Designer drug

Designer drug is a term used to describe drugs which are created (or marketed, if they had already existed) to get around existing drug laws, usually by modifying the molecular structures of existing drugs to varying degrees, or less commonly by finding drugs with entirely different chemical structures that produce similar subjective effects to illegal recreational drugs. The term designer drug also technically applies to the new psychiatric medications, such as the SSRI's and atypical anti-psychotics, as they are designed over many years using testing in animals and neuro-imaging. This is in the form of cooperate drug design.

1920s-1930s
The term "designer drug" was first coined by law enforcement in the 1980s, and has gained widespread use. However the first appearance of what would now be termed designer drugs occurred well before this, in the 1920s. Following the passage of the second International Opium Convention in 1925 which specifically banned morphine and the diacetyl ester of morphine, heroin, a number of alternative esters of morphine quickly started to be manufactured and sold. The most notable of these were dibenzoylmorphine and acetylpropionylmorphine, which had virtually identical effects to heroin but were not covered by the Opium Convention. This then led the Health Committee of the League of Nations to pass several resolutions attempting to bring these new drugs under control, ultimately leading in 1930 to the first broad analogues provisions extending legal control to all esters of morphine, oxycodone and hydromorphone. Another early example of what could loosely be termed designer drug use, was during the Prohibition era in the 1930s, when diethyl ether was sold and used as an alternative to illegal alcoholic beverages in a number of countries.

1960s-1970s
During the 1960s and 1970s, a number of new synthetic hallucinogens were introduced, with a notable example being the sale of highly potent tablets of DOM in San Francisco in 1967. There was little scope to prosecute people over drug analogues at this time, with new compounds instead being added to the controlled drug schedules one by one as they became a problem, but one significant court case from this period was in 1973, when Tim Scully and Nicholas Sand were prosecuted for making the acetyl amide of LSD, known as ALD-52. At this time ALD-52 was not a controlled drug, but they were convicted on the grounds that in order to make ALD-52, they would have had to be in possession of LSD, which was illegal. The late 1970s also saw the introduction of various analogues of phencyclidine (PCP) to the illicit market, although few of them were well accepted by users with only TCP and PCE becoming widely used.

1980s-early 1990s
The modern use of the term designer drug was coined in the 1980s to refer to various synthetic opioid drugs, mostly based on the fentanyl molecule (such as α-methylfentanyl). The term gained widespread popularity when MDMA (ecstasy) experienced a popularity boom in the mid 1980s. When the term was coined in the 1980s, a wide range of narcotics were being sold as heroin on the black market. Many were based on fentanyl or meperidine. One, MPPP, was found in some cases to contain an impurity called MPTP, which caused brain damage that could result in a syndrome identical to full-blown Parkinson's disease, from only a single dose. Other problems were highly potent fentanyl analogues, which were sold as China White, that caused many accidental overdoses.

Because the government was powerless to prosecute people for these drugs until after they had been marketed successfully, laws were passed to give the DEA power to emergency schedule chemicals for a year, with an optional 6-month extension, while gathering evidence to justify permanent scheduling, as well as the analogue laws mentioned previously. Emergency-scheduling power was used for the first time for MDMA. In this case, the DEA scheduled MDMA as a Schedule I drug and retained this classification after review, even though their own judge ruled that MDMA should be classified Schedule III on the basis of its demonstrated uses in medicine. The emergency scheduling power has subsequently been used for a variety of other drugs including 2C-B, AMT, and BZP. In 2004, a piperazine drug, TFMPP, became the first drug that had been emergency-scheduled to be denied permanent scheduling and revert to legal status.

The late 1980s and early 1990s also saw the re-emergence of methamphetamine in the United States as a widespread public health issue, leading to increasing controls on precursor chemicals in an attempt to cut down on domestic manufacture of the drug. This led to several alternative stimulant drugs emerging, most notably methcathinone and 4-methylaminorex, but despite attracting enough attention from authorities to provoke legal scheduling of these compounds, their distribution was relatively limited in extent and methamphetamine continued to dominate the illicit synthetic stimulant market overall.

