Pharmacology of Marijuana: Just Another Sedative

FREDERICK H. MEYERS, M.D.

Professor of Pharmacology, University of California, San Francisco, Ca.

The Drug Policy Foundation's CME Seminar

Washington, D.C. November 13, 1992

Introduction

Change in the laws regulating the use of marijuana-certainly a primary goal of this group-has been effectively blocked by the successful efforts of the enforcement industry to convince the citizenry that the use of marijuana presents a terrible danger to the user and to society. Efforts to rebut the claims of the prohibitionists have been enfeebled by the confusion that some of us feel. Proselytizers insist not on an absence of significant danger but on some positive, mystic and generally ineffable benefit from the use of marijuana. Observers with less subjective overlay also appear at a loss in formulating the pharmacology of Cannabis, and both groups thus play into the hand of those who encoded marijuana as an hallucinogen or who plead for delaying action pending further research.

Even the technical or scientific reviews of the drug by nominal experts are little more than catalogues suffused with uncertainty, timidity and even error generated by the confusion imposed by law and street lore. The defects in the literature are not due to a lack of data from research but to a failure or inability to apply any unifying or organizing concept to the fragments of information. It will not be difficult to supply you with that key: cannabis in its several forms and essences is just another member of a large group of drugs, call them for the moment general anesthetic-sedative-hypnotics, all of which are used (and abused) at some time and in some form by some technique by some individuals to relieve anxiety, to provide surcease from memory and to cross the borders of consciousness and sometimes even of life.

Members of this group of drugs, exemplified by alcohol, Valium, and the other agents in the incomplete list in Figure 1, all have characteristic, identifying effects in common, They differ one from another largely in their duration of action and speed of onset of effect. Some of them, especially alcohol, have important organic toxicity not seen in others. It will also be necessary to discuss the differences in the slope of the dose-response relationship, that is the margin of safety. However, the most important preliminary matter is the effect of the route of administration on the manifest actions of a drug.

SMOKE AS A DRUG DELIVERY SYSTEM

Many people, including those smokers of marijuana who use wine or beer to reinforce and prolong the effect, will resist the conclusion, established below, that marijuana and alcohol are comparable pharmacologically. Their intuitive feeling that there can be no relation between the instantaneous, transient euphoria from a joint and the more slowly developing and persistent good feeling after a drink is understandable but mistaken. Before the similarity of effects can be convincingly presented, however, the influence of the route of administration on the temporal relations of the response must be clarified by as brief as possible a discussion of the distribution and transformation of THC, the active ingredient of cannabis, after it enters the body whether swallowed or inhaled.

The differences claimed to exist between marijuana and alcohol (or Valium or whatever) virtually disappear if the reference drug is given by mouth and is compared with THC also orally administered. (Careful metabolic studies of crude drug using special chocolate cookies are also available.) THC, it turns out, is actually much more slowly metabolized and excreted than alcohol (Figure 3 and 6). THC, like phenobarbital or chlordiazepoxide (Librium), is best given as a cumulative drug, and the amount in the body at equilibration is enormous compared to the amount provided by one cigarette. Why then does the cigarette provide such an immediate and intense effect?

First of all, realize that the particles in the smoke that carry the drug are colloidal in size; so small that they are carried by the inspired air to the depths of the lung where the drug can be instantaneously absorbed across the alveolar membrane. The efficiency of this process is already apparent to you by analogy with the two common methods of cocaine delivery. Smoked free-based (crack) is absorbed with a velocity resulting in levels comparable to those seen after intravenous injection. In contrast, the particles of inhaled cocaine salt are relatively large, are deposited on the mucosa of the upper respiratory tract and absorption is not much more rapid than after swallowing the drug.

The THC in smoke is rapidly transferred to the essentially aqueous blood and carried immediately to the left heart and into the arteries, that is, the liver is not included in this first pass and the absorbed THC is diluted by a relatively small volume of arterial blood that is pumped to the tissues. Difference vascular beds have differing blood flows. The cerebral blood flow is relatively large and the brain is a fatty organ in the chemical sense. THC is partitioned from the blood into the lipids of the brain tissue. Immediately after inhalation, then, a high concentration of THC is built up in the brain and the subjective experience begins.

