Archive for the ‘ Journal Papers ’ Category

Leminger’s Scalines

Otakar Leminger was a little-known Czechoslovakian chemist who worked for years in industry and lived on the banks of the Elbe River in Ústí north of Prague. When he retired in the early 1970s he published a paper entitled “A Contribution to the Chemistry of Alkoxylated Phenethylamines” in which he describes the synthesis of several novel phenethylamines which he tested on himself to determine activity.

(1) allylescaline, 3,5-dimethoxy-4-allyloxy-phenethylamine (2) proscaline, 3,5-dimethoxy-4-n-propoxy-phenethylamine (3) escaline, 3,5-dimethoxy-4-ethoxy-phenethylamine (4) MAPEA, 3-methoxy-4-allyloxy-phenethylamine (5) MEPEA, 3-methoxy-4-ethoxy-phenethylamine

We can classify the compounds he discussed into two groups depending on the number of ring substitutions. Allylescaline, proscaline, and escaline have three while MAPEA and MEPEA have two. Generally phenethylamines with two ring substitutions are not active, but Leminger had found some exceptions. This knowledge might have been lost to time if not for the fact that Stanislov Wistupkin brought the paper to the attention of Alexander Shulgin.

[MAPEA and MEPEA are some] of the few phenethylamines with only two substituents that show even a hint of central activity. And there is an interesting story attached. I got a call out of absolutely nowhere, from a Stanislov Wistupkin, that he had discovered a number of new psychedelic drugs which he would like to share with me. They were simple phenethylamines, one with an ethoxy group at the 4-position, and one with an allyloxy group there. Both, he said, were mood elevators active between 100 and 300 milligrams. One of them was a material called MEPEA, and the other one was 3-methoxy-4-allyloxyphenethylamine, or MAPEA. When I did meet him in person, he gave me a most remarkable publication which had been authored some ten years earlier, by a person named Leminger, now dead. It was all in Czech, but quite unmistakably, right there on the third page, were the structures of MEPEA and MAPEA, and the statement that they were active at between 100 and 300 milligrams.

– Alexander Shulgin

MAPEA and MEPEA are only mildly active and interesting mostly in the sense that they appear to be the exception to the rule that phenethylamines with two ring substitutions are inactive. Leminger also created several mescaline variants with three ring substitutions by modifying the methoxy group at the 4 position and replacing it with an allyloxy, propoxy, or ethoxy group. The resulting compounds allylescaline, proscaline, and escaline were then tested on himself and found to be much more potent and intriguing.

Physiological effects of the compounds were examined only approximately on my body. The sulphate salts of MEPEA and MAPEA in doses 0.1-0.3 g were mild mood-elevators and were also cough calming agents. Allylescaline, proscaline, and escaline were much more active. Qualitatively there wasn’t a big difference among them and quantitatively their effect decreased: allylescaline was more potent than proscaline, and proscaline more potent than escaline. As an example the allylescaline experience is described:

“One hour after a 20 mg dose of allylescaline: perhaps slight vertigo, light drunkeness and pleasant excitation with locomotion need was observed. Eye perceptions were pricked up, colours seemed to be more warm and objects more plastic. Surroundings were much more interesting than usual. Colourful hallucinations were observed in the dark. Moreover, a calming effect to the breathing system and some kind of constriction of the digestive system was observed. Sleep at night was restless with megalomaniacal fantasies. Even 12 h after administration the effects were present. More serious studies of physiological activity are in contemplation.”

– Otakar Leminger

Leminger was the first to synthesize and consume allylescaline, the most potent of the mescaline derivatives explored. He was able to identify active phenethyamines with only two ring substitutions, a notoriously unproductive class of compounds. Did he conduct additional experimentation and screening beyond that detailed in this paper? No other publications by Leminger relating to psychedelic compounds are known.

Might there be other treasures that he had discovered, and never published? Was young Wistupkin a student of his? Are there unrecognized notes of Otakar Leminger sitting in some farm house attic in Northern Czechoslovakia? I extend my heartfelt salute to an almost unknown explorer in the psychedelic drug area.

– Alexander Shulgin

Otakar Leminger, A Contribution to the Chemistry of Alkoxylated Phenethylamines – Part 2. Chemicky Prumysl 22, 553 (1972).

Alexander Shulgin, #2 Allylescaline. Phenethylamines I Have Known and Loved, Transform Press (1991).

Alexander Shulgin, #123 MEPEA. Phenethylamines I Have Known and Loved, Transform Press (1991).

Biosynthesis of 4-Substituted Tryptamine Derivatives

Biological organisms are wondrous little molecular factories, their enzyme catalyzed reactions often accomplishing in a single step what would confound a chemist in a well-stocked laboratory. Researchers have attempted to harness these biosynthetic pathways to create complex molecules not easily synthesized by conventional methods.

