Mostly Harmless Hallucinogens - Evidence From a Medical Textbook

I’ve been reading a textbook called Karch’s Pathology of Drug Abuse. It discusses all the major drug categories, their histories, their chemical structure, their effects, the various kinds of organ damage they cause, etc. There is a chapter on hallucinogens, and it turns out this category of drugs is extremely non-toxic. Below I’ll share some of the passages I’ve highlighted with some commentary. It depends on which particular one you’re talking about, but by-and-large these drugs *won’t* kill you. They have a very good safety profile. Near the beginning of the chapter, the authors say:

“Except for the designer amphetamines, none of the hallucinogens discussed is associated with unique or specific pathologic lesions.”

Translation: Out of an entire chapter on hallucinogens, only one class of these drugs (MDMA/Ecstacy and its analogs) causes physical damage to the body.

Mescaline

“No mescaline-related deaths or emergency room visits have ever been reported in any DAWN survey, and only two case reports describing mescaline-related deaths have appeared in the world literature.”

In other words, mescaline is completely non-toxic. If one of those “mescaline-related deaths” is the same one described in Paul Gahlinger’s book Illegal Drugs, it was “a man who had severe alcoholic liver disease and died from bleeding into the stomach when he vomited.” Out of millions upon millions of uses, they can only find two deaths in the entire world literature, one of which is more appropriately blamed on alcohol than on mescaline. Given the safety profile (and inserting a little bit of Bayesian reasoning), it’s extremely likely that this other death was one where mescaline use was incidental.

“No specific pathologic findings have been identified. A search of the California Poison Control System database (1997–2008) uncovered 31 single-substance exposures to peyote or mescaline. Almost all of these (97%) were intentional and the drug was taken orally, with only individual patients who insufflated mescaline powder. None of these subjects died or even required hospital care (Carstairs and Cantrell, 2010).”

This is the profile of an extremely non-toxic drug. However:

“According to the Drug Enforcement Agency, the hallucinogenic dose of mescaline is about 0.3–0.5 g and the effects last about 12 h.”

So I can see why someone might freak out and call poison control or go to the emergency room, even though they aren’t in any physical danger. This is an issue with marijuana as well. Some critics of marijuana legalization point to the number of ER visits reported in government statistics, but it needs to be remembered that these people aren’t in any physical danger. The peyote/mescaline chapter in “Illegal Drugs” says that basically someone who takes an “overdose” just vomits up the excess, so a fatal overdose is ruled out of the question. (There is apparently a lot of vomiting involved in these mescaline trips.)

MDMA

“Later in the 1950s, the U.S. Army contracted with a group of researchers at the University of Michigan to perform MDMA toxicity studies. The results of the Michigan study remained classified until 1973, when they were finally released. The studies showed that MDMA was somewhat less toxic than MDA but more toxic than mescaline (Hardman et al., 1973). MDMA was classified as a schedule I drug in 1985.”

This is kind of a subjective judgment, but I appreciate that the author is talking about *relative* risk, not  just taking the line that “anything risky is bad”, as some anti-drug rhetoric does.

“No MDMA-related deaths are listed in the DAWN report for 1999 (Kissin et al., 2000). The emergency room component of the most current DAWN report lists 8621 MDMArelated visits (CI 5,985–11,257). Whether any were fatal is not known (SAMHSA, 2006).”

With probably a million or so users and several million incidents of use, this is pretty stunning.

“In a 2006 U.K. survey, based upon medical death certificates, coroners’ reports in the United Kingdom tended to underestimate the problem of MDMA, MDA, and MBDB deaths occurring from 1994 to 2003 found a total of 394 deaths, although suicides are rare and deaths are almost always accidental. In 42% of the deaths identified, MDMA was the only drug detected. All of the other deaths occurred in polydrug abusers, making causality assessment all but impossible.”

So there is a very real danger with MDMA. It’s possible to overdose. But this is mostly a problem that prohibition has saddled us with, not a problem inherent to the drug itself.

“Once MDMA is produced, it is converted into tablets, each with a recognizable logo (see Figure 4.16). The tablets quickly develop names based upon the imprinted logo. Brand loyalties evolve, and users ask for particular tablets by name (tablets with the Mitsubishi label were once particularly popular, with a very loyal following). Some of the logos often have whimsical themes, ranging from an imprint of McDonald’s Golden Arches to the Rolex trademark symbol, the Mercedes symbol, and even the skull and crossbones. A recognized logo is, however, no guarantee of quality, safety, or purity. Once the makers have developed a following for a pill with a particular logo, they then begin substituting cheaper ingredients in the pill such as methamphetamine or even PMA (a much more dangerous drug than MDMA) (Lora-Tamayo et al., 2004).”

