On Pellote (Second Communication)

On Pellote: Contributions to the Chemical and Pharmacological Knowledge of the Cacti. Second Communication.

From the Pharmacological Institute of the University of Leipzig. By Professor Dr. A. Heffter, First Assistant at the Institute.

[Omitted here: the introduction on the name, distribution and use of pellote among Mexican and North American peoples and on its botanical identification (pp. 385–390), and most of the chemical part, on the extraction of pellotine, anhalonine, anhalonidine and lophophorine (pp. 390–398). The excerpt begins with the separation and description of mescaline.]

Before I turn to the description of the individual alkaloids, a few words must first be said about the method of separating mescaline from anhalonidine. If one is not to work with excessive losses, this separation demands considerable patience and care. The first two crops of crystals usually consist of pure mescaline sulphate; by recrystallization from water, or better from boiling methyl alcohol, it can be obtained at once in the finest purity.

[Omitted here: the further separation of the later crystal fractions and their microscopic testing with platinum chloride (pp. 398–399).]

Mescaline sulphate, (C₁₁H₁₇NO₃)₂H₂SO₄ + 2H₂O, forms highly lustrous flat prisms that can reach several centimetres in length. It is readily soluble in hot water and hot methyl alcohol and separates out on cooling. Ethyl alcohol dissolves very little of it. The water of crystallization is given off completely over sulphuric acid or at 100°.

Mescaline hydrochloride, C₁₁H₁₇NO₃.HCl, is obtained by reacting the sulphate in aqueous solution with barium chloride. After concentration in the desiccator and final addition of alcohol, the salt is obtained in fine white needles, extremely soluble in water and somewhat less so in alcohol.

[Omitted here: the hydriodide.]

Mescaline, C₁₁H₁₇NO₃. If a hot concentrated solution of the sulphate is treated with caustic soda, nothing separates out, either at once or on cooling. The free base is obtained by shaking out with chloroform; ether added to the residue left after distilling off the chloroform precipitates it as a fine white powder made up of microscopic needles. It dissolves readily in water with a strongly alkaline reaction, and still more readily in alcohol and chloroform. Benzene and anhydrous ether take up very little, petroleum ether almost none.

Mescaline is a very strong base. Its aqueous solution precipitates the corresponding hydroxides from solutions of copper sulphate, lead acetate and zinc chloride, and on gentle warming drives ammonia out of solutions of ammonium salts.

When heated in a tube the crystals soften at 105° but melt only indistinctly between 150° and 160°.

[Omitted here: the platinum, gold and methiodide compounds (p. 400).]

Concerning the further constitution of mescaline, it has so far been established that the three oxygen atoms are present in the form of methoxyl groups, and that a methyl group is attached to the nitrogen. The formula is therefore to be written C₇H₅(OCH₃)₃NCH₃.

[Editorial note: The N-methyl assignment was mistaken. Ernst Späth's synthesis of 1919 established mescaline as 3,4,5-trimethoxyphenethylamine, with a primary amino group; the empirical formula C₁₁H₁₇NO₃ given here is correct.]

[Omitted here: the oxidation with permanganate, the other alkaloids, their proportions in the drug, and the whole pharmacological part on the action of the five alkaloids in frogs and mammals (pp. 400–418).]

VI. The action of mescal buttons on human beings

The wondrous effects that the Indians attribute to pellote, or the mescal button, led one to suspect from the outset that animal experiments would shed no light on its physiological effects in human beings. This has indeed proved to be the case, since experience has shown that only experiment on a human being brings out the specific physiological properties of the mescal substances.

[Omitted here: Heffter's summary of the self-experiments reported by Prentiss and Morgan (1895), S. Weir Mitchell and Eshner (1896), and Havelock Ellis (1897) (pp. 418–420).]

In turning now to an account of my own experiments, I should say first that their purpose was, to begin with, to learn the effect of pellote on human beings at all, and then, chiefly, to determine which constituent of the drug is responsible for this strange effect. All the experiments were made on myself.

Experiment of 5 June 1897

Between 10.15 and 10.45 in the morning I took, in wafers, a thick alcoholic extract (extractum spissum) corresponding to 16.6 g of the drug (about 5 mescal buttons). My pulse rate, 76 at the start of the experiment, fell to 56 over the course of 2 hours and then rose again to normal. About half an hour after the last dose came nausea, pain in the back of the head, strong giddiness and heaviness of movement. Very soon afterwards (12.18) my vision became indistinct; the pupils were moderately dilated. The nausea increased; at lunch I had no appetite at all. At 1.30, with lids closed, I perceived the first colour phenomena: dark blue stripes, then an arbour walk with red and yellow flowers. When reading, which the dilated pupils made an effort, pale violet and green spots appeared on the paper, as it were behind the letters, like a delicate wallpaper pattern.

