Smiles: 2C-I or not 2C-I?

Designer drugs in the news

This is tiring enough for a science writer. I cannot imagine being in law enforcement.

The pace at which psychoactive designer drugs are appearing on the street is about as challenging for me as keeping up with dietary supplement companies that adulterate their products with actual prescription drugs (an area I’ve been covering since 2007 but a practice that goes back decades.)

This week’s designer drug hullabaloo comes to us courtesy of last week’s frightful murder-suicide by Sons of Anarchy actor, the late Johnny Lewis. ABC News is reporting today that Lewis was reportedly taking “Smiles,” a street name for 2C-I, the phenethylamine hallucinogen first synthesized by Alexander Shulgin.

2C-I is more properly known as 2,5-dimethoxy-4-iodophenethylamine. This structural analog of mescaline (3,4,5-trimethoxyphenylethylamine) was among a litany of designer drugs that was criminalized in the US back in July with the Synthetic Drug Abuse Prevention Act of 2012 (Cheryl Hogue had a nice discussion of the Act, including some quotes from yours truly, in the 27 August 2012 issue of C&EN.).

25I-NBOMe or 2C-I-NBOMe as shown in Nichols et al. as cited in the text.

But the psychedelic drug information website, Erowid, is proposing that the effects reported for “Smiles” are more likely due to the compound 25I-NBOMe (or 2C-I-NBOMe): the more complex and much more potent 5-HT2A agonist, 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine.

The radiolabelled version of this drug was made, it turns out, by some radiochemistry colleagues down the road at RTI International and characterized by Purdue pharmacologist, David E. Nichols (Bioorg Med Chem 2008;16:6116-6123 DOI:10.1016/j.bmc.2008.04.050.

Depending on your institutional access, the DOI may not work so you can view the PDF here through the NIH Public Access Program.

Again, here is a case of where a laboratory tool has been co-opted by the recreational drug market, a case that Nichols himself lamented in Nature at the beginning of 2011.

Why should the non-chemist or general reader care about this structural gobbledygook?

25I-NBOMe/2C-I-NBOMe is about 20 times more potent than 2C-I in binding those 5-HT2A receptors in the brain, the same ones that mediate the psychedelic effects of old-fashioned hallucinogens such as LSD and mescaline. This means that it takes a very low dose of this chemical — low, sub-milligram doses — to experience rather complex sensory and behavioral effects.

Here at Erowid is a user experience after a very high dose reported at 3.75 mg – the individual had previously reported a “very enjoyable night” after taking only 0.75 mg.

With an unemotional view of the user’s experience, I find it stunning that the human brain is capable of such complex sensory activity after being tickled with some synthetic molecules.

But in the context of the Lewis murder-suicide, one would not be surprised for an inexperienced user to be led to commit such heinous acts in reality.

Unfortunately, it takes a high-profile case like Lewis’s for mass media to pay attention to what law enforcement officials deal with on the streets daily (and nightly). And after all the work on the Synthetic Drug Abuse Prevention Act of 2012, 25I-NBOMe is not explicitly criminalized.

Analog Act, anyone?


Author: David Kroll

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  1. I don’t understand why people are so quick to think correlation = causation, especially someone who is thoroughly ensconced in the sciences. This is surely an existing psychological condition of his. So few drugs can make you cross the line of not killing people, to killing someone and then yourself.

    In all my years watching my friends first take the very pure form of 2C-I and then the more watered down stuff as authorities cracked down on it, not a one has been in any way aggressive. The effect the drug has, is as a depressant. You’d much rather be far away from other people, and to just sit, and do nothing. If this guy was actually on 2C-I, while murdering someone, it would’ve been working against him with all its might, to make him leave human contact and go sit in a quiet, secluded space and look at the pretty things.

  2. Ash, I didn’t mean to imply causation. As news reports and Erowid have stated, we don’t even know what compound he allegedly took.

    As a pharmacologist, I was at first puzzled by the discord between his reported behavior and user experiences posted on Erowid for either compound.

    But as you appear to be familiar with people who’ve taken these drugs, you’ll recognize that the nature of the experience is dependent in part on the basal mental state and environment of the user. I don’t want to speculate more than I already have but others have reported that Lewis may have had bipolar disorder.

