Category: Remembering

Addiction Inbox has an interview with pharmacologist David Kroll where he discusses the origin of the countless synthetic cannabinoids that have recently flooded the market as ‘legal highs’ and ‘incense’.

You may know Kroll better as the author of the long-running top-notch pharmacology blog Terra Sigillata where he has been tracking the ‘synthetic marijuana’ story since its early days.

In this recent interview he gives a fantastic brief description of how these compounds were born and became big business as ‘legal highs’.

Every area of CNS pharmacology has chemists who try to figure out the smallest possible chemical structure that can have a biological effect. In fact, this is a longstanding practice of any area of pharmacology. Huffman was an excellent chemist who in the 1990s was trying to figure out the most important part of the active component of marijuana that might have psychotropic effects. These compounds made by him and his students, surprisingly simple ones, I prefer to call cannabimimetics since they mimic the effect of the more complex cannabinoids in marijuana. These basic chemistry and pharmacology studies are what ultimately lead to new drugs in every field – a facet of chemistry called “structure-activity relationships” or SAR.

But since they are simple, they are relatively easy to make – some of Huffman’s work at Clemson was actually done by undergraduate chemistry majors. So, it was no surprise that they would be picked up by clandestine drug marketers, even though cannabis (UK) and marijuana (US) are freely available. The attraction to users was, until recently, that Huffman compounds (prefixed with “JWH-” for his initials) could not be detected in urine by routine drug testing. Hence, incense products containing these compounds have been called “probationer’s weed.”

In the interview he also discusses drug legality, drug development and prescription. Well worth checking out.
 

Link to David Kroll interview at Addiction Inbox.

For a short time, the scientific community was excited about the smell of schizophrenia.

In 1960, a curious article appeared in the Archives of General Psychiatry suggesting not only that people with schizophrenia had a distinctive smell, but that the odour could be experimentally verified.

The paper by psychiatrists Kathleen Smith and Jacob Sines noted that “Many have commented upon the strange odour that pervades the back wards of mental hospitals” and went on to recount numerous anecdotes of the supposedly curious scent associated with the diagnosis.

Having worked on a fair few ‘back wards of mental hospitals’ in my time, my first reaction would be to point out that the ‘strange odour’ is more likely to be the staff than the patients but Smith and Sines were clearly committed to their observations.

They collected the sweat from 14 white male patients with schizophrenia and 14 comparable patients with ‘organic brain syndromes’ and found they could train rats to reliably distinguish the odours while a human panel of sweat sniffers seemed to be able to do the same.

Seemingly backed up by the nasal ninja skills of two different species, science attempted to determine the source of the ‘schizophrenic odour’.

Two years later researchers from Washington suggested the smell might be triggered by the bacteria Pseudomonas aeruginosa but an investigation found it was no more common in people with schizophrenia than those without the diagnosis.

But just before the end of the 60s, the original research team dropped a scientific bombshell. They claimed to have identified the schizophrenia specific scent and got their results published in glittery headline journal Science.

Using gas chromotography they identified the ‘odorous substance’ as trans-3-methyl-2-hexenoic acid, now known as TMHA.

At this point, you may be staring blankly at the screen, batting your eyelids in disinterest at the mention of a seemingly minor chemical associated with the mental illness, but to understand why it got splashed across the scientific equivalent of Vogue magazine you need to understand something about the history, hopes and dreams of psychiatry research.

For a great part of the early 20th century, psychiatry was on the hunt for what was called an ‘endogenous schizotoxin’ – a theorised internal toxin that supposedly triggered the disorder.

A great part of the early scientific interest in psychedelics drew on the same idea as psychiatrists wondered whether reality-bending drugs like LSD and mescaline were affecting the same chemicals, or, in some cases, might actually be the ‘schizotoxins’ themselves.

So a chemical uniquely identified in the sweat of people with schizophrenia was big news. Dreams of Nobel Prizes undoubtedly flashed through the minds of the investigators as they briefly allowed themselves to think about the possibility of finally cracking the ‘mystery of madness’.

As the wave of excitement hit, other scientists quickly hit the labs but just couldn’t confirm the link – the results kept coming in negative. In 1973 the original research team added their own study to the disappointment and concluded that the ‘schizophrenic odour’ was dead.

Looking back, we now know that TMHA is genuinely an important component in sweat odour. Curiously, it turns out it is largely restricted to Caucasian populations but no link to mental illness or psychiatric disorder has ever been confirmed.

The theory seems like an curious anomaly in the history of psychiatry but it occasionally makes a reappearance. In 2005 a study claimed that the odour exists but is “complex and cannot be limited to a single compound, but rather to a global variation of the body odor” but no replications or further investigations followed.

I, on the other hand, am still convinced it was the staff that were the source of the ‘strange odour’, but have yet to get research funding to confirm my pioneering theories.

Now available in Italian L’odore della schizofrenia
(thanks Giuliana!)

I’ve just found this fascinating discussion on the psychopharmacology of ‘witches ointments’, that supposedly allowed 16th century witches to ‘fly’.

It’s from a fantastic 1998 Anesthesiology article about atropine containing plants, like belladona, deadly nightshade and hemlock, and their effects.

De Laguna was not the sole commentator about the relationship of mind‐altering drugs and witchcraft in the 16th century. In De Praestigiis Daemonum, which Freud called one of the 10 most significant books of all time, Johann Weyer (1515–1588 CE) concluded henbane was a principal ingredient of witches’ brew, along with deadly nightshade and mandrake.

According to Weyer, there were other ointments, but the essential ingredients remained the same in all. The preparations, when applied to the upper thighs or genitals, were said to induce the sensation of rising into the air of flying.

Witches were thought to anoint a chair or broomstick with the devil’s ointment, and after self‐application, would fly through the air to meet for devil worship at the sabbat. Francis Bacon (1561–1626 CE) observed that “… the witches themselves are imaginative, and believe oftentimes they do that, which they do not … transforming themselves into other bodies … not by incantations or ceremonies, but by ointments, and annointing themselves all over.”

In an extensive review of psychotropic plant ointments of the Renaissance, Piomelli and Pollio examined transcripts of witchcraft trials, writings on demonology, and the botanical composition of ointments that alleged witches used on themselves during the 15th and 16th centuries.

Despite the difficulty with accurate identification of the plants, the documents reported consistent pharmacologic effects. Further, the biochemical logic of applying these plants in a fat‐based unguent was sound, as it would promote passage of the alkaloids through the intact skin and mucosa.

The use of soot (slightly alkaline) likely would enhance the passage of organic bases because a weakly alkaline environment would be sufficient to neutralize the positive ionic charge. That this is an effective ethnobotanical technique may be seen with Peruvian coca chewers, who mix in their mouths the cocaine‐containing leaves with alkaline cinders to enhance uptake.

There is even experimental evidence for believing that a fatty base was used in these ointments; an ointment from the 13th or 14th century, found accidentally, was subjected to chemical analysis and had an animal fat content of 40%.

The full article is well worth checking out as it tackles how the plants have been used in potions and preparations through history and were a early form of anaesthesia in ancient and medieval surgery.
 

Link to Anesthesiology article.