Psilocybin is produced via a biosynthetic grid where enzymes act on various closely related intermediate compounds in turn. The enzymes do not appear to be particularly picky about the compounds they modify. For instance, dimethyltryptamine (DMT) is hydroxylated to 4-HO-DMT naturally in psilocybin mushrooms. Other precursor compounds like tryptamine and methyltryptamine are also hydroxlyated to 4-hydroxy-tryptamine and 4-hydroxy-methyltryptamine respectively.

If an entirely new synthetic tryptamine of similar structure was introduced to these mushrooms, would the same enzymes act on it? This could produce a new and unique psychedelic compound where some of the heavy lifting of synthesis is accomplished by the biological expertise of the mushroom itself and not by conventional laboratory chemistry.

Jochen Gartz decided to attempt this by adding diethyltryptamine (DET, a close relative of DMT) to the fruiting body of psilocybe cubensis. He hoped that it would be hydroxylated to 4-HO-DET, or possibly phosphorylated even further to 4-PO-DET. He first colonized a mixture of cow dung and rice grain with psilocybe cubensis, and then injected it with a solution of DET. Within four weeks mushrooms were produced, and five total flushes of mushrooms were obtained.

First Second Third Fourth Fifth
4-HO-DET 2.5% 0.2% 3.1% 3.3% 2.1%
4-PO-DET 0.8% 0.01% 0.02%

all values % by weight of dry mushroom

The project was a success, with significant amounts of 4-HO-DET produced. No DET was found in the dried mushrooms. A mass balance was not conducted to determine the efficiency of the conversion and possible losses in the fruiting body itself. The demonstrated non-selectivity of the enzymes in psilocybe cubensis toward other tryptamine derivatives opened to the door to the possibility of producing truly exotic and difficult to synthesize compounds such as 4-HO-5-MeO-DMT.

Despite this little additional data is available on the tryptamine derivatives that are able to be substituted in the fruiting body and the repeatability of the experiment. Some have found little success, noting only a decrease in the size of the mushrooms produced. Other attempts have discovered perhaps a qualitative difference in potency and character of the psychedelic experience, but this has not been substantiated by quantitative measurement.


Biotransformation of tryptamine derivatives in mycelial cultures of Psilocybe
. Gartz, J. Journal of Basic Microbiology, Volume 29, Issue 6, Pages 347-352 (1989).

Why Does Cannabis Potentiate Psychedelics?

It’s an effect that many psychedelic users are familiar with – at the tail end of trip, with the experience waning, smoking cannabis will tend to increase the psychedelic effects and “bring the trip back”. Similar effects occur on the comedown of drugs like MDMA. Why does this happen?

It appears that this may be a result of the interrelationship between the brain’s natural cannabinoid receptors and the GABA system.

Nerve cells are designed to fire repetitively, and are subject to a barrage of stimuli. The brain prevents itself from spiraling out of control into hyperexcitable states by inhibition, a way of “turning down the volume” in the brain. The major workhorse for this is gamma animobutyric acid, or GABA. In a strange parallel, the brain synthesizes GABA in one step from glutamate, the brain’s major excitatory neurotransmitter.

We know that cannabis gets us “high”, that it produces a general excitatory effect across many areas of the brain. First this was thought to be a result of cannabinoid (specifically CB1) receptors being expressed on glutamate receptors. This was not the case. Instead, they appear to be almost exclusively expressed on GABAergic neurons where they have an inhibitory effect.

So it seems that cannabis inhibits the inhibitor, and ends up having a general excitatory effect. In the same manner that a benzodiazepine or alcohol may dull a trip via direct GABA agonism, cannabis may increase the effects of a waning psychedelic due to GABA inhibition.

Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations. N. Hajos et. al. European Journal of Neuroscience, Vol. 12, pp. 3239-3249, 2000.

Grid Biosynthesis of Psilocybin

The biosynthesis of psilocybin in psychedelic mushrooms is a multi-step process, and the precise mechanism is debated by many authors. The essential amino acid l-tryptophan undergoes several modifying reactions (decarboxylation, N-methylation, 4-hydroxylation, and O-phosphorylation) but the specific order is unclear. A series of steps similar to the following is generally accepted.

Experiments with radiolabled precursors have shown that this is likely the primary path to psilocybin, however, labelled 4-hydroxytryptamine was also shown to be incorporated into the produced psilocybin indicating the possibility of an additional biosynthetic pathway. Other alkaloids present in psilocybin mushrooms such as baeocystin or norbaeocystin are not explained by this single pathway as well.