The THC remaining in the blood undergoes two additional processes. Some reaches the liver and a fraction is altered chemically- some accumulates in other fatty organs especially ordinary adipose tissue. This accumulation slowly removes THC from the blood. :The accumulation is slow because blood flow to these depots is low. However, as THC is removed from the blood, the concentration in the blood falls below that in the brain and the THC passes from the brain back into the blood and the behavioral effects at least rapidly diminish (Figure 5).

It is this rapid accumulation of agent in the brain and its subsequent redistribution rather than its chemical transformation that explains the brevity and intensity of the effect. The effect begins before the subject exhales. As an illustration of the efficiency of smoking consider that in one trial 10-15 mg of Smoked THC resulted in a peak concentration about eight times as great as followed 20 mg by mouth (Figure 3).

There are some correlates of THC metabolism unrelated to our immediate discussion but worth mentioning in passing. THC accumulates in fat to a concentration at least twenty fold that in any other organ, and the slow release of the stored substance explains the persistent appearance of THC and its metabolite in the urine for weeks. (Figures 4 and 6.) Unlike the blood levels of the very water soluble alcohol, THC levels do not correlate with its biological effects.

Now that we are able to adjust to the different routes of the administration, we can examine the effects of marijuana and compare them with the effects of other sedatives.

THE SEDATIVE -HYPNOTIC -GENERAL ANESTHETIC GROUP

Physicians are conditioned at great expense by the drug industry to think of available therapeutic agents as thousands of individual cases properly identified only by a euphonious tradename. However, the vast amount of information available can be managed only if drugs are put into classes or categories. The same properties that make for a useful therapeutic agent may make for an enticing social drug, and it is not surprising then that most social drugs fit into known categories.

There are a very large number of drugs that have similar effects and are fairly included in the category sedative-hypnotics or anxiolytics although sedative-hypnotic-general anesthetics would be more accurate. Gases and volatile liquids are often selected for use as general anesthetics because their use can be by inhalation and allow minute to minute control of dosage and rapid recovery. Solids are more easily dispensed and administered as tablets or capsules and are chosen for use in treating anxiety or inducing sleep, but pharmacologicaly all are similar. Figure 1 lists some common drugs from this group.

This exercise will now examine the pharmacology of marijuana and establish that all of the properties of sedatives are present. Remember, please, throughout the discussion that effects are described to establish the drug type. It does not follow that these effects are induced regularly or even at all as marijuana is used in our culture, but they are established by quantitative experiments in the animal laboratory and by controlled clinical observations.

EFFECTS OF GRADED DOSE:

The simplest way to characterize marijuana and equate the effects with those of all other sedatives and general anesthetics is to study the effects of doses of increasing size. It is important to study the drug over a range of doses because the effects manifested at a single dose level may mislead. Alcohol even today is regarded as a stimulant by many people because they see only the excitement and acting out; with larger or smaller doses it becomes apparent that alcohol is a depressant and that the excitement is actually disinhibition. The sequence of changes are those still conveniently described as the stages of anesthesia. These changes reflect a diffuse depression of the neuraxis that begins at the highest level of the cortex and at the caudal segments of the cord. The depression descends and ascends until it meets at the medulla and even vegetative function stops.

Stage 1 was long called the stage of analgesia. With small doses, the subject experiences relief of anxiety or euphoria (a positively good feeling) and possibly a slight drowsiness. Psychomotor performance, concentration, short term memory are progressively impaired in the laboratory situation. Actual performance (driving on a test course) deteriorates if the dose is adequate and the timing consonant. The flight simulator is a useful tool and shows the same prolonged (24 hours) decrement in performance seen after the acute effects of the barbiturates. Judgment is obviously difficult to test, but most observers consider as evidence the inappropriate high humor and confidence in a fumbling, discursive subject. The one generalization that is hard

for users of marijuana or of other sedatives to accept is that users, whose function and ability to judge their function are both impaired, are the persons least competent to analyze the effects of a downer.