Late 1990s-2004
In the late 1990s and early 2000s, there was a huge explosion in designer drugs being sold over the internet. The term and concept of "research chemicals" was coined by some marketers of designer drugs (particularly of psychedelic drugs in the tryptamine and phenethylamine family). The idea was that by selling the chemicals as for "scientific research" rather than human consumption, the intent clause of the U.S. analogue drug laws would be avoided. Nonetheless the DEA raided multiple suppliers, first JLF Primary Materials, and then multiple vendors (such as RAC Research) several years later in Operation Web Tryp. This process was accelerated greatly when vendors began advertising via search engines like Google by linking their sites to searches on key words such as chemical names and terms like psychedelic or hallucinogen. Widespread discussion of consumptive use and the sources for the chemicals in public forums also drew the attention of the media and authorities.

In 2004, the US Drug Enforcement Administration raided and shut down several internet based research chemical vendors in an operation called Web Tryp. With help from the authorities in India and China, two chemical manufacturers were also closed. Many other internet based vendors promptly stopped doing business, even though their products were still legal throughout much of the world.

Most substances that were sold as "research chemicals" in this period of time are hallucinogens and bear a chemical resemblance to well-known drugs, such as psilocybin and mescaline. As with other hallucinogens, these substances are often taken for the purposes of facilitating spiritual processes (see entheogen), mental reflection (see psychedelic) or recreation. Some research chemicals on the market were not psychoactive, but can be used as precursors in the synthesis of other potentially psychoactive substances, for example, 2C-H which could be used to make 2C-B and 2C-I among others. Extensive surveys of structural variations have been conducted by pharmaceutical corporations, universities and independent researchers over the last century, from which some of the presently available research chemicals derive. One particularly notable researcher is Dr. Alexander Shulgin, who presented syntheses and pharmacological explorations of hundreds of substances in the books TiHKAL and PiHKAL (co-authored with Ann Shulgin), and has served as an expert witness for the defense in several court cases against manufacturers of psychoactive drugs.

The majority of chemical suppliers sold research chemicals in bulk form as powder, not as pills, as selling in pill form would invalidate the claims that they were being sold for non-consumptive research. Active dosages vary widely from substance to substance, ranging from sub-microgram levels to hundreds of milligrams, but while it is critical for the end user to weigh doses with a precision scale, instead of guessing ("eyeballing"), many users did not do this and this led to many emergency room visits and several deaths, which were a prominent factor leading to the emergency scheduling of several substances and eventually Operation Web Tryp. Some compounds such as 2C-B and 5-Meo-DiPT did eventually increase in popularity to the point that they were sold in pill form to reach a wider market, and acquired popular street names ("Nexus" and "Foxy" respectively). Once a chemical reaches this kind of popularity, it is usually just a matter of time before it is added to the list of scheduled (i.e. illegal) drugs.

The late 1990s and early 2000s also saw the first widespread use of novel anabolic steroids by athletes in competition. Steroids had been banned by the International Olympic Committee since 1976, but due to the large number of different anabolic agents available for human and veterinary use, the ability of laboratories to test for all available drugs had always lagged behind the ability of athletes to find new compounds to use. The introduction of increasingly formalised testing procedures, especially with the creation of the World Anti-Doping Agency in 1999, made it much more difficult for athletes to get away with using these drugs without detection, which then led to the synthesis of novel and potent anabolic steroid drugs such as tetrahydrogestrinone (THG) which were not detectable by the standard tests.

2005-2009
While historically most designer drugs had been either opioids, hallucinogens or anabolic steroids, the range of possible compounds is limited only by the scientific and patent literature, and recent years have been characterised by a broadening of the range of compounds sold as designer drugs. These have included a wide variety of designer stimulants such as geranamine, mephedrone, MDPV and desoxypipradrol, several designer sedatives such as methylmethaqualone and premazepam, and designer analogues of sildenafil (Viagra), which have been reported as active compounds in supposedly "herbal" aphrodisiac products. Designer cannabinoids are another recent development, with two compounds JWH-018 and (C8)-CP 47,497 initially found in December 2008 as active components of "herbal smoking blends" sold as legal alternatives to marijuana, and subsequently a growing range of synthetic cannabinoid agonists have continued to appear. The relative market saturation with the wide variety of opioid and hallucinogenic drugs already available has slowed the emergence of new compounds in these areas, although with some exceptions such as the popularisation and widespread internet sale of the opioid-bearing plant Mitragyna speciosa (Kratom) and its extracted active component 7-hydroxymitragynine, as well as the continuing trickle of novel hallucinogens and dissociatives such as NBOMe-2CC (cf. NBOMe-2CI) and 3-MeO-PCP. Another novel development is the use of research ligands for cosmetic rather than strictly recreational purposes, such as grey-market internet sales of the unapproved tanning drug melanotan II.