An elegant alternative has been proposed. What if instead of a single path and a set order of modifying reactions, there were multiple paths to psilocybin – with branching edges that led to baeocystin and norbaeocystin? The enzymes would compete and feed back among each other in a biosynthetic grid that preferred to produce psilocybin and psilocin but also produced small amounts of baeocystin and norbaeocystin as typically seen in nature.

There is no longer a preferred order to the modifying reactions, except for the obvious that 4-hydroxylation must precede O-phosphorylation. There are three paths to psilocin and psilocybin (the predominant alkaloids in psychedelic mushrooms), two paths to baeocystin (found in lesser concentrations than the two signature alkaloids), and one path to norbaeocystin (found in the lowest concentrations, if it is detectable at all). The number of paths does not indicate the absolute likelihood of producing a certain alkaloid, but it can be seen as a measure of resiliency. The precise weighting of each connection in the network is not clear at this point, or even if a steady state model would be an appropriate approximation.

Biosynthesis of Psilocybin. Part II: Introduction of Labelled Tryptamine Derivatives. S. Agurell and J. Lars G. Nilsson. Acta Chemica Scandinavica 22 (1968), 1210-1218.

Baeocystin and Norbaeocystin: New Analogs of Psilocybin from Psilocybe baeocystis. A.Y. Leung and A.G. Paul. Journal of Pharmaceutical Sciences, Vol. 57, No. 10, October 1968, 1667-1671.

Tryptamines as Ligands and Modulators of the Serotonin 5-HT2A Receptor and the
Isolation of Aeruginascin from the Hallucinogenic Mushroom Inocybe aeruginascens
. Niels Jensen, Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultäten der Georg-August-Universität zu Göttingen, 2004.

Clarifying the Confusion Regarding LSD-25

The following article was published in the mid-1960s as an attempt to provide an educated response to the increasing hysteria about LSD use in the popular media of the time. It proposes a model of responsible psychedelic use through an understanding of the experience itself, factors affecting the experience, and typical routes of misuse.

An edited version follows, and a link to the original paper may be found at the end of the post.

In recent months, both the lay and medical press have been filled with warnings about the dangers and harmful effects of the hallucinogenic agents such as LSD-25, mescaline and psilocybin. These warnings have risen in response to flagrant misuse of the substances by illicit operators using black-market materials for parties and “kicks,” and by irresponsible investigators who, enthralled with the remarkable possibilities of these chemicals, have sponsored and encouraged their widespread use under improperly controlled conditions without medical supervision.

In view of the substantial promise which even a cursory study of the work of the leading investigators in this field reveals, it is puzzling that there should be so little acceptance of the usefulness of the hallucinogens. Following are probably the outstanding reasons:

1) Lack of understanding of the drug experience: The hallucinogens (more properly called psychedelic agents when used to explore new understanding of the mind) open up dimensions of consciousness with which few therapists are familiar. The heightened sensitivity and enhancement of sensory modalities, the reliving of events in time and other dimensionless phenomena, and the oft-reported profound philosophic and universal experiences, tend to lie outside the therapists’ conceptual frame of reference. By denying these experiences, or attempting to restrict the experience to his own theoretical framework, the therapist can produce great conflict in the subject, and cause him to reject important parts of the experience or force him into delusional solutions.

2) Lack of knowledge of factors affecting the experience: Contrary to the belief of many investigators, the hallucinogens do not produce experiences but inhibit repressive mechanisms that ordinarily operate and simply allow subjects to explore the contents of their own minds. The nature of his exploration will depend on a) the mental content, the subject’s individual personality, conditioning, attitudes, values and beliefs; b) his preparation for the experience, which determines in part how he will use the opportunity; and c) his environment during the experience, which very appreciably affects how he will deal with the material he touches on and the opportunities afforded. Most investigators now agree that preparation and setting profoundly affect the subject’s experience, and the presence of supportive, understanding, accepting companions is essential to a comfortable and rewarding session.

3) Misuse of the hallucinogens: Unfortunately, the dramatic appeal of the psychedelic experience has attracted many elements of the community–the “beatnik” crowd seeking new experiences or escape from the established and the humdrum, the unsavory elements sensing an opportunity to expand narcotic traffic, and persons genuinely seeking greater knowledge. There are included many unstable persons seeking a ready solution to their difficulties, which has led to flourishing black-market trade in the psychedelics, as well as widespread, uncontrolled clandestine usage, in settings that afford little in the way of safeguards. It is from precisely such illicit usage that has come the bulk of the reports of harmful outcomes.

Even professional investigators have sometimes used these substances improperly, which undoubtedly accounts for the absence of support for research in these fields. Such misuse includes:

Inadequate preparation: If the nature of the experience and the factors affecting it are not properly understood (as mentioned above), then the subject is unlikely to be in a frame of mind to take full advantage of the exploration the experience affords.

