Tryptamines include serotonin and melatonin as well as other compounds known for their hallucinogenic properties, such as psilocybin in ‘Magic mushrooms’ and dimethyltryptamine (DMT) in Ayahuasca brews.

Neuropharmacology of New Psychoactive Substances (NPS) Focus on the Rewarding and Reinforcing Properties of Cannabimimetics and Amphetamine-Like Stimulants.

http://www.fsijournal.org/article/S0379-0738(14)00157-1/pdf::

Abstract

Following the initial popularity of mephedrone (4-methylmethcathinone) there has been a stream of new “recreational drugs” entering the global market. The lack of clinical studies on the effects and toxicity of these drugs has made interpretation of toxicological findings difficult. In an attempt to assist in a better understanding of the extent of their use and the fatalities that have been linked to these compounds we present our collated findings in post-mortem and criminal casework where these have been detected and/or implicated. Between January 2010 and December 2012 we have detected new psychoactive substances (NPS) in 203 cases, with 120 cases in 2012 alone. The drugs detected in in life or post-mortem blood and urine are, in order of decreasing frequency; mephedrone, 4-methylethcathinone, BZP, MDPV, TFMPP, methoxetamine, 4-fluoromethcathinone, 4-methylamphetamine, PMA, methylone, PMMA, naphyrone, alpha-methyltryptamine, butylone, MDAI, desoxypipradrol, D2PM, MPA, synthetic cannabinoids, 2-AI, 5-IAI, 5-MeODALT, MDPBP, 5/6-APB, pentedrone and pentylone. Other drugs or alcohol were detected in 84% of the cases including other NPS and in fatalities it should be noted that alternative causes of death (including mechanical suicide, accidental death and non-psychoactive drug overdose) accounted for the majority. Related to this was that of all fatalities involving cathinones, 41% of these were hangings or other mechanical suicides, this was a higher proportion than seen with other drugs found in such cases. The presence of multiple NPS and/or other stimulants was a particular feature in various cases, however, of the drug deaths only 7% solely involved NPS. Across all case types and including some cases investigated in 2013, NPS concentrations showed a wide range but these and selected cases are presented to assist toxicological interpretation in future cases.

Trifluoromethylphenylpiperazine (TFMPP) is a recreational drug of the piperazine chemical class. Usually in combination with its analogue benzylpiperazine (BZP), it is sold as an alternative to the illicit drug MDMA (“Ecstasy”) under the name “Legal X

α-Methyltryptamine (abbreviated as αMT, AMT) is a psychedelic, stimulant, and entactogen drug of the tryptamine class.[2][3] It was originally developed as an antidepressant by workers at Upjohn in the 1960s,[4] and was used briefly as an antidepressant in Russia under the trade name Indopan before being discontinued

https://psychonautwiki.org/wiki/5-MeO-DALT   << Psychonaut WIKI

5-MeO-DALT, or N,N-diallyl-5-methoxytryptamine, is a psychedelic tryptamine first synthesized by Alexander Shulgin. It is chemically related to the compounds 5-MeO-DPT and DALT. It is described as having rapid, intense and short-acting entheogenic effects.

Alexander Shulgin sent the first material regarding the synthesis and effects of 5-MeO-DALT to a researcher in May 2004; afterwards, it soon circulated online. In June 2004, it became available through the use of online research chemical vendors. In August 2004, the synthesis and effects of 5-MeO-DALT were published by Erowid.

Ephenidine_ A new psychoactive agent with ketamine-like NMDA receptor antagonist properties

Legal Highs– novel and emerging psychoactive drugs a chemical overview for the toxicologist

Spice Kryptonite Black Mamba An Overview of Brand Names and Marketing Strategies of Novel Psychoactive Substances on the Web

An Internet Study of User s Experiences of the Synthetic Cathinone 4 Methylethcathinone 4 MEC

Investigation of Bath Salts Use Patterns Within an Online Sample of Users in the United States

Exploring the Attractiveness of New Psychoactive Substances NPS among Experienced Drug Users

New psychoactive substances and British drug policy A view from the cyber psychonauts

 

https://psychonautwiki.org/wiki/Main_Page

Self-Reported Use of Novel Psychoactive Substances in a US survey

Psychinfo

Web of KNowledge

Who database

Lilacs database

https://health.ebsco.com/products/the-cinahl-database

In chronic fentanyl users, such as those patients who use fentanyl therapeutically for their chronic pain, a ratio of postmortem blood fentanyl to norfentanyl concentrations of less than 2.5 probably indicate chronic fentanyl usage rather than acute fentanyl toxicity, while that of greater than 8 is consistent with acute fentanyl toxicity

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