This would obviously not be the case in a legal market. Producers would compete on the safety and purity of the MDMA they are selling, and buyers could be reasonably sure of what they are getting. It’s impossible to have government regulators or third-party auditors testify to the purity of a drug that’s produced and sold in an illegal market. Such third-party assurances, however, are the norm in legal markets.

“The most feared complications of MDMA use are serotonin syndrome (now increasingly referred to as serotonin toxicity), hyperthermia with rhabdomyolysis, and hyponatremic encephalopathy. The first disorder is characterized by the rapid onset of confusion, diaphoresis, diarrhea, increased muscle tone, and cardiac arrhythmias. There may also be shivering, myoclonus, and increased deep tendon reflexes.”

I don’t want to understate the dangers of MDMA use. Serotoninsyndrome sounds scary as hell. But it sounds like this is mostly an effect of multi-drug use, including prescription antidepressants:

“Risks for developing the syndrome are higher in individuals taking SSRI and monoamine oxidase inhibitor (MAOI) drugs. Most adult drug users take multiple drugs, and it is worth remembering that many of these other drugs may have weak, but quite real, SSRI and MAOI activity (methadone, tramadol, dextromethorphan, and meperidine).”

I remember hearing reports that Ecstasy use “turns your brain into Swiss cheese.” I think this passage sheds some light on that claim:

“When intracranial bleeding does occur, it is usually as a consequence of a preexisting malformation such as undiagnosed aneurysm or arteriovenous malformation (Hughes et al., 1993; Auer et al., 2002; Drees et al., 2009). Several reports of cerebral infarction were published in the early 1990s (Manchanda and Connolly, 1993; Hanyu et al., 1996); few new cases have been published recently (Goldstein and Mordish, 2006). Given the very great number of users today and the paucity of new cases, intracerebral infarction or hemorrhage should not be high in the differential diagnosis. Similar considerations apply to the one report of MDMA-related spongiform encephalopathy (Bertram et al., 1999), where the victim may have used other drugs in the past.”

Emphasis mine. So in those cases where MDMA users have some kind of brain lesions or bleeding, it’s usually do to some other cause, perhaps exacerbated slightly by MDMA use.

“Even though there is a wealth of experimental evidence, much of it derived from PET and fMRI scanning of human volunteers, suggesting that MDMA is toxic to serotonergic neurons, there is no clinical evidence that humans ever develop the typical symptoms of 5-HT depletion (disorders of sleep, mood, appetite), and the most recent evidence suggests that depressive symptomology simply does not occur in occasional users (Falck et al., 2008).”

I read this as saying, you can see these anatomical effects in the lab, but you don’t actually see it out in the field. The brain scans are suggestive of a disease that doesn’t actually manifest itself in the population of users.

DMT

Tellingly, the section on DMT is very short, because the drug is fairly harmless. An incredibly intense and long-lasting version of the drug is called ayahuasca. Massive quantities of DMT are ingested, and the trip lasts an entire day. And yet deaths are exceedingly rare, with only a single death recorded in the entire world literature. Ryan Grim describes an ayahuasca trip in his book “This is Your Country on Drugs.” He describes the intense and introspective vision quest, in which his conscience convinced him to stop being a journalist. After sobering up, he promptly realized that he liked being a journalist and his “revelation” was a false one. As with other psychedelics, it can give the user false moments of clarity and false insights, but it certainly doesn’t compel them to do anything. According to Grim’s account, there’s a lot of giggling, some barfing, and some false revelations, all done in the presence of a shaman (essentially a “trip-sitter”). But nothing dangerous or permanent. False revelations are simply ignored.

“Only one alleged case of ayahuasca poisoning associated with recreational abuse has ever been reported or studied. Autopsy was performed within 24 h of death and no gross lesions were apparent. Blood levels from various sites were measured (see Table 4.10); however, these levels cannot be reliably used to determine the cause of death for a number of reasons: (1) the decedent, a 25-year-old, could well have suffered from a heritable channelopathy, but no testing was done; and (2) nothing is known about blood levels in the living or the behavior of any of these compounds after death, nor is anything known about the toxicokinetics of smoked DMT;”

“The risk of addiction is thought to be negligible (Gable, 2007). Overall, the risk compared to other drugs seems to be very low. In spite of earlier work suggesting hormonal and blood pressure changes, in the most recent human study, where freeze-dried ayahuasca was given (two doses, 12 h apart, 0.75 mg/kg), the only statistically significant findings were mild decrease in heart rate and blood pressure and a marked rise in growth hormone secretion (Dos Santos et al., 2012).”

This is a remarkably safe drug. There is no reason whatsoever to ban it.

