Manufacturers of so-called designer drugs, sold under names K2, Vanilla Sky, and bath salts, have managed to keep on the right side of U.S. law in recent years. For instance, when several states outlawed a number of synthetic marijuana compounds and recreational stimulants, these items remained legal for sale elsewhere in the U.S. Then, the Drug Enforcement Administration (DEA) used its emergency powers to outlaw some of these chemicals temporarily. But chemists at both domestic and offshore enterprises producing these compounds tweaked the molecules to make analogs that were not explicitly illicit. Sales continued at retail stores and through Internet sites, including a number based in China.
But now, anyone in the U.S. who concocts, distributes, or possesses any of a host of certain designer drugs is on the wrong side of the law. That’s because last month President Barack Obama signed legislation that illegalizes essentially all synthetic marijuana compounds along with two stimulants sold as bath salts and nine hallucinogens called 2C substances. Congress tucked this provision into a bill that is now the Food & Drug Administration Safety & Innovation Act. This new statute extends user fee programs for prescription drugs and medical devices (C&EN, July 2, page 9).
Sen. Charles E. Schumer (D-N.Y.), who was instrumental in getting the synthetic drugs provision incorporated into the new FDA statute, says, “This law will close loopholes that have allowed manufacturers to circumvent local and state bans.”
By passing this legislation, Congress is “trying to prevent a whack-a-mole approach to drug enforcement,” says David J. Kroll, a natural products pharmacologist at the North Carolina Museum of Natural Sciences, who blogs on designer drug issues at CENtral Science and elsewhere.
Technically, the new law adds all synthetic marijuana compounds, two bath salts drugs, and nine 2C hallucinogens to a list called Schedule I in the Controlled Substances Act. According to DEA, the tightly controlled Schedule I substances “have a high potential for abuse [and] have no currently accepted medical use in treatment in the United States.”
Schedule I includes a number of well-known illicit drugs such as marijuana, heroin, lysergic acid diethylamide (LSD), peyote, and 3,4-methylenedioxymethamphetamine (Ecstacy). Convicted traffickers of Schedule I substances face years to decades in prison and fines that can run into the millions of dollars. Scientists who want to conduct legitimate research with Schedule I drugs must undergo a strict registration process with DEA.
Most of the substances just added to Schedule I were invented in the past 40 years. However, their popularity among recreational users is relatively recent, exploding in 2011, a DEA spokeswoman says.
The 57 poison centers in the U.S. began receiving calls about people having serious, life-threatening reactions to synthetic marijuana in 2009 and to bath salts in 2010, says Rick Dart, president of the American Association of Poison Control Centers.
“In 2010, poison centers nationwide responded to about 3,200 calls related to synthetic marijuana and bath salts,” Dart says. “In 2011, that number jumped to more than 13,000 calls; 60% of the cases involved patients 25 and younger.”
The term synthetic marijuana refers to a mixture of legal herbs and spices sprayed with compounds similar to the psychoactive constituents in marijuana. Termed cannabimimetic agents in the new law, these chemicals are also called synthetic cannabinoids.
Faux pot, labeled “not for human consumption,” has been sold in retail shops and over the Internet as incense under names such as K2 or Spice, DEA says. The agency in late 2010 used its emergency authority to add a handful of cannabimimetic compounds temporarily to Schedule I.
Cannabimimetic agents that have been used to make synthetic marijuana are full agonists for cannabinoid receptors in cell membranes, Kroll says. In contrast, Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of marijuana, is a partial agonist. This means that the synthetic cannabinoids create more intense effects than THC and can cause pronounced feelings of anxiety and paranoia in users, he explains.
“This freaks people out and sends them to emergency rooms” or worse, Kroll says. For example, extreme paranoia after smoking synthetic marijuana led an 18-year-old in Iowa to commit suicide in 2010, according to published news reports.
In the past decade or so, cannabimimetic compounds caught the attention of recreational drug suppliers, Kroll says. Their first use as recreational drugs started in Europe. European nations began to ban these chemicals, and manufacture and sales moved into North America, he says. A DEA laboratory first detected cannabimimetic agents in herbal incense products in November 2008, says the White House Office of National Drug Control Policy.
Several of the substances mentioned by scientific name in the new law as examples of this class of chemicals were research compounds discovered in the 1990s by academic groups studying cannabinoid receptors. The research groups were led by John W. Huffman, a now-retired Clemson University chemistry professor, and Alexandros Makriyannis, currently a Northeastern University professor of biotechnology and bioorganic chemistry. An example of these chemicals is 1-pentyl-3-(1-naphthoyl)indole, a substance first synthesized by Huffman’s group in 1995. It is known as JWH-018 because it was the 18th of these compounds the group made.