Stage 2 begins with the appearance of excitement. The degree of excitement depends not alone on the dose but also on the expectation of the subject and the setting, that is, on the amount and nature of stimuli from the surroundings. In a calm environment the subject may show only an intensification of the changes listed for Stage 1. In another situation, the patient may respond to stimuli in an uncontrolled, exaggerated way. This excitement must not be confused with stimulation. These "drunks" from whatever drug are disinhibited, that is, the highest cortical centers are depressed and lower centers and more primitive behaviors are released from the inhibition from above that ordinarily controls them. The stage ends with the loss of consciousness.

The flat dose response curve mentioned above now becomes of crucial importance in understanding why marijuana does not cause, as a direct drug effect, the same disinhibited criminal and antisocial activity as does alcohol. Marijuana is in part benign in this regard because the brief effect after smoking is achieved with a small absolute dose. However, even if the subject is swallowing hashish or THC (which is now marketed), the dangerous (to self or others) dose is many multiples of the threshold dose and, so far as I can establish, never achieved in humans in this country. (There never was any basis for the picture of the hash-crazed assassin. The assassins were a sect in Islam active at the time of the crusades who were given to religio-political murder but not under the influence of hashish. Their assassinations were carefully planned and sometimes required years of preparation while, for example, the designated hit man learned a language and a trade and insinuated himself into the court of the victim.)

Stage 3, the stage of surgical anesthesia, is easily reached with cannabis in the animal laboratory, but the dose-effect curve is so flat that is, so much is required, that it is doubtful if anyone in the U.S. has ever been anesthetized by cannabis resin in any form. For our purpose, classification, however, the animal data are enough.

Stage 4, the stage of medullary paralysis, is demonstrable with difficulty even in animals. The oral LD50 of THC in rats is in excess of 600 mg/kg.

ANOTHER ACUTE EFFECT

Dreamy, Fantasizing State

The law thinks that marijuana is an hallucinogen, and any number of groups and individuals refer to marijuana as a "mild hallucinogen" and thus terribly confuse the perception of the drug by many citizens.

What marijuana does is induce the same state that has been described in association with every sedative-hypnotic that has had wide use. The effect is most easily and commonly defined in hospitals or offices where sedated patients can make known to doctors and nurses their difficulty in distinguishing dreams and waking fantasies from reality. The patient may complain bitterly of the frightening nightmares or may accuse a staff member of molesting her. At home the nightmares may be equally frightening, but the erotic dreams cannot be projected onto an attendant and the dreamy float may actually be pleasurable. The absence of an exact statement about the associated level of consciousness is not accidental. The process appears separate from the developing concept of lucid dreaming.

This effect is also totally different than that of the nominal hallucinogens such as acid. I say "nominal" because the dreams of the sedated patient are by definition closer to hallucinations than the distortions of perception experienced with what, it appears, we will soon have to call rave drugs. These magic agents all have the properties of the sympathomimetic stimulants to a greater (MDA, MDMA) or lesser (LSD) degree.

Where the misconceived labeling of marijuana as hallucinatory originated, and how it is maintained is a question of interest to those of us who hope to see the laws regulating marijuana rationalized. The 1937 enactment, designed to criminalize marijuana use and thus provide continued federal employment for redundant prohibition agents and a fiefdom for Anslinger, classified marijuana as a narcotic. This irrationality, together with the ruling by the Supreme Court that applying for a tax stamp to handle an illegal substance constituted self incrimination and would not fly, forced some revisions at just about the time the early proselytizers for LSD were active. When the hallucinogens were added to the index, marijuana was transferred to that category. The enforcement industry is, of course, still happy to have it separated from anything familiar. Unfortunately several groups of professionals and marijuana advocates are as responsible for maintaining the fallacy as those from the criminal justice system.

EFFECTS DURING CONTINUOUS USE

Tolerance and Withdrawal

The tolerance and withdrawal expected of a sedative does develop with the use of cannabis in concentrated forms. Tolerance strictly defined has been demonstrated only with the use of concentrated forms of cannabis or of THC and an analogue. However, a learning process that is fairly called behavioral tolerance explains some otherwise puzzling observations that are made on people who smoke grass.

