rational exploration of the underground

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).

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.

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.

While researching lysergic acid derivatives, Dr. Albert Hofmann first synthesized LSD on November 16, 1938. The main intention of the synthesis was to obtain a respiratory and circulatory stimulant. It was set aside for five years, until April 16, 1943, when Hofmann decided to take a second look at it. While re-synthesizing LSD, he accidentally absorbed a small quantity through his fingertips and serendipitously discovered its powerful effects. He described what he felt as being:

… affected by a remarkable restlessness, combined with a slight dizziness. At home I lay down and sank into a not unpleasant intoxicated-like condition, characterized by an extremely stimulated imagination. In a dreamlike state, with eyes closed (I found the daylight to be unpleasantly glaring), I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors. After some two hours this condition faded away.”

Three days later, April 19, 1943, Hofmann performed a self-experiment to determine the true effects of LSD, intentionally ingesting 0.25 miligrams (250 micrograms) of the substance, an amount he predicted to be a threshold dose (an actual threshold dose is 20 micrograms). Less than an hour later, Hofmann experienced sudden and intense changes in perception. He asked his laboratory assistant to escort him home and, as use of motor vehicles was prohibited because of wartime restrictions, they had to make the journey on a bicycle. On the way, Hofmann’s condition rapidly deteriorated as he struggled with feelings of anxiety, alternating in his beliefs that the next-door neighbor was a malevolent witch, that he was going insane, and that the LSD had poisoned him. When the house doctor arrived, however, he could detect no physical abnormalities, save for a pair of incredibly dilated pupils. Hofmann was reassured, and soon his terror began to give way to a sense of good fortune and enjoyment, as he later wrote.

“… little by little I could begin to enjoy the unprecedented colors and plays of shapes that persisted behind my closed eyes. Kaleidoscopic, fantastic images surged in on me, alternating, variegated, opening and then closing themselves in circles and spirals, exploding in colored fountains, rearranging and hybridizing themselves in constant flux …”

The events of the first LSD trip, now known as “Bicycle Day”, after the bicycle ride home, proved to Hofmann that he had indeed made a significant discovery. A psychoactive substance with extraordinary potency, capable of causing significant shifts of consciousness in incredibly low doses, Hofmann foresaw the drug as a powerful psychiatric tool; because of its intense and introspective nature, he couldn’t imagine anyone using it recreationally.

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.