The law also names two chemicals not associated with these researchers: 1-pentyl-3-[(4-methoxy)-benzoyl]indole, known as SR-19 and RCS-4, and 1-cyclohexylethyl-3-(2-methoxyphenylactetyl)indole, known as SR-18 and RCS-8. The SR and RCS designations for these compounds resemble the nomenclature used for compounds made in Huffman’s and Makriyannis’ laboratories. But the initials are merely street names “and cannot be linked to a legitimate researcher or organization’s compound library,” DEA tells C&EN.
Many more cannabimimetic compounds do—or could—exist. According to the United Nations Office on Drugs & Crime: “A creative chemist would be able to easily synthesize hundreds of similar compounds with a high probability of showing cannabimimetic action by the addition of a halogen, alkyl, alkoxy, or other substituents to one of the aromatic ring systems.”
Because of these possibilities, the UN agency adds: “Scheduling single substances will not be effective as there are hundreds of compounds which can quickly replace the ones being controlled.”
Congress realized this, and the new law broadly covers any material or mixture that contains any amount of cannabimimetic agents, their salts, isomers, or salts of isomers.
This move adds hundreds, if not thousands, of chemicals to Schedule I, Kroll tells C&EN. And it creates a “living nightmare” for analytical chemists involved in law enforcement, he says. The new statute will require the generation of reference standards for all cannabimimetic agents, including those with the same molecular weights, he says.
In addition to cannabimimetic compounds, the new federal statute outlaws two synthetic cathinones—mephedrone and 3,4-methylenedioxypyrovalerone (MDPV)—that have been sold as bath salts or “plant food” but have been used as recreational stimulants.
Popular among teens and young adults, the chemicals have been sold under names such as Vanilla Sky and Purple Wave, according to DEA. Users report the effects of these substances are similar to those of cocaine, Ecstasy, LSD, or methamphetamine, the agency says. These drugs are sometimes called empathogens because users report feelings of empathy.
The Office of National Drug Control Policy says use of these compounds is associated with “increased heart rate and blood pressure, extreme paranoia, hallucinations, and violent behavior, which causes users to harm themselves or others.”
The new law also bans nine dimethoxyphenethylamines that are synthetic hallucinogens. Most of the nine were first synthesized by biochemist and pharmacologist Alexander T. (Sasha) Shulgin, who tested many of the compounds he developed on himself. Shulgin dubbed the dimethoxyphenethylamines “2C” after the two-carbon bridge linking the benzene ring and amino group in these compounds. He described dozens of similar compounds in a 1991 book, “PiHKAL (Phenethylamines I Have Known And Loved): A Chemical Love Story.”
Some of the 2C drugs produce empathetic feelings in users as well as LSD-like hallucinations and visual distortions, DEA says.
As is the case with synthetic marijuana and the bath salts chemicals, the use of 2C chemicals as recreational drugs has grown in recent years. In 2006, federal, state, and local forensic laboratories analyzing material for drug enforcement cases reported only 28 instances of 2C compounds. This number grew to 228 in 2010, the agency says.
One of these now-outlawed drugs—2-(2,5-dimethoxy-4-ethylphenyl)ethanamine, commonly called 2C-E—caused the 2011 deaths of a 19-year-old in Minnesota and two 22-year-olds in Oklahoma, DEA says.
Since the new law was enacted, DEA has wasted no time in cracking down on designer drugs. In late July, DEA and U.S. Immigration & Customs Enforcement led federal, state, and local law enforcement officials in the first nationwide raid on designer drug retailers, wholesalers, and manufacturers. The sweep netted 90 arrests, more than 5 million packets of synthetic marijuana and synthetic cathinones, and materials to make an estimated 13 million more packets.
DEA acknowledges that not all of the designer drugs seized in the effort are listed on Schedule I. But the agency says prosecutors will rely on a federal law that allows these nonlisted compounds to be treated like a controlled substance if they are proven in court to be chemically or pharmacologically similar to a Schedule I drug.
DEA Administrator Michele M. Leonhart vows to fight the spread of designer drugs, regardless of the creativity of producers who have managed to skirt the law in the past. Leonhart says, “We are committed to targeting these new and emerging drugs with every scientific, legislative, and investigative tool at our disposal.”