Even as states across the U.S. relax laws governing real marijuana, synthetic cannabinoids—commonly known as fake weed, spice or K2—have become increasingly difficult to control. So far this year more than 5,300 incidents involving the drugs have been reported to U.S. poison control offices. That’s more than double the number of calls in all of 2013, according to the American Association of Poison Control Centers. Health departments from Alabama to New York State have issued alerts after a wave of emergencies with the drugs. In New York alone the drugs caused more than 1,900 emergency department visits from April to June.

Users smoke or inhale synthetic pot through vaporizers, and the resulting high roughly mimics the effects of marijuana but with much harsher side effects, including heart attacks, strokes and kidney damage. Synthetic drug users also sometimes become so delusional and violent that restraining them requires multiple people and the use of antipsychotics.

Producers of the drug use a continually rotating list of ingredients. And each time the federal government places a compound on its schedule of illegal substances, the suppliers replace that chemical with a new one. These ever-shifting recipes make it hard for researchers to identify new drug formulations and link them to their side effects.

Marilyn Huestis, chief of the Chemistry and Drug Metabolism Section at the National Institute on Drug Abuse, spoke with Scientific American about the history of these drugs, what researchers know about them and how they can affect the brain.

[An edited transcript of the interview follows.]

How do synthetic cannabinoids work in the brain?
We have cannabinoid receptors in the brain. They are there to respond to endogenous neurotransmitters that control things like hunger, reproductive function and memory. When people use cannabinoids—whether it is a synthetic drug like spice or [real] marijuana [with its primary psychoactive ingredient, delta-9 tetrahydrocannabinol, better known as THC], they act on the same pathway in the brain. After smoking or inhaling these substances through a vaporizer or a vape pen the drug travels right to the lungs then the left side of the heart and directly into the blood. From there it goes straight to the brain. That whole process takes very little time. The compounds strongly bind to cannabinoid receptors—primarily the CB1 receptors and CB2 receptors.

Where do synthetic cannabinoids come from?
Initially, these synthetic cannabinoids were developed by chemists to help study the brain and how it works. Papers on how these substances work in the brain were published in good journals. But clandestine labs in China and now in other places synthesized these same compounds. The compounds bind to the same receptors as THC in the brain but they are up to 100 times more potent. 

How do these drugs resemble pot?
The side effects from these drugs are similar to those of marijuana, but they are much more potent. One of the most characteristic side effects of smoking marijuana is increased heart rate. With these synthetic cannabinoids that happens to a greater degree. That’s why there have been heart attacks among people in their early teens. There have also been seizures and strokes and very strong cardiovascular effects. Like THC, these cannabinoids can also produce panic—but again, it’s more potent. 

Also of concern are the crash effects: After using cannabis people tend to get sleepy, but coming off a high with synthetic cannabinoids, there is a lot of sleepiness. We have seen problems with people driving impaired—people have stopped in the fast lane of the highway. There is also a lot more violence and aggression with these drugs than you would normally see with marijuana. Some of these synthetic cannabinoids have caused severe kidney damage, too, and that’s something we don’t tend to see much with users of cannabis.

Who is making the compounds now?
Primarily, still the Chinese, but it is also coming out of other countries. There have been some raids in India and in some of the former Soviet Republic countries in eastern Europe. I have not heard of any synthesis going on in the United States. It is so easy to sell on the Internet, and the chance of getting caught by selling on the Internet is very small. If [authorities] do find a Web site and close it down, they pop up with a new Web site. What is seized is just the tip of the iceberg. 

Federal officials have placed some of the drug’s ingredients on their most restrictive list of illegal substances (Schedule I), and that has prompted drugmakers to find substitutes for those ingredients. How do the drugs still get people high?
The compounds are continually being tweaked. Producers are trying to get around U.S. law by making small molecular changes and then they try the drugs on themselves or other people to see if they have psychoactive effects. There is no real quality control. 

Basically, you spray chemicals over any kind of plant material. The plant materials themselves actually may have activity themselves and the user never knows that. You really don’t know what you are getting at all.

What are researchers doing to help identify these drugs?
We are in a terrible situation because these new drugs keep coming out, and we only find out when there is a series of deaths or serious side effects. It’s a bit of a national emergency, it really is. I think this is going to be the problem of the future and it’s not going away. The Drug Enforcement Administration (DEA) says the profit margin on these synthetic compounds is just huge, and there are hundreds of these drugs. 

We don’t have the basic toxicology data we need. We don’t know how these drugs affect people or even how they affect animals. We want to do those studies but haven’t been able to do them yet, partly because we don’t have the basic data [the U.S. Food and Drug Administration] would require for testing them in human volunteers. The other issue is funding.

What our plan is, and I’m still hoping we can do this eventually, is to take one of these drugs—one that does not cause heart attacks or kidney failure—and study how it affects humans and then compare all the other versions in the future to that one, comparing how they bind to CB1 and CB2 receptors.

How do you identify new versions?
The drugs are only present in blood for a short period of time, so it’s very difficult to detect them. We don’t know much about how the body metabolizes these substances, but we need to be able to tie adverse events to what users took. 

We have a partnership with the DEA, and as soon as they start seeing seizures they provide the drug to us. We use human liver hepatocytes that metabolize the drug like the liver does. We feed the drug to them and identify metabolites from that process. Once we identify metabolites we can say these are the top three or five metabolites you will find with this drug so please make these standard [for law enforcement drug tests].

Separately, part of our testing is identifying the half-life of the drug. Most of these compounds have short half-lives, but if it has a long half-life, then we worry about a lot more about potential interactions with other drugs or medications and even over-the-counter supplements they might be taking. 

Where are you with research now?
For nine to 12 synthetic cannabinoids, we have already published or have in review the complete metabolic profiles and the suggested metabolites [law enforcement or emergency responders] look for. The other thing we have done is synthesized the drug that we would run in a clinical study—if we ever get to run one. 

It’s become obvious we can’t keep up with the release of all these new chemicals, so now my lab has done a lot of work with high-resolution mass spectrometry. We capture all ions present in a single sample and then analyze what metabolites are present. It’s very analytically challenging but it enables us to look for metabolites that we don’t yet know are produced [in the new formulations]. This kind of nontargeted mass spectrometry has a huge learning curve but I think this is where the field has to go. We can’t keep up with the new drugs that are coming on the market, and I think this is our only hope.