Drugs which block serotonin-2, -1C, and -1A subtypes have been found to block the effects of hallucinogens in lower animals. However, tests of "hallucinogenicity" in lower animals are open to criticism because of the difficulty in knowing exactly what the animal is responding to. Clearly, human studies are necessary to refute, confirm, or modify existing hypotheses generated by lower animals experiments. Thus, we are interesting in determine which serotonin receptors, in man, mediate specific effects of DMT.
Our original DMT study demonstrated that DMT raised blood levels of beta- endorphin, cortisol, adrenal stimulating hormone, and prolactin; all of these hormones' regulation is believed controlled, to some extent, by serotonin receptors in the brain. In addition, we found rises in blood pressure, heart rate, pupil diameter, and core temperature in response to DMT; these variables also are regulated to some extent by serotonin nerve cells. Finally, we have carefully mapped out the psychological effects of DMT using the Hallucinogen Rating Scale, the development of which was discussed in a previous article. Now that we have this data describing effects of DMT by itself, we can pre-treat subjects with drugs that block certain types of serotonin receptors, and see what happens to these factors. For example, if pre-treatment with a serotonin-1A blocking drug enhances visual effects, but reduces beta-endorphin stimulation, we can suggest that the serotonin-1A receptor mediates those functions. These data could have use in developing antidotes for certain problematic reactions to psychedelics, and provide insights into important brain-mind interactions. They also might provide glimpses of understanding into spontaneous "psychedelic" states, such as some naturally occurring psychotic phenomena.
We have found a likely candidate for a serotonin-1A blocking drug, our first blockade project. However, we have been unsuccessful in locating a serotonin-2 and serotonin-1C drug, the second series of studies. These two latter receptors are extremely similar, and drugs that block the "2" subtype usually block the "1C" as well. There are several "2/1C" agents at various stages of development within human and animal studies, but so far, no one has agreed to provide such a drug to us. Efforts are continuing.
The importance of developing (or not developing) tolerance to DMT derives from at least two perspectives. One is the fact that the inability to generate tolerance to DMT in humans is one of DMT's strongest characteristics suggesting its role in spontaneous psychotic states. Recall that the discovery of DMT in human body fluids set off a flurry of investigations assessing whether it was involved in psychoses. If DMT does have a role in spontaneous hallucinations, and it were possible to develop tolerance to its effects with repeated and/or continuous exposure, then people would only hallucinate when tolerance was no longer in effect. However, that is contrary to clinical experience, inasmuch as people with psychotic illness often hallucinate continuously. Therefore, if we cannot develop tolerance, a role for DMT in mental illness would be supported. Secondly, the "tolerant state" is of great interest in the field of psychopharmacology. Why drugs "no longer work" when they used to is of practical importance in treatment of mental illness, understanding how psychoactive drugs (including alcohol, nicotine, cocaine, LSD, and others) work. Particularly with respect to hallucinogens, how a previously psychedelic dose of LSD could have no effect in someone with repeated exposure to the drug is a fascinating question for mind-brain researchers.
Our study will give the smallest dose of DMT four times, separated by one hour. We will gradually, in a small number of subjects, alternatingly shorten the interval to one-half hour if no increase or decrease in effect is seen with the low dose every hour. If no effect is noted with low dose every half-hour, we will try a higher dose every hour, then every half-hour, and so on, up to a possible high dose every half-hour. Enhanced effects of repeated dosing will be apparent with this systematic approach. Once we have found the right dose and interval, the full group of subjects will be in tolerance development, or lack thereof. In the unlikely event no tolerance is seen with repeated administrations, we might consider a slow continuous administration of IV DMT.
The majority of funds will go towards salary support for myself, a laboratory technician, and a psychiatric research nurse. In addition, first-year monies will go toward the syntheses of the psilocybin and remodelling of the research unit room. A significant amount of money is provided for laboratory support for the Clinical Research Center Core Laboratory, for materials, supplies, and maintenance of the equipment, as well as developing a new means of measuring psilocybin in blood.
The original grant application requested a fourth year of support to assess the role of menstrual stage, in women, on DMT's effects. That is, do DMT's effects differ, either in quality or quantity, depending upon which stage of the menstrual cycle a woman receives DMT? However, the review committee at NIDA did not believe this part of the study was scientifically nor clinically as sound as the other parts, and dropped it and the fourth year of support required to perform it.
We are extremely fortunate, here at the University of New Mexico, to have the opportunity to be involved in this renewal of research with hallucinogens in humans. Although not directly "therapeutic," this type of systematic work goes a long way in carefully describing what the effects of psychedelics really are in humans. Only then, I believe, can people's difficulties be approached by using these drugs in a manner in which symptoms or problems are matched to the effects of the drugs themselves.
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email: sylvia@maps.org (Sylvia Thyssen, Network Coordinator)