Tuesday, May 03, 2005

DOB and Other Possible Prodrugs

Dear Dr. Shulgin,

I have been thinking about various materials. Some come on rapidly, but others take 2-3 hours or so. I have a theory. Could it be that the "fast" materials are by themselves active, while the "slow" ones are inert until they are changed within the organism to something else that is active? What have you done in the way of investigating this anomaly? - Anon.

Dear Anon.,

A very good question, I have actually done some experimental research that directly addresses this possibility. It was obvious to me that DOB (4-bromo-2,5-dimethoxyamphetamine) would be a superb material for an answer to this question for two reasons. First, it is very slow to come on (over an hour for the first effects to become apparent), and it can last into the next day. And second, it contains the heavy element bromine, which allowed me to make a radioactive sample. I mentioned some of this study in Pihkal, in the commentary under DOB.

Let me share a few of the interesting unpublished details.

Many many years ago I, and three of my co-workers, had easy access to the radioactive research laboratories (cyclotron, gamma-ray scanners, PET cameras, medical stuff) in Berkeley. And we could come in, in the evening when no one else was there using anything, and run whatever experiments we wanted to. The rules were simple: clean up after yourselves, turn out the lights when done, and remember to lock the door. We made some Br-82 in the cyclotron (it has a 36 hour half-life), converted it to the elemental form and added some 2,5-dimethoxyamphetamine to it. One quick chromatographic clean-up, and we had our radioactive DOB. So into the gamma-ray scanning room, sterilize a water solution of it, and drew straws to see who would be
the first subject.

I won, lay down on the moving bed (the detectors are fixed in a curvy cluster on the floor and the bed moves over them) and got a few milliliters of the solution intravenously in my right arm. The bed started moving me head-first over the scanner, and the detector output appeared as horizontal lines on an oscilloscope monitor over in the corner of the room. In a matter of minutes there was a picture of me vertically on the screen, with a bright spot at the point of injection (a slightly sloppy job!) and with me being scanned repeatedly so that the travel of the DOB could be followed as a function of time. Well, not exactly DOB. It is the radioactive isotope that is being followed and there was no way of telling just what molecular structure it was attached to.

As expected, the bladder gradually increased in size and brightness, but what was not expected was that there was almost no radioactivity in the brain. The stuff preferred going to the lungs. In an hour or so, the lung brightness died back a bit, and finally the brain started to get bright. The amount injected was too little for any effect, but it seemed reasonable that the lung, a pretty effective metabolizing organ, converted the DOB to something else that still held the bromine atom, and this something else was the true active material.

The radioactivity in the urine was not bromide ion, but I had no idea what chemical or chemicals it might be. The same experiment was run on the other three people (that same night and the following night) and they gave very similar patterns of distribution.

This would be a wonderful experiment to repeat today, using our new fantastic analytical instruments, but it would not be easy to do. DOB is now a Schedule I drug, and casual access to a cyclotron and a scanning bed is no longer available.

-- Dr. Shulgin