Improper support to subject: A clinical or judgmental attitude or too ready a desire to analyze or interpret the patient’s experience will inhibit the experience seriously and may cause grave discomfort. The impact of the therapist holding conceptual views that do not encompass what the patient is experiencing has already been discussed.

Too frequent use of LSD: Regardless of the content of the experience and whether or not it is interpretable, every exposure of the deep layers of the mind produces material which must then be assimilated and integrated by him into his personality structure. This takes time, and can only be done in the process of facing life experiences. To have LSD experiences one on top of another can so swamp the psyche with data that dissociation is the inevitable result. The object of any educational experience is to produce data for more successful living, and to adulterate one with additional data before it has been properly assimilated not only distorts all the data, but can result in great confusion.

Improper handling of patients: By not understanding the powerful subjective states experienced under LSD, uninformed therapists or companions can wreak considerable havoc. Subjects left alone can sometimes become quite frightened, or can escape and commit harmful acts. Those permitted to drive while still experiencing imagery are dangerous to themselves and others. Insensitive companions who do not detect the extremely hostile or destructive feelings of the subject may not be ready with restraints when necessary.

Improper dosage: Subjects vary appreciably in their sensitivity to LSD, and in the rigidity of the intellectual defenses to be penetrated. Consequently, the dosage must be adjusted to the individual patient. Under-dosage leads to an unsatisfactory experience, where the patient is unable to break through to a satisfactory resolution of his problems. Far more dangerous is pronounced overdosage, where subjects may be driven into ranges of experience for which they are not prepared or willing to accept, so that they may become considerably unbalanced as a result of the experience.

Overenthusiastic response: Just as damaging as the ignorant and inept administrators of these drugs are those who have become so enthusiastic about them that they have lost their sense of rational judgment. It is not unnatural for those who have had the privilege of experiencing profound philosophic, perhaps even spiritual, truths to be elated about them. But by the same token, it would appear that the more one has learned about the nature of things, the greater is one’s responsibility to society. And it seems only natural that the greater one penetrates beyond the habitual frames of reference, the more time and work and effort is required to assimilate such profound truths into one’s daily life. Apparently there are those who having discovered a fairly simple way to stand on those great pinnacles of knowledge, choose to return to them frequently and enjoy them rather than to go to the effort of readjusting their personalities to be in line with the new truths discovered. The consequences of these repeated high dosages seems to be the twofold result of deteriorated judgment and impaired perception and communication on the usual level of operation. The ability to work creatively within the structures of society seems lost, and inflation and feelings of omnipotence, followed by revolution or withdrawal from society are likely.

By far the greatest damage has been caused by the illicit use of the hallucinogens. Lay interest has been great, both through fascination with the exploration of new experience and knowledge, and as a means of fulfilling special self-interests. Black market usage of LSD is widespread, and becoming an ever greater problem. The most effective counter-measure to improper and uninformed use of these agents is forward and aggressive medical leadership. Should the intense public interest in these substances as new avenues to increased self-understanding and general knowledge prove justified, then the medical profession has an obligation to see that all factors concerning the use of these substances are well known, and that the proper circumstances for their use be well defined and provided.

In summary, there is substantial evidence that many avenues may be opened up by research with the psychedelics, both in developing new treatment methods and improving the understanding of the human mind. Hazards can be reduced to negligible considerations through informed use. In addition, proper medical knowledge is urgently needed to curtail widespread illicit use. In view of these factors, it is hoped that more intensive investigation of these powerful new tools will take place.

Savage, C., and Stolaroff, M.J. Clarifying the confusion regarding LSD-25. The Journal of Nervous and Mental Disease, Vol. 140, No. 3. 1965.

The Mirrored Magic of MDMA

MDMA is one of the most popular illicit drugs in the world, and is unique relative to other stimulating drugs of abuse in that it possesses significant therapeutic potential and is less behaviorally reinforcing. Effects can be described as similar to both stimulants and classical psychedelics. This appears to be more than a simple qualitative description however, as the very geometry of the MDMA molecule seems to produce two distinct drugs.

It is easy to forget when looking at flat diagrams of molecules on paper, but these compounds exist in a three dimensional world. One of the consequences of this is the concept of chirality, or “handedness”. Both your left and right hand contain fingers, a palm, and a thumb which appear to be assembled in the same way – but they are not the same. We can put both of our palms downward – but our thumbs point in different directions. If we point our thumbs in the same direction, one palm faces up and the other down. No matter how hard we try, we cannot wave our hands around and make them line up together perfectly.

Something similar can happen to sufficiently complex molecules, and MDMA is one of these. There are two geometrically distinct enantiomers of MDMA.