Behavioral Tolerance - The manifest expression of sedative effect depends not alone on the pharmacological effect in the strict sense but also on the expectation of the user and on his reaction to the physiological and behavioral changes perceived. Taken at bedtime, a downer will shorten sleep latency; the same dose at five in the afternoon in a situation that provides stimulation and the need to continue to function may lead to excitement. An inexperienced user, notably a first time user or someone unexpectedly experiencing a larger than usual dose or someone using in an anxiety laden situation, may be seized by panic. We have no time for case histories, but the hypomania and paranoia that accompanies the disinhibition and anxiety can be alarming to all. If the episode is followed by feelings of guilt or fear of consequences, the anxiety or panic can be prolonged or recurrent. Possibly these incidents and the withdrawal state to be described were the origin of the now discredited claim of a marijuana psychosis.

The experienced drinker or marijuana user will not show these exaggerated reactions, indeed, he will be able to hide some minor effects consistently. The effects on psychomotor function and cognition will not, however, be lessened, that is the tolerance is more apparent than real.

Metabolic Tolerance.- Behavioral tolerance is usually contrasted with "real" or metabolic tolerance. However, it seems to me that, in this day of disproportionate interest in biotransformation and P450, "real" tolerance should be divided into the metabolic and physiologic.

As we shall see, some kind of tolerance to marijuana clearly must develop since its correlate, withdrawal, is easily demonstrable. Tolerance, however, is quantitatively minor, and it is not necessary to use larger and larger doses to maintain the same effect, nor do fixed doses lose their effect with continued administration. The point at this moment is that enzyme induction cannot be important in this situation since frequent users of marijuana achieve higher plasma levels after a test dose and excrete the dose over a longer period than do infrequent users (Figure 6).

Physiologic Tolerance - Small but statistically significant degrees of tolerance to

the effects on cardiovascular function, amount of REM sleep, psychomotor performance, intraocular pressure, subjective judgment of intensity of effect and others developed rapidly when, to cite one specific paper, 210 mg per day of THC or the equivalent in the form of crude extract was given for 11-21 days.

During the above period of drug administration, physical dependence developed, for, to anticipate the next paragraph, the abrupt replacement of the drug with a placebo led to signs of hyperexcitability or stimulation, that is, to withdrawal. The constant presence in the body of a depressant had led to the activation of antagonizing, stimulant or excitatory physiologic systems.

Withdrawal - The signs of withdrawal or physical dependence appear when the stimulant or excitatory adaptations persist beyond the e effect of the depressant. In the above trial, weight loss, irritability and an increase in time spent in REM sleep were prominent and persisted for 96 hours. Another apparently well executed trial gave large doses of a synthetic analogue of THC for a month. The withdrawal state described upon discontinuing the drug was more in the expected pattern in that it developed on the third day and was characterized by restlessness and disturbed sleep although one subject did develop hypomania. Under the same experimental conditions, subjects were allowed free access to the drug as cigarettes; the average patient smoked seventeen cigarettes per day, but no withdrawal state could be demonstrated.

Insofar as our needs for classifying cannabis are concerned, there remains the question of whether withdrawal from strong cannabis could be as intense as the delirium tremens of alcohol withdrawal and explain some of the "psychotic" episodes alleged to occur. Controlled trials, of course, are not going to become available. The clinical reports, notably those from British physicians serving colonial troops, seem convincing to me.

Potential for Abuse

There is no drug of this category that has not been misused either episodically or compulsively. Relief of anxiety is a seductive pharmacological reward, and countless patients and non-patients are unable to resist using a little more than is prescribed, a little oftener than is necessary. If one looks outside of our culture to the Muslim world, it appears that a compulsive pattern of use is possible, but in this country the mode is the "responsible use" that the consensus applauds in the case of alcohol. The responsible use of the less dangerous cannabis is not countenanced because some agency or forcehas convinced our legislators. that marijuana is somehow different from all of its congeners.

Other Effects

There are a few other minor drug effects common to cannabis and all other sedatives. In the animal laboratory the tetrahydrocannabinols are anticonvulsant and comparable to Phenobarbital. Presumably THC could be used in the human as an antiepileptic, but also presumably the rapid down and up of smoked marijuana could destabilize a seizure prone patient.

