Much research has been reported on the effect of single doses of marihuana or THC on a wide variety of indices of physiologic function in animals. Most animalt studies involved large doses a-rid produced profound changes similar in nature but less in magnitude than those described in the previous paragraphs. These have been comprehensively reviewed elsewhere (Secretary HEW 1972, Forney, 1971; Secretary HEW, 1971) and should be consulted if more detailed information is required.

Similarly, much research has been done in man. As discussed in the previous section on factors influencing the psychopharmacological effect in man, an acute dose-response relationship has been clearly defined over a dose range relevant to human usage patterns for these effects. Thus, with increasing dose, the larger the effect on the index being observed and the longer the effect persists. However, there is a wide variation between individuals' responses but each individual is quite consistent.

The most consistent physiological sign is an increased pulse rate (Mendelson et al., 1972; Johnson and Domino, 1971; Renault et al., 1971; Galanter et al., 1972; Domino, 1970; Hollister et al., 1968 Manno et al., 1970; Mayor's Committee 1944; Waskow et al., 1970; Isbell and Jasinski, 1969; Meyer et al., 1971; Weil et al., 1968; Jones and Stone, 1970; Clark and Nakashima, 1968). This does not appear to be a direct drug effect on the heart (Manno et al., 1970). Instead, the drug appears to cause complex changes in the autonomic nerves regulating heart rate. Thus, Kiplinger et al. (1971) demonstrated that the increase produced by marihuana in heart rate is prevented by pretreatment with a Beta-sympathetic nervous system blocking agent, propranolol. A comparable increase rate was produced by treatment with isoprotemol, a Beta-sympathetic like drug. One subject developed an abnormal bigeminal rhythm after both marihuana and isoproternol.

Renault et al. (1971) noted a consistent effect of marihuana on the cardiac rhythm which also produced an increased heart rate. The effect was the suppression of the normal sinus arrhythmia usually produced by respiration. Respiration usually produces a slowing of heart rate mediated by the vagal parasympathetic nerve supply. This depression of normal vagal tone was further evidenced by the absence of heart rate slowing during forced expiration against a closed glotis (valsalva maneuver). This effect seemed to wax and wane over several minutes producing alternate periods of rapid and slowed heart rate.

Both autonomic nervous systems seem to be affected by marihuana; the sympathetic is stimulated while the parasympathetic is inhibited.

Kiplinger et al. (1971) clearly demonstrated that the amount of increase in _pulse rate was directly related to the dose of THC administered as did Renault et al. (1971) and Johnson and Domino (1971) over a wide range of doses. Both experienced and inexperienced marihuana smokers demonstrated increases regardless of the subjective state described. Tachycardia is noted rapidly and reaches a peak about 15 to 20 minutes after finishing smoking. The pulse rate returns to normal within one to one-and-a-half hours.

Other than the one report of bigeminy (Kiplinger et al., 1971), little or no alteration of normal heart rhythm were noted by electrocardiogram (Isbell et al., 1967; Mayor's Committee, 1944) other than sinus tachycardia (Mendelson et al., 1972). Johnson and Domino (1971) noted premature ventricular contractions in a few of their subjects, but they felt this effect was more likely produced by the smoking itself rather than by the drug.

Conjunctival injection, reddening of the eyes due to increased prominence of the conjunctival blood vessel and dilation of the scleral vessels, (Hepler et al., 1971; Kiplinger, et al., 1971) is another highly consistent occurrence (Mendelson et al., 1972, Allentuck and Bowman, 1942; Ames, 1958; Hollister, et al., 1968; Isbell et al., 1967; Manno et al., 1970; Waskow et al., 1979; Weil et al., 1968) produced by orally ingested and smoked al., 1968). This finding is produced by orally ingested and smoked marihuana (or THC). And thus the effect must be a direct drug effect and not caused by irritation from smoke (Perez-Reyes and Lipton, 1971). Kiplinger et al. (1971) noted that this finding was dose-related although it develops slowly reaching a maximum about one hour after smoking.

Reported effects on blood pressure are inconsistent. Some investigators find lowered pressure (Hollister et al., 1968; Isbell et al., 1967; Waskow, et al., 1970) while others report a slight increase (Johnson and Domino, 1971; Domino, 1970; Mayor's Committee, 1944) and still others report increases and decreases (Mendelson et al., 1972; Perez-Reyes et al., 1971).

Preliminary results of a carefully performed study of the cardiovascular effects (Weiss, 1971) demonstrated orthostatic, hypotension in the erect position and hypertension when supine.

Little or no effect has been demonstrated in humans on a wide variety of parameters investigated. Body temperature is unchanged (Mendelson et al., 1971; Hollister et al., 1968; Isbell et al., 1967; Brooks, 1896) as is respiratory rate (Domino, 1970; Isbell et al., 1967; Weil et al., 1968), lung vital capacity and acute bronchospasni (Mendelson et O., 1972) and basal metabolism (Mayor's Committee, 1944).