R(-)-MDMA Rectus (Latin for right) rotates polarized light counterclockwise (-) in a pure sample
S(+)-MDMA Sinister (Latin for left) rotates polarized light clockwise (+) in a pure sample

Racemic MDMA is “normal” MDMA, a mixture of both.

In the late 1970s, Alexander Shulgin began to collect data about the subjective effects of these stereoisomers of MDMA. Various doses of R(-)-MDMA, S(+)-MDMA, and racemic MDMA were given to volunteers in doses from 40 to 200mg and the relative intensity of their reported experience rated zero to three on the Shulgin scale.

It soon became clear that a subjective difference in potency could be observed between the two stereoisomers. R(-)-MDMA was least potent, with only threshold effects observed between 100 and 200mg. Racemic MDMA caused full effects between 140 and 160mg, while S(+)-MDMA was most potent with full effects observed at 120mg. But was this difference in apparent potency the only distinction between the two?

Shulgin plotted the effects of racemic MDMA (red above) versus a simple average of the regressions he found earlier for R(-)-MDMA and S(+)-MDMA (black above). If the different stereoisomers differed only in apparent potency, these plots should be identical. Interestingly, they were not – with racemic MDMA quite literally reporting effects more than the sum of its parts. This was borne out by user reports as well. The S(+)-MDMA may have been more potent by weight at first glance, but alone it was more stimulating and lacked the indescribable “magic” of the full racemic MDMA experience.

Further investigation was undertaken by researchers including Kevin Murnane, who conducted experiments designed to further delineate the effects of each stereoisomer.


R(–)-MDMA

S(+)-MDMA
2C-T-7, a psychedelic phenethylamine, fully substituted for R(-)-MDMA in trained mice. DPT, a psychedelic tryptamine, acted as a partial substitute. S(+)-amphetamine substituted for S(+)-MDMA in trained mice. Cocaine acted as a partial substitute.
In rhesus monkeys, R(-)-MDMA significantly increased prolactin levels. S(+)-MDMA significantly increased both dopamine and serotonin levels.

In general, R(-)-MDMA appears to produce psychedelic effects and has a longer duration relative to the more stimulating effects of S(+)-MDMA. MDMA is an incredibly unique compound, where each stereoisomer has a distinct and centrally active mode of action. Unlike other compounds where one stereoisomer is more potent or responsible for the majority of effects, each stereoisomer of MDMA contributes to produce a full and complex experience.

Phenethylamines may be classified as stimulants (such as amphetamine where the S(+) entianomer is most active) or psychedelics (such as DOC where the R(-) entianomer is most active). MDMA appears to uniquely straddle this divide.

Shulgin, A.T. Personal Lab Notes (Book 2), page 238.

Murnane KS, Murai N, Howell LL, Fantegrossi WE. Discriminative stimulus effects of psychostimulants and hallucinogens in S(+)-3,4-methylenedioxymethamphetamine (MDMA) and R(-)-MDMA trained mice. J Pharmacol Exp Ther. 2009 Nov;331(2):717-23. Epub 2009 Aug 14.

Murnane KS, Fantegrossi WE, Godfrey JR, Banks ML, Howell LL. Endocrine and neurochemical effects of 3,4-methylenedioxymethamphetamine and its stereoisomers in rhesus monkeys. J Pharmacol Exp Ther. 2010 Aug;334(2):642-50. Epub 2010 May 13.

The Secret Life of Legal Highs

The research chemical market has exploded in recent years primarily due to the emergence of cheap euphoric stimulants produced in volume. The wide appeal and behavioral reinforcement of these compounds relative to the more niche appeal of previous psychedelic research chemicals resulted in a flood of cash from a less discerning clientele. If it made you feel good, it sold – and governments across the world quickly attempted to fill in the blanks in their legislation.

The market has now fragmented, with apparently new compounds popping up based on novel and not explicitly illegal backbones such as the aminoindanes. The effects are touted as nearly identical to older, now illegal alternatives however, and many retail user reports bear this out. This is in contrast to reports from experienced researchers with verified compound, who describe the new aminoindanes such as 5-IAI as effectively worthless.

So why the difference? How can there be such a distinction between reported effects, where a compound that has been found to produce weak threshold effects at best in a controlled setting sell like hotcakes in the retail market? A new research paper provides a rather convincing answer – the “new” retail products simply contain outlawed compounds, and are rebranded with an arbitrarily selected compound name that has some association as a possible replacement.

Seven samples of “new” legal highs were purchased online from multiple sources, sold as MDAI, “benzo fury”, 5-IAI, NRG-3, and E2. They were analyzed using GC-MS, and the results are shocking.

Sold As Active Compounds Identified
MDAI BZP, 3-TFMPP, caffeine.
MDAI MDAI
MDAI BZP, 3-TFMPP, caffeine.