At 1.50 I lay down in a darkened room and closed my eyes. Despite the darkness the after-images were remarkably sharp and long-lasting. Often a series of brilliantly coloured pictures followed on from the after-images, some representing carpet patterns and mosaics, others consisting of intertwined coloured ribbons moving with lightning speed. Coloured rays of great brightness also shot in arcs across the dark visual field, rather like fireworks, but faster. All the colours were represented. These phenomena were followed by a series of beautiful landscapes, distinguished above all by wonderful colour effects. Thus I saw, for example, the seaside promenade at Nervi, with trees of a strangely deep red hanging over the wall. This was, incidentally, the only familiar picture I saw. Despite every effort of will I could exert no influence on the objects that appeared; equally, I could concentrate my thoughts on some unrelated point while the visions changed with lightning speed. Rhythmic sounds or music influenced the pictures to the extent that they then moved in time with it. I then often had the impression of large crowds of people, soldiers and so on, marching past, without being able to make out individuals. Several times I saw on a dark, glossy ground thick, branching violet roots and fibres resembling heavily engorged veins. Often they formed themselves into the network of high Gothic vaults in changing colours. Often, too, I saw the interiors of richly decorated banqueting halls whose friezes, walls and chandeliers were adorned with coloured gemstones, opals and pearls. It was strange that the ceiling sometimes seemed to be below me or vertically to one side, which brought on violent giddiness and increased nausea.

The architectural pictures appeared three-dimensional, while the landscapes mostly gave the impression of being projected onto a screen covered with coarse cloth.

As soon as I opened my eyes, the visions vanished. The nausea, giddiness, headache and a feeling of oppression in the chest remained. Even so, my mood was cheerfully excited and I was inclined to laugh. I had the feeling that I was speaking very loudly; my hearing was dulled, and all voices sounded as if from far away. Consciousness remained clear throughout the experiment and my intellectual faculties were unaffected.

A very striking symptom was the loss of the sense of time: a few minutes were estimated as half an hour. The ten-minute walk from my lodgings to the laboratory seemed endlessly long.

The ability to see visions on closing my eyes lasted until about 5.45, that is, for 4 hours. Towards the end the colours appeared quite dull and I saw only faintly outlined coloured spots. The unpleasant accompanying symptoms disappeared, apart from slight giddiness and the dilated pupils. My appetite returned, and I slept quietly and without interruption that night.

This experiment confirmed in the main the symptoms described by earlier observers: the appearance of coloured visions together with slowing of the pulse, dilatation of the pupils, loss of the sense of time, nausea, giddiness and headache.

The next thing to establish was whether the active constituent was one of the alkaloids. This was best done by using for an experiment the residue of the chloroform extraction, into which all the alkaloids pass.

The alcoholic extract of 50 g of mescal buttons was, after removal of the alcohol, taken up in water; the solution was treated with excess ammonia and then shaken with chloroform for as long as the chloroform took up anything. When the chloroform had been distilled off, there remained a syrupy residue containing all the alkaloids and some resin. To separate the latter, I treated the brown syrup with warm water and added dilute sulphuric acid to neutral reaction, whereupon all the alkaloids went into solution. The undissolved resin amounted to 0.45 g. The alkaloid solution was evaporated and finally dried in the desiccator. A crystalline mass weighing 3 g was left, containing all the alkaloids as sulphates.

The first question to answer was whether the resin was the substance that produces the visions.

Experiment of 21 July 1897

11.17: I took 0.15 g of resin in a wafer, corresponding to 16.67 g of the drug. Pulse 78 per minute.

11.23: Slight headache. Pulse 70.

12.30: Feeling of tiredness. Heaviness of the limbs. Pulse [68?].

Within an hour all symptoms had disappeared. No visions were seen.

This experiment shows that the resin is not the real active substance. It does have a certain physiological activity, but that need not surprise us, since, as explained above, it probably represents a mixture of altered alkaloids.

The following experiment was intended to clarify the activity of the alkaloids.

Experiment of 23 July 1897

12.09: Took 1.0 g of alkaloid sulphate (corresponding to 16.67 g of the drug) dissolved in water. Pulse 76.

12.33: Pain in the back of the head, heaviness in the limbs. Pulse 72.

12.45: Pulse 66.

1.00: Pulse 60. Nausea.

1.15: Pulse 68. When reading, green and violet spots appear on the paper, and likewise when I look at the bright sky. On closing my eyes visions appear, pale at first but gradually becoming sharper and more brilliant. This time they consist less of landscapes and mainly of kaleidoscopic figures, carpet and textile patterns, splendid garments and architectural pictures. There is little blue, chiefly orange, red, green and occasional yellow. In a completely darkened room (a photographic darkroom) I was this time able to see them with open eyes, though not as vividly and distinctly as with closed lids. The ability to perceive them persisted for an extraordinarily long time in this experiment. Even on the morning of the following day coloured (green and violet) spots appeared when I closed my eyes.