Several studies (Mendelson et al., 1972; Mayor's Committee, 1944; Personal Communication, 1970) have examined changes in blood cells and blood chemistry. No acute effects were demonstrated on red blood cell number, or structure; differential and total white blood cell count; platelet count; reticulocyte, count; serum electrolyte concentrations; calcium and phosphorous serum levels; liver function tests; uric acid concentration; type or quantity of serum proteins. Although increased frequency of urination is often reported, increased urine volume has not been demonstrated (Ames, 1958; Mayor's Committee, 1944) and no alteration of kidney function identified (Personal Communication, 1970; Hollister et al., 1968; Mayor's Committee, 194-4; Mendelson et al. 1972).

Reports of increased hunger, especially for sweets (Allentuck and Bowman, 1942; Ames, 1958; Manno et al., 1970; Mayor's Committee, 1944), have focused attention on blood sugar and food intake. No consistent significant change in blood sugar has been demonstrated (Dornbush and Freedman, 1971; Hollister, 1971; Hollister et al., 1968; Isbell et al., 1967; Manno et -al., 1970; Personal Communication, 1970; Weil et al., 1968) with some investigators finding decreases (Beringer et al., 1932; Lindemann, 1933-1934), others finding increases (Manno, 1970; Mayor"s Committee, 1944), still others finding both increases and decreases (Miras, 1965).

Podolsky (1971) found that although fasting blood glucose was unchanged by smoking marihuana, higher 30 and 60 minute glucose levels were noted after a standard dose of glucose. No corresponding alteration in insulin or growth hormone levels was demonstrated.

Hollister and Gillespie (1970) found an increased total food intake when the drug was administered after breakfast but not after an overnight fast. Half the subjects reported subjective increased hunger. Subjects' free fatty acid levels and blood glucose remained unchanged while the placebo controls' free fatty acid values decreased. Another study suggested increased appetite and food intake but was without adequate controls (Personal Communication, 1970).

An investigation of physiological parameters of stress after marihuana (Hollister, 1969; Hollister et al., 1970) revealed only a minimal increase in white blood cells and a minimal decrease in cosinophils but no changes in serotonin, cortisol level and urinary catecholamines. However, another investigator (Chopra, 1969) demonstrated increased catecholamine excretion especially those from the adrenal medulla.

Hepler and Frank (1971) and Frank et, al(1971) have carefully studied ophthalmological changes produced by marihuana. Swelling of the eyelids (Ames, 1958), ptosis (Isbell et al., 1967), photophobia and nystagmus (Allentuck and Bowman, 1942) and dilated, sluggish reacting pupils (Mayer-Gross et al., 1960; Mayor's Committee, 1944) were all mentioned in earlier discussions but were not demonstrated (Hepler et al., 1971).

Findings which were quantifiable (Hepler et al., 1971) were a slight pupillary constriction with normal responsiveness to light and accommodation and an increase in glare recovery time. No change was evident on near and far visual acuity, fundiscopic exam, visual field acuity and depth and color perception. However, a decrease in tear secretion and an increase in conjunctival injection was demonstrated.

Hepler and Frank (1971) reported an average of about 25% decrease in the intraocular pressure of most normal subjects after smoking marihuana. A preliminary trial in one patient with glaucoma demonstrated similar findings (Frank, 1971).

No objective impairment of improvement invisual acuity or brightness perception (Caldwell et al., 1970; Caldwell et al., 1969) nor effect on depth perception and duration of after image (Clark and Nakashima, 1968) was noted in other studies.

Neurological examinations have consistently revealed no major abnormalities during marihuana intoxication. (Mayor's Committee, 1944; Rodin and Domino, 1970; Rodin et al., 1970; Personal Communication, 1970). Subjects often report muscle weakness. Minimal decreased leg, hand and finger maximum muscle strength have been demonstrated objectively (Fere, 1901; Hollister et al., 1968; Mayor's Committee, 1944). However, electromyography was reported to be normal (Personal Communication, 1970

A slightly increased briskness in the knee jerk has been detected (Domino, 1971 - Rodin and Domino, 1970) while no change in threshold or elicitation of deep tendon reflexes is usually, reported (Hollister et al., 1968; Isbell et al., 1967).

Incoordination, fine tremor and ataxia are often experienced by the user (Ames, 1958; Beringer et al., 1932; Clark et al., 1970; Mayor's Committee, 1944). The presence of a fine tremor and decrements in hand steadiness and static body equilibrium leave been demonstrated with refined measuring devices when they are not grossly observable (Manno et al., 1970; Mayor's Committee, 1944; Mendelson et al., 1972). Kiplinger et al. (1971) using sensitive apparatus demonstrated these fine hand tremors and changes in body equilibrium are also dose related.

Cranial nerve function and somatic sensation have not been significantly impaired or improved. Subjective reports of increased auditory sensitivity contributing to greater esthetic appreciation of music (Winick, 1960) have been generally unconfirmed in objective tests of auditory acuity and pitch, frequency or intensity or threshold discrimination (Aldrich, 1944; Caldwell et al., 1970; Caldwell et al., 1969; Clark and Nakashima 1968; Mayor's Committee, 1944; Meyers and Caldwell, 1969). Objective improvement in auditory acuity in several subjects was noted (Walton, 1938; Williams et al., 1946).