Three samples of “MDAI” were tested. Only one actually contained MDAI, while the other two contained a mixture of caffeine and the illegal piperazines BZP and 3-TFMPP.

Sold As Active Compounds Identified
Benzo Fury BZP, 3-TFMPP, caffeine.
5-IAI BZP, 3-TFMPP, caffeine.
NRG-3 BZP, 3-TFMPP, caffeine.
E2 Caffeine

The results for the other products are equally depressing, none of which match the label. Three samples once again contained a mixture of BZP, 3-TFMPP, and caffeine, while one (E2) only contained large amounts of caffeine. Most interesting was the fact that correlation between various samples was extremely high – the same mixture of compounds was simply sold in differently labelled (and priced) bags!

These products were sold as legal (when they weren’t) and as new and novel different compounds (which they didn’t contain). This practice appears to be far more widespread than many would like to admit.

Baron, Mark and Elie, Mathieu and Elie, Leonie. (2011) Analysis of legal highs – do they contain what it says on the tin? Drug Testing and Analysis. ISSN 1942-7603 (Submitted)

Form Constants and the Visual Cortex

There are common visual concepts which cut across boundaries of culture and time and reflect what it truly means to be human. Near death experiences are often associated with seeing a “light at the end of a tunnel”. In the Bible, God appeared to Ezekiel as a “wheel within a wheel”. Spirals and concentric circles are commonly found in petrogylphs carved by cultures long dead. Similar visual effects are reported during extreme psychological stress, fever delirium, psychotic episodes, sensory deprivation, and are reliably induced by psychedelic drugs.

In 1926, Heinrich Klüver undertook a groundbreaking series of experiments where he categorized the visual effects produced by mescaline. Various volunteers were recruited, peyote administered, reports taken, and results classified into categories. There were general perceptual effects, variations in color and distortions of shape. But the most interesting reports were consistent visual concepts he dubbed “form constants”. Across many volunteers and many sessions, all reported seeing visual patterns with similar structure.

They were classified into four main types: I) tunnels, II) spirals, III) lattices, and IV) cobwebs. For almost fifty years, these form constants were regarded as a strange mystery of visual perception, a seemingly unexplainable common human experience.

In 1979 Jack Cowan and G. Bard Ermentrout put forward a very interesting explanation, supported by a rigorous mathematical treatment. These visual effects are the result of specific noise patterns in the visual cortex, which are then transformed by the wiring between the brain and the eye to produce these unique shapes. They generated simple biologically allowable noise patterns, transformed them, and produced graphs of these form constants.

Let’s dive a bit deeper into how this was done, by first having a look at the structure of the visual cortex. We’ll look specifically at V1, the first layer of visual processing where information from the retina is fed to. We can think of it as a sheet of hypercolumns, cells sensitive to lines oriented in any direction. This surface is crinkled up like a ball of paper in your brain, but we can unfold it in a theoretical sense. These hypercolumns are linked together in a specific manner, which allows noise patterns of only certain types to form. Just like a tarp in the wind will only flap in certain predictable ways assuming it does not tear, so too will noise only travel across the visual cortex in specific ways. Four types of noise were found.

These stable planforms can be thought of as excited noisy states in contrast to the normal low-activity state of the visual cortex. We can refer to them as I) the non-contoured roll, II) the non-contoured hexagon, III) the even contoured hexagon, and IV) the even contoured square.

So now that we have our noise patterns, how are they mapped from the visual cortex to what we actually see? Biology provides a clue here. Experiments have been done which allow mapping of how the visual cortex represents input from the retina. By stimulating a certain point or region of the retina, the corresponding cells which light up in V1 can be measured. The easiest mapping you might think of would be for the input of the retina to be represented as a flat sheet, which is then passed to the visual cortex like a photocopy. Instead, it turns out that the circular retina’s image is twisted and mapped in a slightly more complex manner to the flat surface of V1.

Visual Cortex (V1) Retina

We can see that straight lines in our visual cortex are mapped to curved lines in the retina, and vice versa. We can represent this relationship mathematically using the complex logarithm, so let’s apply this complex log transform to our four types of visual cortex noise.

And beautifully, Klüver’s four form constants are produced, visual cortex noise twisted by the wiring between mind and eye. This hypothesis fits the fact that these high energy states may be caused by a variety of stimuli affecting excitability of the brain but most reliably by psychedelic drugs which bind to serotonin receptors richly expressed in the visual cortex.

It is compelling to think that these powerful symbols rely on no religion, no culture, and no time. They are a product of the fact that we are all human and share the same biology. A true tragedy that these visions have been used as an excuse to kill others when we all see the same wheels within wheels.