The other symptoms — dilatation of the pupils, giddiness, extremely distressing nausea that this time lasted until about 8 o'clock, loss of the sense of time, indistinct hearing, a feeling of weariness in the limbs — were present just as in the experiment of 6 July. They disappeared gradually in the course of the evening; only the pupils were still somewhat dilated the next morning. During this experiment, too, there was no clouding of consciousness, but I found it hard to concentrate my thoughts when calculating and speaking. Speech itself was somewhat slow and laboured.

[Editorial note: The first experiment is dated 5 June 1897 in print, but here and in the next paragraph Heffter refers to an "experiment of 6 July." The printed text is reproduced as it stands.]

The important result of the experiment just described, which agrees entirely in its main features with that of 6 July, is that the alkaloids of the drug produced the same physiological effect as the mescal buttons themselves. One of these bases must therefore have those peculiar effects on the visual apparatus, and the further task was to identify the essential active constituent by experiments on human beings with the isolated alkaloids.

Mescaline in doses of 0.02–0.08 g of the hydrochloride produces slowing of the pulse, headache and a feeling of weariness in the limbs, effects that lasted from one to several hours depending on the size of the dose.

After 0.1 g of the hydrochloride the pulse rate fell from 82 to 64 within 3 hours and then began to rise again. There was headache, heaviness in the limbs and a slight feeling of nausea and fullness of the stomach. After 3 hours I thought I saw visions with closed eyes but was not entirely sure.

A further experiment was therefore made with a still higher dose.

Experiment of 23 November 1897

11.45 a.m. With a pulse rate of 78 I took 0.15 g of mescaline hydrochloride. The pulse fell to 66 beats by 1.00.

12.06: Fullness in the head. Sensitivity to light. Moderately dilated pupils.

12.45: Pain in the back of the head. Giddiness, heavy limbs.

1.00: Nausea, but appetite for food.

1.50: Pulse rate 72.

2.00: When reading, violet and green spots appear on the paper. With closed eyes visions appear: first indistinctly outlined violet and green spots, then carpet patterns, cross vaults and so on. Now and then single points in the most brilliant colours float across the visual field. On the whole the phenomena are not quite as sharp as in the two preceding experiments. Later, however, landscapes, halls and architectural pictures (for example pillars decorated with flowers) are likewise seen. The visions could be observed until about 5.30. The nausea was at times very distressing, and so was the giddiness. The sense of time was reduced in the early afternoon hours. In the evening I felt entirely well, had an appetite, and did not suffer from sleeplessness.

Anhalonidine in doses of 0.1–0.25 g of the hydrochloride causes some drowsiness and a dull feeling in the head. The pulse was unaffected. No visions were seen.

Anhalonine: 0.1 g of the hydrochloride produced no distinct effect in me apart from slight drowsiness.

Lophophorine: it was unlikely from the outset that this alkaloid, present in the drug in such small amounts, played any prominent part in its activity. One experiment showed that 0.02 g of lophophorine hydrochloride produced after 15 minutes a strong, painful pressure in the back of the head and heat and flushing in the face. There was also a slight fall in pulse rate (from 78 to 70 beats). All the phenomena had disappeared again after 40 minutes.

These experimental results show that mescaline alone produces the essential symptoms of mescal intoxication, and above all that it alone causes the visions, which so far stand without parallel. As the experiment of 23 November shows, 0.15 g of mescaline hydrochloride produces a complex of symptoms that differs in only a few points from the result obtained in the experiment with the drug itself. Common to both are the slowing of the pulse, dilatation of the pupils, headache, giddiness, laboured movement of the limbs, loss of the sense of time and, most important, the characteristic visions. That in the mescaline experiment these were not quite as vivid and brilliant as in the earlier experiments may have two causes. The likeliest is that the dose was still chosen somewhat too low, and that a somewhat larger dose — about 0.175 g of the hydrochloride or 0.2 g of the sulphate — will produce visions as beautiful as the drug itself. Another possibility is that the other alkaloids also play a part in mescal intoxication, although the negative experiments, and the much smaller proportion in which these substances occur in the drug, speak little for this view.

To attempt a detailed discussion of the action of mescaline on the basis of so few experiments would be a futile undertaking. Here there are rewarding tasks for the physiologist and the experimental psychologist. That the effects are essentially on the central nervous system is very probable, although stimulation of the peripheral visual apparatus is not ruled out. In this connection I may add that during the experiment of 23 November Privatdocent Dr. Krückmann, First Assistant at the Leipzig eye clinic, kindly examined me and could find no general restriction of the visual field, nor any for colours.

Whether one or another of the mescal alkaloids can be used therapeutically I should like to leave open for the present. As regards mescaline, the answer is probably no.

Weir Mitchell, and Ellis likewise, believe that the drug will become popular as an intoxicant among civilized peoples too. In my experience I do not think this likely, because the side effects are such that they greatly spoil the enjoyment of the beautiful visions.

[Omitted here: the appendix on alkaloids in further species of cacti (pp. 425–429).]