The 1995 Marijuana Rescheduling Petition

Technical Flaws With Early Experiments

Until 1980 the cell membrane perturbation theory dominated scientific research on marijuana, and consequently the cell membrane perturbation theory formed the basis for policy decisions by the Department of Justice on the scheduling of marijuana under the CSA. Herkenham's 1990 discovery proved that the cell membrane perturbation theory was incorrect, and that this was due to technical flaws with the research. Ironically, Martin's 1986 paper which concludes with marijuana affects every biological system studied is now oft-cited as a reference to those technical flaws.

The primary technical problem is that it is hard to make a liquid cannabis solution to test on animals and cell tissue. Cannabinoids are not water soluble, and the creation of usable solutions for experimental research was fraught with problems. Even Gabriel Nahas took note of these difficulties:

"Many different methods for suspending, solubilizing, or emulsifying delta-9-THC have been suggested. These include the use of surficants (Tween 80, Triton X-110, Pluronic), solvents (ethanol, propylene glycol, dimethylsulfoxide, olive or sesame oil), and suspending agents (resin, albumin, dextrans), as well as ultra sonic emulsifiers. None of these methods is entirely satisfactory, because they all influence the rate of absorption as well as pharmacological activity. The fact that all of these methods have been used by various investigators makes quantitative comparison difficult."(5)

This problem was also widely recognized by his contemporaries. Sir Paton warned as early as 1975:

"A technical warning note that the pattern of extracting cannabinoids by different solvents varies with the tissue carries intriguing physiochemical implications."(6)

With hindsight, those two comments exhibit considerable understatement. According to Miles Herkenham of the National Institute of Mental Health, the early biochemical studies have three flaws:

"Most of the biochemical studies employed concentrations of D9-THC that were in excess of physiologically meaningful concentrations that might be found in brain. In addition, the criterion of structure-activity relationship was not met -- that is, the potencies of the various cannabinoids in the in vitro assays did not correlate with their relative potencies in eliciting characteristic behavioral effects. Particularly damaging to the relevance of these in vitro studies was the absence of enantioselectivity."(7)

In simpler terms, it took incredibly unrealistic potencies to produce results, and there were no guarantees that the solutions did not alter the compounds being studied.

Cannabinoids are sticky, although scientists refer to this as a "tendency to adhere to glass and plastic in in vitro experiments." One problem is that this stickiness is not uniform. Different amounts of the compound precipitate out of various test solutions. British pharmacologist R.G. Pertwee explains that this feature contributes to variance in the concentrations of the cannabinoid compounds used in research, complicating interpretation of results. (8)

As explained in 1986 by B.R. Martin:

"These properties of cannabinoids disallow an estimate of the concentration of agent at its site of action and hence compromise assessment of responsiveness."(9)

Given the available evidence and technology, Martin's concerns had foundation. However technology changes, and as it changes it radically alters the evidence available to scientists for theory evaluation. As Herkenham reiterates in 1992:

"Until recently, very little was known about the cellular mechanisms through which cannabinoids act . . .Without evidence that cannabinoids act through a specific receptor coupled to a functional effector system, researchers were prone to study the effects of cannabinoids on membrane properties, membrane-bound enzymes, eicosanoid production, metabolism, and other neurotransmitter systems in vitro."(10)

This is a very confusing point for non-scientists to grasp, but conclusions based on many of the studies on membrane properties and the like are no longer scientifically valid. The researchers most responsible for the 1990 breakthrough explain.

"Because the cellular and biochemical mechanisms of action of psychoactive cannabinoids were not understood, neuroscientists were allowed great breadth to speculate upon the influence that these compounds might have on the neurons of the brain."(11)

For the same reason, policy making was also allowed the same breadth of speculation. Marijuana's current schedule I status is based on an FDA conclusion

"that abuse of the plant material may lead to severe psychological dependence in some individuals but the information was insufficient to determine with certainty whether the plant material produce physical dependence."(12)


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