Sunday, September 25, 2016

Mostly Harmless Dissociative Anesthetics – More Evidence From a Medical Text

There is an entire chapter in Karch’s Pathology of Drug Abuse (fifth edition) covering “dissociative anesthetics.” These are drugs that put people in a detached state of mind. Some are used as surgical anesthetics. It turns out this is a very safe class of drugs. From the first page of the chapter:

 In 1999, only 93 PCP-related deaths were reported in the Drug Abuse Warning Network (DAWN) survey (SAMHSA, 2000), and even fewer were attributed to ketamine. The Substance Abuse and Mental Health Services Administration (SAMHSA) report from December 2013 cites information from the Drug Enforcement Administration (DEA) indicating that, save for one or two “hot spots” (New York and Chicago), use has declined to negligible levels (SAMHSA, 2013). Neither Salvia nor GHB has ever been mentioned in any federal report dealing with death or morbidity. Clearly, deaths from GHB overdose do occur, but they must be relatively uncommon to rate so little mention. Deaths from PCP derivatives may be more common than deaths from PCP itself.

This can be contrasted with cocaine and heroin, which both cause a few thousand deaths every year. Of course a rate per user might be more meaningful than a raw number, but clearly there aren’t a lot of deaths. PCP has a really terrible reputation as a monster drug, but 93 deaths in a country of 300 million people (admittedly very few being users) is not at all scary.

The emergency room (ER) component of the 2009 DAWN report places the number of PCP-related ER visits at 12/100,000 persons, compared to 0.6/100,000 for GHB and 0.2/100,000 for ketamine (SAMHSA, 2010). No deaths from Salvia or propofol were listed in any of the official drug surveys, although, as mentioned, cases of propofol-related deaths have been reported (Kirby et al., 2009; Han et al., 2013).

The book is full of death statistics, along with stats on ER visits. Often there aren’t enough users of the drug or enough deaths to warrant any statistics-gathering, so the author has to rely on case studies of isolated deaths. Any drug whose mortality rate is quantified by a few case studies rather than population statistics is probably pretty safe.

Phencyclidine (PCP)

I don’t want to understate the risks. Clearly PCP can cause psychotic states, and the book discusses this possibility in some detail. But then again, potential users *know* about this risk, and most people avoid the drug for this reason. By all accounts, uncontrolled psychotic episodes are relatively rare.

Episodes of fatal PCP intoxication from direct toxicity (as opposed to homicides and trauma deaths where PCP is an incidental finding) are uncommon (Noguchi and Nakamura, 1978; Budd and Liu, 1982; Poklis et al., 1990; Li and Smialek, 1996) and, in any event, blood levels in patients dying directly from the effects of PCP overlap with the blood levels seen in victims of accidental deaths (Poklis et al., 1990).

Most cases of sudden death in police custody involve abusers with many years’ history of polydrug abuse who have already undergone left ventricular remodeling. At least two reported deaths thought to involve neck hold restraint actually involved intoxicated PCP abusers (Barton et al., 1981; Mercy et al., 1990). Neck hold restraint produces carotid sinus stimulation and reflex bradycardia.

In other words, even those few deaths attributed to PCP use might be due to other causes, like a history of drug use.

What is known now, but was not known then, is that ~35% of sudden unexplained death cases and ~20% of sudden infant death syndrome cases may be explained by mutations in cardiac ion channels (cardiac channelopathies) (Mizzanti et al., 2014; Wang et al., 2014). Without DNA resequencing, it would be very difficult to say, absent any obvious signs of toxicity (such as rhabdomyolysis), that PCP and not some genetic aberration is the case of death.

This is a common theme in the book: attributing a cause of death is difficult, because people drop dead from undetectable conditions all the time.


The 1999 [DAWN] report contains 21 ketamine mentions, with an insignificant increase in the number of deaths from 3 to 16 deaths reported a year earlier, ranking ketamine in the 71st position on the DAWN drug-related deaths lists in 2000 and accounting for 0.18% of all drug-related deaths reported to the federal government that year (Kissin et al., 2000). According to the DAWN’s 2005 report, there were only 275 ketamine-related ER visits in the preceding year, and none was fatal (SAMHSA, 2006).

“DAWN” = Drug Abuse Warning Network, a government survey based on hospital surveys in select hospitals in representative cities/communities. The point here is that ketamine is a very small driver of drug-related mortality.

Ketamine is classified as a “dangerous drug,” but it has quite an extraordinary safety profile. A 1996 study on the use of ketamine as an anesthetic in the developing world surveyed 122 physicians about their experiences in operating on 12,000 patients. … One unexplained pediatric death occurred during unmonitored recovery, and one adult suffered cardiac arrest after a failed intubation attempt. Apnea, possibly related to ketamine, was reported in 10 patients and laryngospasm in six. The Red Cross in its field hospitals (Lenz and Stehle, 1984) reported similar experiences. Even in the case of a substantial overdose, the main effect seems to be prolonged sedation. Green et al. described nine cases of inadvertent ketamine overdose in children. Three of the children received five times the recommended dose, five received 10 times the ordered dose, and one child was given a dose 100 times greater than ordered (all by intravenous or intramuscular route). All nine experienced prolonged sedation (3–24 h). Except for prolonged sedation, no adverse outcomes were noted (Green et al., 1999).