As is necessary to validate our thesis, marijuana depresses polysynaptic spinal cord reflexes. In the laboratory this effect can be demonstrated independent of the behavioral sedation, but clinically the voluntary muscle relaxant effect of the sedatives cannot be shown to be useful beyond or independent of the anxiolytic effect.

A discussion of the therapeutic applications of marijuana or of THC, which is available on prescription, would contribute to our argument to the extent that the drug can be shown to act as a sedative or anxiety relieving agent. The use of synhexyl as an antidepressant is often mention. Review of the paper by Stockings usually cited in this regard will establish that he actually used the drug for the relief of anxiety. He clearly characterizes his ambulant patients as neurotic and describes the development after the administration of the analogue of THC of mild intoxication, euphoria, and dreamy apathy. Given a patient whose vision and ocular structure has been destroyed by glaucoma no one would withhold whatever subjective relief a joint would provide, but it would be misleading to say that marijuana is acting on the glaucomatous process. Whether marijuana has important therapeutic applications is an emotional issue that can be settled only by controlled clinical trials of each proposed application as is required for any other new drug or new application. In any case, the questions associated with the use of marijuana as a social drug are unrelated.

MECHANISM OF ACTION

The mechanism of action of this large group of drugs is, as has been mentioned, a diffuse depression of the entire central nervous system. However, one action is more specific and is useful in developing our analogy. The ability of a sedative or anesthetic to cause loss of consciousness is due to the sensitivity of the reticular activating system to their depressant effects. When electrodes are implanted into the reticular formation and several functionally related areas in the brain,, the effect of synhexyl cannot be distinguished from that of thiopental (Pentothal), that is, the barbiturate and the cannabinoid have a similar mechanism of action. (Synhexyl is a close analogue of THC that was available in pure form before THC. Careful, controlled double blind studies have shown that human subjects are unable to distinguish between the two.)

In summary then marijuana is a drug which is pharmacologicly similar to all other sedatives. There are differences between the various sedatives, but these are largely matters of onset and duration of action. The exception is alcohol which must be ingested in grams rather than milligrams and which provides empty calories that replace food that contains protein and vitamins. and in some people the thiamin deficiency can lead to atrophy of the brain. Alcohol also has direct toxic effects on the liver, upper GI and respiratory tracts and brain As a direct effect of its persistent action and the ease with which a grossly disinhibiting action can be reached, it is responsible for massive social and criminal problems.

Having provided you with an outline or framework upon which you can hang your further studies and experience with marijuana, I have reached the boundary of my province as a Pharmacologist. In considering the social problems presented by our societal reaction to the use of marijuana, I am a citizen with one vote. However, I believe that the objective pharmacology that I have presented suggests a well advised direction for change.

People who prefer marijuana to alcohol as a social drug can fairly point out that the disinhibitory effect is brief, a dangerously intense effect difficult to achieve and the organic toxicity infinitely less than is the case with alcohol. From what I regard as an objective pharmacologic point of view, I do not see how we can with any hope of useful outcome acknowledge that prohibition failed in the case of alcohol and at the same time apply the discredited remedy to marijuana. It would also be useful to eliminate the market that bleeds dollars into other economies, and undeniably the criminal justice system would become more useful if relieved of the burden posed by the huge number of people who do not feel guilty.

Yet I do not wish to encourage the use of marijuana; we certainly must not reduce regulation to the point that another cigarette or liquor industry develops. My suggestion is to legalize cultivation for personal use.

References For Figures

1. Huestis, et. al., Characterization of the absorption phase of marijuana smoking Clin Pharmacol Therap 1992;52:31

2. Kreuz and Axelrod, Delta-9-tetrahydrocannabinol: Localization in body fat Science 1973;179:391

3. Ohlsson et. al. Plasma delta-9- tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking Clin Pharmacol Therap 1980; 28:409

4. Peat, Jones, et. al., The disposition of delta-9-tetrahydrocannabinol... in frequent

and infrequent marijuana users J Pharmacol Exp Therap 1987 (Preprint)