"“...what is new is the wide range of substances now being explored, the aggressive marketing of products that have been intentionally mislabelled, the growing use of the internet, and the speed at which the market reacts to control measures.”"

- EMCDDA director Wolfgang Goetz (November 2009).

Safety
The safety of research chemicals is untested and little if any research has been done on the toxicology or pharmacology of most of these drugs. Few, if any, human or animal studies have been done. Unlike better-known drugs like alcohol or cannabis, which have been used by billions of people worldwide, research chemicals are new and may only have been used by a few thousand people for a few months although some of the more popular drugs such as 2C-B, MDMA and BZP have been used by millions of people. Many research compounds have produced unexpected side effects and adverse incidents due to the lack of screening for off-target effects prior to marketing; both bromo-dragonfly and mephedrone seem to be capable of producing pronounced vasoconstriction under some circumstances which has resulted in several deaths, although the mechanism remains unclear. More commonly adverse incidents and overdoses arise accidentally, from poor handling of potent chemicals where the margin of error is too narrow for guesswork, or simply from excessive abuse of the drug.

Law
Due to the recent development of many designer drugs, laws banning or regulating their use have not been developed yet, and in recent cases novel drugs have appeared directly in response to legislative action, to replace a similar compound that had recently been banned. Many of the chemicals fall under the various drug analogue legislations in certain countries, but most countries have no general analogue act or equivalent legislation and so novel compounds may fall outside of the law after only minor structural modifications. In the United States, the Controlled Substances Act was amended by the Controlled Substance Analogue Enforcement of 1986, which attempted to ban designer drugs pre-emptively by making it illegal to manufacture, sell, or possess chemicals that were substantially similar in chemistry and pharmacology to Schedule I or Schedule II drugs. Other countries have dealt with the issue differently. In some, they simply ban new drugs as they become a concern, as do Germany, Canada, and the United Kingdom. Some countries, such as Australia and New Zealand, have gone the opposite direction and enacted sweeping bans based on chemical structure only, making chemicals illegal even before they are created—if a theoretical chemical fits a set of rules regarding substitutions and alterations of an already banned drug, it too is banned. The controlled substance analogue law under both Australian Federal law and that of some individual states such as New South Wales, is so broad that it would cover millions of compounds that have never been made, simply on the basis that they bear a vague resemblance to one of the drugs on the illegal list. However it would still not cover drugs which have no structural similarity to any controlled drug, even if they produced similar effects.

Common designer drugs
Most of the best known research chemicals are structural analogues of tryptamines or phenethylamines, but there are also many other completely unrelated chemicals which can be considered as part of the group. It is very difficult to determine psychoactivity or other pharmaceutical properties of these compounds based strictly upon structural examination. Many of the substances have common effects whilst structurally different and vice versa (see also SAR paradox). As a result of no real official naming for some of these compounds, as well as regional naming, this can all lead to (and is anecdotally known to have led to) potentially hazardous mix ups for users.

Opioids

 * α-methylfentanyl, became well known as "China White" on the heroin market
 * parafluorofentanyl
 * 3-methylfentanyl, extremely potent opioid, allegedly used as a chemical weapon by the Russian military in the Moscow theater hostage crisis
 * MPPP, especially infamous due to an impurity in some batches called MPTP which caused permanent Parkinsonism with a single use
 * O-Desmethyltramadol
 * 7-Acetoxymitragynine
 * 4'-Nitromethopholine

Hallucinogens

 * Lysergamide-based
 * ALD-52, N-acetyllysergic acid diethylamide, famously believed have been the active ingredient in the "Orange Sunshine" acid of the 1960s
 * ETH-LAD, which has been sold by some research chemical suppliers.
 * AL-LAD, which has been sold by some research chemical suppliers.
 * PRO-LAD, which has been sold by some research chemical suppliers.