Similarly, improvement in visual acuity and discrimination and altered depth perception reported by users has been unconfirmed objectively (Caldwell et al., 1970; Caldwell et al., 1969; Clark and Nakashima, 1968; Mayor's Committee, 1944; Hollister and Gillespie, 1970; Jones and Stone, 1970; Frank et al., 1971).

A slight improvement in vibratory sensation (Rodin and Domino, 1970), no change in touch or two-point discrimination (Rodin and Domino, 1970; Williams et al., 1946) nor olfactory and gustatory senses (Williams et al., 1946) have been demonstrated. Decreased sensitivity to pain has been objectively demonstrated (Personal Communication, 1970) which corroborates its past therapeutic use as an analgesic.

One of the most frequently reported subjective effects of marihuana intoxication is a distortion of time sense (Tart, 1971). Actual elapsed time is overestimated or perceived as being longer than actual clock time. Thus, present events are perceived as prolonged when intoxicated and isolated from the past and future. They are in the "hereand-now" (Melges et al., 1971). Many have confirmed this experimentally (Ames, 19,58; Clark et al., 1970; Mendelson et al., 1972; Dornbush and Freeman, 1971; Hollister and Gillespie, 1970; Weil et al., 1968; Williams et al., 1946). The over-estimate is much greater during periods lit which the subject is performing a task than for unfilled time, and the error is (greater as the time period is longer (Clark et al., 1970).

Melges et al. (1971) have demonstrated that marihuana intoxication induces temporal distortions with a greater concentration on the present and a shortening of span of awareness into the past and future. They believe that under the drug's influence, as the, subject becomes less able to integrate past, present and future, his awareness becomes more concentrated on present events. These present events are experienced as prolonged or timeless because they no longer appear to the intoxicated individual as transitions from the past to the future.

Melges and Bowlby (1969) have described habitual marihuana smokers who specifically use the drug to achieve the "here-and-now" orientation. These smokers claim this focus on the present permits them to be more open to immediate experience while being less troubled by past and future concerns. This focus may also explain the belief that perceptions during intoxications are both unexpected and never experienced previously.

The effect of intoxication on the resting electroencephalogram are still unclear but generally have been minimal, inconsistent and within normal limits. In early studies (Wikler and Lloyd, 1945; Williams et al., 1946) a decrease in alpha activity was noted. More recently (Ames, 1958) noted a delayed alpha increase with concomitant increases in beta and theta activity. Rodin and Domino (1971) reported a slight shift toward slower alpha frequencies.

Three other studies (Jones and Stone, 1970; Hollister et al., 1971; Rickles et al., 1970), failed to find consistent changes but noted increased alpha frequency, increased synchronization and occasional paroxysmal activity. These effects were ascribed to relaxation and drowsiness.

Two investigators (Chopra, 1935; Miras, 1969) reported decreased fast activity and other variable effects. Most recently, Volavka et al. (1971) and Fink et al. (1971), reported a significant rapid onset effect occurring during the five-minute smoking period and of short duration (less than 30 minutes) in continuously alert individuals. The principal changes detected by computer analysis were a dose related increase in percent alpha time and an associated reduction in theta and beta hands.

Roth et al. (1972), demonstrated that auditory evoked responses were decreased in amplitude by marihuana and THC particularly during the first few minutes of stimulation. These results may indicate that the intoxicated individual may receive external auditory stimuli differently during the intoxication period.

The prominent and frequently reported sedative effects of marihuana and the dreamlike states occurring during intoxication directed several investigators to study the effects of marihuana on sleep. Fragmentary data from one sleep laboratory (Pivik et al., 1969) indicated decreased rapideye-movement (REM) sleep time. Another sleep lab (Rickles et al., 1970), in preliminary work demonstrated an increase in REM sleep time. Fink et al. (1971) noted that EEG defined sleep (stages one and two) were dose dependent but THC did not act like a classical sedative. The occurrence of EEG sleep was much more frequent in the placebo and low dose (10 mg THC) conditions than in the high dose condition (20 mg THC).

Mendelson et al. (1972) noticed an increased amount of total sleep as well as an increase in discrete episodes of sleep related to marihuana smoking. These findings correlate well with questionnaire data (Tart, 1970) indicating that at moderate doses, users found it easier to induce sleep and that sleep was considered to be more refreshing, while at higher doses both aspects were impaired.

In summary, marihuana containing Delta-9-THC is a pharmacologically active drug with minimal acute physiological effects at the low to moderate doses used by man.

Based on its few consistently observed physiological effects, marihuana is a rather unexciting compound of negligible acute physiological toxicity at the usual doses consumed by man. The subjective state characteristically described by the intoxicated user is far more interesting to both the user and the scientist than the objective one observed by the investigator.