Take that in for a second. Read it again a few times if you have to. The authors are saying that even a massive overdose (given to children) isn’t all that dangerous. An “overdose” (unless it’s truly massive) just means you spend more time napping. I find this amusing, because so much of the anti-drug rhetoric begins and ends with “Think of the children!” Here is a pretty damn safe drug. Children who are accidentally given a massive overdose turn out okay. Granted some of these were probably in a hospital setting with frequent monitoring, but clearly it's quite non-toxic:

Compared to other anesthetic agents, ketamine appears to possess little intrinsic toxicity. In a published review of 87 ketamine-positive deaths that occurred over a 2-year period, almost all of the positive test results were found in hospitalized patients following surgical procedures or burn treatment patients, and not a single case of death could be attributed to intoxication with ketamine (Gill and Stajic, 2000).
 Ketamine rarely causes death by itself, and if it does, peripheral blood concentrations are likely to be well over 5 mg/L in the case of acute intoxication. Drug interactions and presence of significant natural disease are more likely to be present in a forensic case. As always, the interpretation of the significance of the results cannot be made on tissue concentrations alone.


I recommend reading Illlegal Drugs by Paul Gahlinger on GHB. There is a chapter dedicated to this drug, and it goes much more into the history and sociology of the drug. Still, Karch’s Pathology of Drug Abuse offers some useful details.

GHB-related ER visits increased significantly during the 1990s, but the number of deaths attributable to GHB today has declined, at least within the United States, to a level that is difficult to estimate.

So whatever statistics exist, take them with a grain of salt.

In the past, nearly two-thirds of GHB-related ER visits were due to overdose and one-third to unexpected reactions. Sixty percent of ER visits were said to have involved the use of multiple other drugs, usually GHB in combination with ethanol (76%), cocaine (6%), marijuana (5%), and MDMA (4%) (Woodworth and DEA, 1999).

This is a common theme in drug-related morality. Poly-drug use is the driving factor. Most of these deaths involve multiple substances interacting with each other. A sensible person using a single drug at an appropriate dosage has nothing to worry about.

The body metabolizes GHB at an extraordinary rate:
 The half-life of GHB in humans is known to be approximately 20 min...

The book Illegal Drugs mentions cases of ER patients in a deep coma who wake up an hour later and walk out of the emergency room with no issues. Clearly overdoses happen, but given the high rate of metabolism, even an overdose is unlikely to be fatal. This seems to be a point of contention. The book Buzzed suggests that the fatal dose is within a factor of two of the effective dose. I suspect these “doses” are hard to quantify given that there are so few overdose deaths to extrapolate from. But beware that there is some controversy over the safety of GHB.

GHB users often coingest ethanol. That practice may be dangerous because, in animal studies, high concentrations of either drug affect the metabolism of the other. When large doses of GHB are given, ethanol elimination is reduced (Hoes et al., 1981), an effect that would almost certainly lead to higher ethanol concentrations and probably to increased GHB toxicity. The picture becomes even more complicated when other drugs are used in addition to alcohol, as is often the case (Liechti et al., 2006).

So don’t take GHB with alcohol.

GHB is commonly abused in combination with other drugs acting on the CNS [(Central Nervous System)] (Caldicott et al., 2004). For example, in Sweden, 21 of 23 deaths attributed to GHB were found to involve other substances as well, particularly alcohol and opioids (Knudsen et al., 2010).
Don’t take it with opioids, either. But if you avoid other drugs, and you know what dose you’re taking, you’re probably safe. And just to reiterate, the section on GHB ends with this comment:

Clearly, as with any forensic matter, the context of the case is paramount. Witnesses to ingestion of GHB and other substances will be most helpful. High postmortem blood concentrations alone do not necessarily prove that the drug was taken or that it caused the death. Indeed, death from GHB is relatively uncommon, and when it does occur, it is usually in conjunction with the use of ethanol and/or other CNS depressants.

Salvia Divinorum

This is a plant that’s a member of the mint family. When smoked it causes intense hallucinations and loopy behavior. (Look at some Youtube videos  of people smoking it to see what I mean.) Most users don’t enjoy it and promptly stop using, often ending with the first use.

I’ll start with the punchline, the very last sentence of the section on salvia:

No deaths from Salvia abuse have ever been reported.

This is in spite of millions of users:

 According to the “National Survey on Drug Use and Health Report,” published by SAMHSA in February 2008, an estimated 1.8 million U.S. citizens aged 12 or older reported having used S. divinorum in their lifetime. Nearly one-third of those had done so in the past year.

And this:

An epidemiologic study of 42,179 Canadian adolescents, aged 12–17 years, during the years from 2008 to 2009, found that overall 3.8% of adolescents reported using Salvia in the past year and 6.2% had used the substance in their lifetime. Surprisingly, in this study, the prevalence of 12-month Salvia use was higher than use of cocaine and amphetamine, but lower than use of ecstasy, cannabis, and other hallucinogens.