Ermentrout, G.B. and Cowan, J.D., “A mathematical theory of visual hallucination patterns.” Biol. Cybernet. 34 (1979), no. 3, 137-150.

Bressloff, Paul C.; Cowan, Jack D.; Golubitsky, Martin; Thomas, Peter J.; Weiner, Matthew C. (March 2002). “What Geometric Visual Hallucinations Tell Us About the Visual Cortex“. Neural Computation (The MIT Press) 14 (3): 473–491.

Phenylacetylindoles

The alkylated napthoylindoles were the first synthetic cannabinoids cheap and potent enough to make real noise on the recreational drug market. Concern was initially raised about metabolism of the naphthalene ring and resulting carcinogenic risk, which turned out to be validated (abstract O43) although perhaps initially overstated as it lies within a similar risk envelope as cigarettes. Compounds have now been produced that replace the naphthalene ring with a phenylacetyl group. These represent a new and unique class of synthetic cannabinoids, with applications as both replacements for banned cannabinoids and use as a possibly healthier alternative for informed users. Without substitution the structure is much less potent than JWH-018, but various substitutions at the 2, 3, and 4-position have been attempted. The 2-position substitutions demonstrate the highest potency as a class, and are outlined here.


JWH-167 (CB1 Ki = 90 ± 17 nM, CB2 Ki = 159 ± 14 nM) is shown here with JWH-018 and its naphthalene group in a light grey underlay for reference. Without any substitutions this base phenylacetylindole is not potent enough for sale on the recreational drug market, as it is roughly a tenth as potent as JWH-018 as measured by binding affinity.


JWH-251 (CB1 Ki = 29 ± 3 nM, CB2 Ki = 146 ± 36 nM). A methyl group at the 2-position increases potency, but binding affinities seem to be too weak for practical sale. This is contrasted with the facts that JWH-251 was found to be a component of certain Japanese “herbal smoke” blends and limited reports indicate this to be of somewhat similar qualitative potency to JWH-250. Time will tell if this compound will remain on the edge of the market or gain popularity.


JWH-250 (CB1 Ki = 11 ± 2 nM, CB2 Ki = 33 ± 2 nM). Currently the most popular phenylacetylindole. The 2-methoxy substitution produces a compound that is qualitatively slightly less potent than JWH-018, but produces a much more pleasant effect in higher dose ranges. As such, this compound has found favor with those who prefer a stronger cannabinoid experience without the near-certainty of anxiety in higher doses that JWH-018 was known to cause.


JWH-311 (CB1 Ki = 23 ± 2 nM, CB2 Ki = 39 ± 3 nM). Fluorine substitution provides the least potent outcome of the three halogens Huffman explored. Not widely available or tested.


JWH-203 (CB1 Ki = 8.0 ± 0.9 nM, CB2 Ki = 7.0 ± 1.3 nM). The most potent halogen substitution, and one of the most potent phenylacetylindoles along with JWH-250. Currently available for sale, but not widely explored.


JWH-249 (CB1 Ki = 8.4 ± 1.8 nM, CB2 Ki = 20 ± 2 nM). Slightly less potent than JWH-203, with a lower CB2 affinity that may be associated with reduced anxiety effects. Not widely available for sale, but could be waiting in the wings if JWH-203 takes off and is scheduled.

John W. Huffman, P. V. Szklennik, A. Almond, K. Bushell, D. E. Selley, H. He, M. P. Cassidy, J. L. Wiley, B. R. Martin, 1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles, Bioorganic & Medicinal Chemistry Letters, Volume 15, Issue 18, 15 September 2005, Pages 4110-4113, ISSN 0960-894X, DOI: 10.1016/j.bmcl.2005.06.008.

Burn it up, Thoughts on JWH-18 carcinogenicity, 01-05-2010, 02:22, Bluelight > Drug Discussion > Advanced Drug Discussion.

Synthetic Cannabinoids: The Alkylated Naphthoylindoles

There are a huge variety of synthetic cannabinoids possible, including variations on THC and other natural cannabinoids, the CP series created by Pfizer in the 1970s but never brought to market, anti-Alzheimer’s treatment HU-210, and aminoalkylindole derivatives like WIN 55,212-2. But the most popular and prevalent synthetic cannabinoids in today’s recreational drug market are a subset of what are colloquially known as “JWHs”, after the researcher who completed a large body of work on them, John W. Huffman. There are several hundred of these compounds, named in the format JWH-001 and up. Some of the first compounds in this long list to be diverted to the recreational drug market are certain alkylated naphthoylindoles, which also happen to be very easy to synthesize. Have you used “herbal incense”, “Spice”, “K2”, or any of the other cannabis substitutes that have been popping up lately? A safe bet is that they’re an inactive herbal carrier with these synthetic cannabinoids dissolved in a solvent sprayed on top.