Psilocybin

Psilocybin is the active chemical in “magic mushrooms.” Ironically, the biggest danger in consuming these is mistaking a poisonous mushroom for the (very non-toxic) psilocybin-containing variety. This is another danger that isn’t really inherent to the drug itself but is exacerbated by prohibition. No doubt some amateur mushroom-hunters have poisoned themselves, whereas a legal supplier would never sell a toxic mushroom by accident, given reputational risk and the risk of license revocation implied by such an error. Here is what Karch has to say about this problem:

“Identifying wild Psilocybe is difficult and dangerous. Psilocybin-containing mushrooms grow side by side with the poisonous Galerina autumnalis. Galerina species have rust-brown-colored spores, while the spores of Psilocybe species are gray to lilac. Some, but not all, species can be distinguished from poisonous mushrooms by their reaction to room air; when Psilocybe mushrooms are cut, they oxidize and turn blue within 30–60 min. Unfortunately, some poisonous mushrooms can do the same thing. Pathologists are much more likely to encounter cases of mushroom poisoning than they are to encounter psilocybin-associated medical problems!”

Physically, the effects are quite mild:

“After oral doses of up to 15 mg, psilocybin produces no significant alteration in heart rate, blood pressure, or neuroendocrine function, although profound psychological alterations do occur (Gouzoulis-Mayfrank et al., 1999).”

There is no discussion of mortality or long-term health effects, presumably because there just aren’t any. The authors comment on the toxic effects of every other drug discussed in the book, even mentioning when there are only a handful of deaths (or a *single* death, as in the case of ayahuasca/DMT). This is another safe drug. Legalization is a no-brainer. The textbook doesn’t mention this, but my understanding is that users develop such a fast tolerance to psilocybin that it’s impossible to use it on consecutive days. Users have to give it a break for a week or so for it to have an effect again. So it’s  not “habit-forming” in the sense of compelling the user to take more, as in the case of opioids or tobacco.

LSD

LSD is powerful even at extremely low doses, but it’s fairly non-toxic.

“In the late 1990s, interest in LSD seemed to renew, but reports of toxicity continued to remain extremely rare. The emergency room component of the DAWN report contains 2006 LSD mentions during the first half of the year 2000 and 2028 in 2009 (compared with 422,896 cocaine-related visits in the same year).”

It’s not terribly surprising that some people having bad trips ended up in the emergency room, but note the lack of death statistics (also tracked by DAWN, and mentioned throughout the book for drugs that are significantly lethal).

“When formal neuropsychological testing is performed, few, if any, sequelae can be attributed to LSD use (or to the use of any other hallucinogen, for that matter) (Halpern and Pope, 2003).”

“Sequelae” being a fancy word for “bad stuff that happens after you take drugs.” This is a fitting summary, on the last page of the chapter on hallucinogens.

“As recently as 1990, it was generally believed that no death had ever been caused by the direct action of LSD; however, several very probable cases have been reported and more than a few have required medical care.”

“Several probably cases” out of decades of use by millions of people is a pretty good safety profile.

“In 1975, “eight patients were seen within 15 min of intranasal self-administration of large amounts of pure d-LSD tartrate powder. Emesis and collapse occurred along with sign of sympathetic overactivity, hyperthermia, coma, and respiratory arrest. Mild generalized bleeding occurred in several patients and evidence of platelet dysfunction was present in all. Serum and gastric concentrations of LSD tartrate ranged from 2.1 to 26 ng/ml and 1000 to 7000 ng/100 ml, respectively. With supportive care, all patients recovered” (Klock et al., 1975). However, the situation has changed drastically since LSD was so popular and now, more often than not, one of the designer amphetamines such as 25I-NBOMe is likely to be detected.”

In the above passage, the author describes eight patients who recovered from a bad acid trip. The last sentence is saying that “LSD” sold today is likely to be something else, possibly something much more dangerous. Once again, this is not an inherent danger of the drugs themselves. The danger is an artifact of the illegal market, where it’s difficult to hold sellers and distributers to account for selling a bad product. It’s another problem that would go away if we allowed people to legally sell these substances in well-labeled dosages, so the user knows what they are taking.

This is a remarkably safe class of drugs. They also have therapeutic value. Some have been used to successfully help patients with drug or alcohol addiction. It would be great to shift people from, say, cocaine or heroin use to psilocybin use. Surely a significant (non-zero, anyway) number of existing drug abusers would make that substitution if it were easier. If we want to implement a harm-reduction approach to the drug problem, this is very low-hanging fruit. Hell, some of it is literally on the ground.

I’ve never personally used any of these. Anyone considering doing so should read anything and everything they can find before doing so. “Karch’s Pathology of Drug Abuse” is sometimes hard to read, but it’s worth doing the basic research if you’re potentially monkeying with your health. Erowid is another great source. Wikipedia is fine, so long as you check a few of the references. “Illegal Drugs”, “Saying Yes”, and “Buzzed” are some good reference books. And this post at Less Wrong is a must read. Stay safe out there, but don't fall for the propaganda. Some of these substances are either completely safe or are safe in comparison to risks that we all take on every day of our lives. Their legal status as "banned" is absurd.