I think it’s probably a good thing that kids are using savlia *instead of* cocaine and amphetamines, taking it as a given that there is going to be some amount of drug use. Drug policy ought to take this harm reduction approach of directing people to the least dangerous drugs. That’s in contrast to the current strategy of banning everything that’s fun. Luckily, salvia is still legal in most states and countries, though some have banned it. It’s often included on lists of “legal ways to get high.”

Dextromethorphan (DXM)

This is the active ingredient in many cough medications. Some people have figured out that you can get high if you take several times the suggested dose. The effect of a large dose is qualitatively different from the effect of a small dose. (This was the topic of a South Park episode. The helpful pharmacist tells them, “Now, this is the one you want if you *really* want to trip balls.”) Deaths are rare. There were 283 deaths with “antitussives” listed on the death certificate in 2014 according to CDC statistics, but if you look at the death records almost all of these involve multiple substances. Alcohol, heroin, benzodiazepines, and prescription opioids are very common in “antitussive” poisonings; it’s not at all clear that DXM even contributed to any of these deaths. It may well be an incidental finding in most of these cases. DXM is probably pretty safe if it’s all you’re taking, and you aren’t taking a massive dose of it.

A 6-year retrospective study, from 1999 to 2004, of the CPCS showed a 10-fold increase in the rate of DXM abuse cases in all age groups and a 15-fold increase in the rate of abuse cases in adolescents. In 2004, CPCS reported 1382 DXM abuse cases. Extrapolating these figures to the national level suggests there may be millions of users, but without additional information, the conclusion must remain speculative.

It’s not at all clear that this is a big problem, considering the safety profile of DXM. I did know someone who was abusing DXM and it really did cause problems in his life. If you’re spending all your time zonked out, or you try to go into work or operate a vehicle in a zonked state, then obviously there’s a problem. But let’s be clear that there’s nothing inherently addictive about the drug, and it doesn’t seem to cause cumulative organ damage like alcohol or cocaine.

A normal dose of DXM is 15–30 mg. It is claimed that hallucinatory effects may be experienced with doses as low as 100 mg and frank psychosis at higher levels (Roberge et al., 1999; Miller 2005). Ingestion of hundreds of milligrams has been reported, with few or no significant side effects.

Because deaths involving DXM are rare and produce only nonspecific findings, such as pulmonary and cerebral edema, it is hard to say what sort of mechanism would be involved.


This is the drug that killed Michael Jackson. (Although it was inappropriately administered by his doctor.) Its use is not common and not much is known about its incidence and epidemiology:

Nothing has ever been published about the prevalence or epidemiology of propofol abuse or propofol-related deaths. According to a review paper published in 2009, there had been 38 reported deaths, most of which were the result of accidental overdoses (Kirby et al., 2009). Prevalence of abuse is highest among medical professional and allied staff (e.g., nurses and radiologists) as they have the most ready access.

So this one is a big question mark. It looks like most of the users are medical professionals who have access to a legitimate stash of the drug. Clearly it can be fatal, but without knowing the number of total users there’s no way to quantify the risk. (We don’t know what denominator goes with those 38 deaths if we wanted a death rate per 100k users.)

Here’s a common theme in the book: blood concentrations rise after death. So even something that looks like a massive overdose may not be:

As a consequence, blood concentrations measured at autopsy will almost certainly be higher than plasma concentrations during life. Consequently, there is no concentration postmortem that will indicate the likely contribution to death without a thorough review of the circumstances and associated medical and pathologic information (Kranioti et al., 2007; Kirby et al., 2009).

So some of these drugs are almost completely safe, and some of them less so. None of them appear to be quite as deadly as alcohol, tobacco, cocaine, heroin, or prescription drugs in terms of sheer numbers or even rates-per-user. They don’t seem to cause the decades-long addiction problems that these other drugs cause in their users. But they clearly aren’t very popular. Salvia is still legal in many places, but salvia use appears to be mostly a phenomenon of teenagers, perhaps acting on a dare. (Again, watch some of the youtube videos. It looks like they’re doing it for the novelty, but most aren’t really enjoying themselves.) DXM, being the active ingredient of cough syrup, is readily available, even to the kids of South Park. GHB is illegal, but given its good safety profile it should probably be de-scheduled by the DEA and outright legalized. It’s still somewhat popular as a party drug. If it’s keeping people away from heroin or cocaine, or even alcohol, that’s a good thing. Or maybe there’s a yet-undiscovered drug in this class that gives users a mellow high without any nasty side-effects. Perhaps Star Trek's "synthahol" is a yet to be discovered drug within this category. Our drug policy needs to take the approach of substituting safe recreational drugs for the dangerous ones, because the “ban everything/Just Say No” approach isn’t working. The desire to get high doesn’t magically change when you pass a law, but we can at least nudge people toward relatively safe substances. This class of drugs shows some promise in that vein. 

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