Synthetic cannabinoids sold in this manner drive a large and profitable industry, a strange bastard child of prohibition that would simply not exist if the sale of cannabis was regulated. While a small subset of informed drug users would likely still create demand for pure versions of these products, “incense” consumption would be effectively zero if the general population had access to quality cannabis and did not have to worry about metabolic products being tested for.

Imagine the state of the synthetic cannabis industry a few years ago. There have been whispers of some interesting cannabinoids being developed by academics for medical use and research. But how is it possible to tell which of these might substitute for THC in recreational users? Let’s investigate the binding affinity, a measure of how well a compound binds to a receptor. We can use Ki values to do this, which measure how concentrated the compound must be in order for it to have an equal chance of being bound to a receptor or not. Lower values mean high potency as only a small amount of compound is required, while higher values indicate lower potency. While having similar binding affinities doesn’t always mean similar recreational effects, it can certainly help narrow the field. Let’s see how the first seven alkylated naphthoylindoles stack up against THC.

Compound CB1 Ki (nM) CB2 Ki (nM) Image
THC
(reference)
40.7 ± 1.7 36.4 ± 10
JWH-070
(methyl)
>10000 >10000
JWH-071
(ethyl)
1340 ± 123 2940 ± 852
JWH-072
(n-propyl)
1050 ± 55.0 170 ± 54.0
JWH-073
(n-butyl)
8.90 ± 1.80 38.0 ± 24.0
JWH-018
(n-pentyl)
9.00 ± 5.00 2.94 ± 2.65
JWH-019
(n-hexyl)
9.80 ± 2.00 5.55 ± 2.00
JWH-020
(n-heptyl)
128 ± 17.0 205 ± 20

The shorter alkyl chain lengths of JWH-070 (ethyl) and JWH-071 (methyl) show negligible activity. As we move to the propyl chain of JWH-072 we see little change in CB1 binding affinity but CB2 affinity increases almost 15 times. JWH-073 and its butyl chain are a bit more promising, with higher affinity for CB1 and a similar affinity for CB2 compared to THC. JWH-018 (pentyl) and JWH-019 (hexyl) stand out, with higher potency at both receptors than THC itself. So far so good, but as we increase the chain length in JWH-020 (heptyl) our streak ends, as we see a a 13 fold decrease in binding affinity at the CB1 receptor and a 40 fold reduction at the CB2 receptor.

Activity appears to peak around the five carbon pentyl chain in these naphthoylindoles, as opposed to the classical cannabinoids which peak at the seven carbon heptyl chain. Judging from binding affinities It looks like JWH-073, JWH-018, and JWH-019 would be the best bets – so did any of them pan out?

JWH-018 is likely the world’s most popular synthetic cannabinoid, and was one of the first introduced for wide sale. It entered the public psyche in late 2008 when German company THC-Pharm identified it as a primary ingredient in the “Spice” herbal smoke blend. Quickly outlawed in Germany and several other European countries in early 2009, it has since gained popularity in other markets including the US. Active in smoked dosages of only a few milligrams, tolerance builds quickly revealing a dirty secret relative to natural cannabis. JWH-018 is a single compound active as a full cannabinoid agonist, while cannabis acts as a mixture of many phytocannabinoids including partial agonists and antagonists. This complex balancing act provides a safety net that JWH-018 lacks, as the synthetic compound can activate cannabinoid receptors in a far more specific and potent manner. For instance, GABA may be inhibited far more effectively than natural cannabis, leading to severe anxiety and reduced seizure threshold at high doses. This may be the origin of the infamous “fear” JWH-018 is known to induce in overdose.

JWH-073 is not as potent as JWH-018, but has arguably a more pleasant high with less anxious effects. After JWH-018 was outlawed in Germany, a seizure and analysis of a new batch of Spice shipped only 4 weeks after the ban showed that the manufacturers had quickly switched active ingredients to the uncontrolled JWH-073.

JWH-019 has not reached the same fame as the others likely due to timing and distribution rather than any real shortcomings. It was introduced to a more saturated market along with many other competing synthetic cannabinoids after JWH-018 and JWH-073 were banned in some areas. This is likely to represent the new normal, as a wide number of these compounds targeting various recreational effects pop in and out of the market depending on economic and legal factors.

Mie Mie Aung, Graeme Griffin, John W Huffman, Ming-Jung Wu, Cheryl Keel, Bin Yang, Vincent M Showalter, Mary E Abood, Billy R Martin, Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding, Drug and Alcohol Dependence, Volume 60, Issue 2, 1 August 2000, Pages 133-140, ISSN 0376-8716, DOI: 10.1016/S0376-8716(99)00152-0.