  3. Shouldn’t you at least wait for the toxicology results? This is a really irresponsible article.

    Where is the evidence that the drug has ever caused people to go on violent rampages?

  4. Rudy, as with Ash, you’ve not convinced me that what I’ve written is irresponsible. I can certainly see how some of my final sentences might be implied as considering causation.

    However — and I’m not sure if you’re a regular reader — I’ll often comment on stories from the mainstream media where issues of chemistry and pharmacology might need clarification. In this example, I note specifically that the drug, if any, has yet to be identified. That’s even before we get to the issue of causation.

    But since these chemicals and their initials and acronyms are all over the place, I’m fulfilling my personal mission of providing readers with supplemental information on the drugs that are cited. I try not to speculate too far but it’s sometimes unavoidable when commenting on claims made in the mainstream media.

    Based on what I know about 2C-I and 25I-NBOMe being hallucinogens, I can hypothesize significant interindividual variation in qualitative responses to ingesting these substances. For some, like the Erowid contributor cited above, it was a personally transforming and positive experience. However, hallucinogen experiences are greatly influenced of prevailing mental state and physical environment. Mr. Lewis may have had different personal and environmental circumstances than the experienced user. But I agree that this is only important if he did indeed take one of these substances.

    Otherwise, please consider this article a mini-explainer on two designer hallucinogens that are increasingly cited in news reports.

    Thanks so much for taking the time to comment.

  5. As one of the original researchers involved in determining the (in vitro) activity of the “NB” series of phenethylamines, I must commend the author of this article for a fair and rational assessment of this horrible situation. I understand Ash and Rudy’s concerns; discussions about hallucinogens are a very emotionally charged subject. Many people have found very positive experiences using these substances. On the other hand, there are plenty of stories of very horrible experiences. It is too easy to focus on the extremes. I agree with the author that mental state and setting are incredibly important contributors to the overall effect of such strong psychoactive agents. Drugs do not make people crazy, but they certainly do not help those with a lose grip on sanity hold on any tighter.

    It is essential that someone who is interested in these substances know themselves, know their drug, and know their source (to quote the wonderful site Erowid once again). I personally do not agree with the criminalization of these substances. But without proper information and/or regulation, it is far too easy to misidentify or mis-dose with these compounds with minimal to no testing data available.

    Thank you again to the author for the clarification of the press hullabaloo.

  6. I feel it pertinent to mention that, as of this year, no deaths have ever been confirmed as caused by 2C-I; anecdotal evidence online suggests that users taking many times the active dose level have lived. (Note that I am not encouraging irresponsible use of any drug, hallucinogenic or not. In fact, I’m strongly in favor of the opposite; extremely careful use with an emphasis on safety)

    It’s unfortunate that the mass media has latched onto this as part of their blind crusade against any and all drugs. With something as relatively obscure as a 2C-x series phenethylamine, the public is apt to believe anything the news throws at them. All in all a regrettable situation.

    As an aside, I found this article to be substantially less biased than anything in the mass media. Props to the author for avoiding premature conclusions.

  7. David Kroll: Thank you for your thorough and nuanced coverage of novel psychoactives. Your knowledgeable viewpoint is a breath of fresh air.

    While searching on the extent to which media outlets are conflating 2C-I and 2C-I-NBOMe — because of speculation as to the identity of “Smiles” — I came across your Oct 1 piece as the very top search result. The entire Johnny Lewis story is reminiscent of the ‘bath salt cannibal’ story of early summer, another heinous act pinned on a rumor about an unspecified drug with a goofy name. (It wouldn’t be surprising if the tox report for Lewis reveals no novel chemical on board.)

    Meanwhile, several fatalities have plausibly been linked to 2C-I-NBOMe (“25i”) since June of this year, although reliable details remain scarce, as is typically the case with “research chemical”-related deaths:

    In any case, thanks again for sharing your voice online.

  8. Whoever wrote this blog, is for laws against people using drugs. Therefore he is an enemy of freedom and a piece of shit.

  9. Hmmm. Perhaps you need a drug that’s calming and cultivates introspection.

  10. Murder suicides? Try looking at SSRIs, which are implicated in most mass-murder suicides in the news.
    Glad to see my earlier comment censored.


  1. NBOMics: The Science of “Smiles” | Take As Directed - [...] earlier version of this post appeared originally on 1 October 2012 at Terra [...]