 * Tryptamine-based
 * 4-Acetoxy-DiPT, N,N-diisopropyl-4-acetoxytryptamine
 * 5-MeO-AMT, 5-methoxy-alpha-methyltryptamine
 * 5-MeO-DiPT, 5-methoxy-di-isopropyltryptamine (also known as "Foxy" or "Foxy Methoxy")
 * 5-MeO-DMT, 5-methoxy-dimethyltryptamine
 * 5-MeO-MiPT, 5-methoxy-methylisopropyltryptamine
 * AMT, α-methyltryptamine
 * DiPT, N,N-diisopropyl-tryptamine
 * DPT, N,N-dipropyltryptamine


 * Phenethylamine-based
 * 2C-B, 4-bromo-2,5-dimethoxyphenethylamine
 * 2C-C, 2,5-dimethoxy-4-chlorophenethylamine
 * 2C-D, 2,5-dimethoxy-4-methyl-phenethylamine
 * 2C-E, 2,5-dimethoxy-4-ethyl-phenethylamine
 * 2C-I, 2,5-dimethoxy-4-iodophenethylamine
 * 2C-T-2, 2,5-dimethoxy-4-ethylthiophenethylamine
 * 2C-T-4, 2,5-dimethyoxy-4-(i)-propylthiophenethylamine
 * 2C-T-7, 2,5-dimethoxy-4-(n)-propylthiophenethylamine
 * 2C-T-21, 2,5-dimethoxy-4-(2-fluoroethylthio)phenethylamine
 * DOB, 2,5-dimethoxy-4-bromoamphetamine
 * DOC, 2,5-dimethoxy-4-chloroamphetamine
 * DOM, 2,5-dimethoxy-4-methylamphetamine
 * TMA-2, 2,4,5-Trimethoxyamphetamine
 * 2CB-FLY
 * Bromodragonfly

Dissociatives

 * 3-MeO-PCP
 * 4-MeO-PCP
 * Dizocilpine (MK-801; (+)-5-methyl-10,11- dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine)
 * Eticyclidine (PCE; CI-400; N-ethyl-1-phenylcyclohexylamine)
 * Rolicyclidine (PCPy; 1-(1-phenylcyclohexyl)pyrrolidine)
 * Tenocyclidine (TCP; 1-(1-(2-Thienyl)cyclohexyl)piperidine)

Piperazine-based

 * BZP, 1-benzylpiperazine
 * mCPP, 1-(3-chlorophenyl)piperazine
 * MeOPP, 1-(4-methoxyphenyl)piperazine
 * pFPP, 1-(4-fluorophenyl)piperazine
 * TFMPP, 3-trifluoromethylphenylpiperazine, has the unique distinction of being the only drug to be emergency scheduled into Schedule I and then allowed to become legal because the DEA was unable to justify permanent scheduling

Entactogens

 * 4-MTA
 * 5-Me-MDA
 * AET, α-ethyltryptamine
 * Butylone
 * Ethylone
 * IAP
 * MBDB
 * MDAI
 * MDMA, 3,4-methylenedioxymethamphetamine
 * MDEA, 3,4-methylenedioxy-N-ethylamphetamine
 * Methylone
 * MMA
 * PMA, a highly dangerous amphetamine derivative responsible for many accidental deaths
 * PMMA, similar to PMA
 * PMEA, also similar to PMA

Stimulants

 * α-Pyrrolidinopropiophenone (α-PPP)
 * 2-Fluoroamphetamine
 * 4-Fluoroamphetamine
 * 4-Methylaminorex (4-MAR)
 * Buphedrone
 * Desoxypipradrol
 * Dimethocaine
 * Diphenylprolinol
 * Ethcathinone
 * Flephedrone (4-FMC), and its 3-fluoro isomer 3-FMC
 * Geranamine
 * MDPV
 * Mephedrone
 * Methedrone
 * Naphyrone
 * Pentylone

Sedatives

 * GBL, gamma-butyrolactone, both a precursor to and substitute for GHB
 * 1,4-Butanediol, another GHB analogue
 * GHV, gamma-hydroxyvaleric acid (4-methyl-GHB)
 * GVL, gamma-valerolactone
 * Methylmethaqualone, an analogue of the sedative methaqualone
 * Mebroqualone
 * Phenazepam
 * Premazepam
 * Diazepam

Cannabinoids

 * THC-O-acetate
 * JWH-018
 * JWH-073
 * JWH-200
 * JWH-250
 * CP 47,497 and (C8) homologue
 * CP 55,940
 * HU-210

Anabolic Steroids

 * Norbolethone
 * THG, "The Clear"
 * Madol (sometimes confusingly referred to as "DMT")
 * Methasterone
 * Prostanozol

Erectile dysfunction

 * Acetildenafil
 * Aminotadalafil
 * Homosildenafil
 * Hydroxyacetildenafil
 * Hydroxyhomosildenafil
 * Piperidino-acetildenafil
 * Piperidino-vardenafil
 * Thiosildenafil
 * Thiomethisosildenafil