Descriptive accounts of marihuana intoxication have been written by noted authors, Beaudelaire (1961), scientists, Moreau (1945), and common users Tart, 1970, 1971; Isbell et al., 1967; Report by Advisory Committee, 1968). Adequate description of the state of mind produced by low doses is difficult because it is not approximated in the usual states of consciousness or by other commonly used drugs. The closest non-drug approximation may be the altered state of consciousness experienced in the hypnotic trance or transcendental meditation or the, transition zone between waking and sleep (Weil, 1971). Due to the highly subjective nature of the experience, there is much individual variation in the effects described.

Tart (1970, 1971) studied the range of potential common effects in an extensive survey of 150 users. Changes noted by these studies at low doses (usually smoked dose about five mg. THC) include euphoria, with restlessness and mild mental confusion. Sensory perception of the external environment. is altered. Users often perceive an overestimation or slowing of elapsed time and expansion of space, enhanced sense of tactile, olfactory, gustatory perceptions and often a feeling of hunger. Visual alterations reported are more vivid imagery and seeing forms and patterns in objects that are usually amorphous. Increased awareness of subtle qualities of sound such as purity, distinctness or rhythm are characteristically perceived by users. A dreamy, relaxed state and disinhibition, with uncontrollable laughter is reported and users often believe that interpersonal relations are altered, and act to potentiate social interaction.

At moderate doses intensifications of changes experienced are reported. Users' reports include disturbed associations, dulling of attention, vivid visual imagery, fixed ideas, rapidly changing positive and negative emotions, fragmentation of thought, flight of ideas, impaired immediate memory, altered sense of identity, increased suggestibility and a feeling of enhanced insight. At higher doses, interpersonal relations are dulled and the user feels less social and more withdrawn.

At larger doses psychotomimetic (hallucinogenic-like) phenomena are experienced in a wavelike fashion. These include distortion of body image, depersonalization, visual illusions and distortions, synesthesia, dream-like fantasies and vivid hallucinations.

Data from Isbell et a]. (1967) and Perez-Reyes et al. (1971) have indicated that the hallucinogenic oral dose is in the range of 0.4 to 0.5 mg./kg Delta 9 THC. Thus, the hallucinogenic dose is 80 times larger than the delivered dose of smoked marihuana producing minimal subjective effects (five micrograms/kg.) or about 11 to 14 times larger than the usual smoked dose.

LETHALITY

There is no conclusive evidence that short-term marihuana use alone directly results in any physical damage to man. A few scattered fatalities associated with marihuana use are occasionally reported. Most are from 19th century Indian experiences with large oral doses of charas (Deakin, 1880; Bouquet, 1951; Ewens, 1904, Walton, 1938; Indian Hemp Drugs, 1893). Brill et al. (1970) and Smith (1968) have noted that there have not been any reliable reports of human fatalities attributable purely to marihuana, although very high doses have been administered by users.

A frequently cited recent report from Belgium by Heyndrickx et al. (1970) describes an essentially negative pathological and toxicological study of a 23-year-old man found dead in the presence of marihuana, and hashish. A cannabinoid was detected in his urine. However, this finding in no way inculpates marihuana as the responsible agent. There are many possible causes of sudden death which are not toxins and do not produce observable pathology; e.g. anaphylactic reactions, insulin shock, cardiac arhythmias, etc.

A case report (Nahas, 1971) of an attempted suicide by smoking hashish, recently in France is even more anecdotal. An individual was reported to have smoked consecutively ten pipes of hashish containing approximately 200 mg of Delta 9 THC each before losing consciousness. But recovery occurred after supportive treatment.

Another case report (Hughes et al., 1970) relates severe diabetic coma with ketoacidosis after the ingestion of huge amounts of marihuana by a mental patient. However, it appears that the pronounced vomiting secondary to the marihuana ingestion caused a severe electrolyte imbalance and alkalosis. Possibly a vulnerable glucose-regulating system responded to the severe stress inappropriately. Retrospectively, there was no history of diabetes noted previously but this was not confirmed or ruled out by lab tests prior to the episode.

Several case reports (Henderson and Pugsley, 1968 King and Cowen, 1970; King et al., 1970; Lundberg et al., 1971; Gary and Keylon, 1970) noted acute severe, physiological disturbances and acute collapse (shock, chills and fever) subsequent to intravenous injection of suspensions of marihuana. These symptoms may have been due to an allergic reaction to injected foreign plant material, to a bacteremia and/or to the injection of insoluble particles which are filtered by the organs. The symptoms may be considered a complication of the mode of use, rather than results of the drug.

Although a median lethal dose has not been established in man (Brill et al., 1970), one has been found in laboratory animals. Earlier reports (Lowe, 1946; Joachimoglu, 1965) used materials of uncertain potency and composition. Recent studies utilized carefully quantified materials. One group, Phillips et al. (1971), utilizing THC extracted from marihuana, demonstrated the following LD50 (the dose that causes death in 50% of the animals) in units of mg/kg of Delta 9 THC from mice,/rats: oral 481.9/666, intraperitoneal 454-9/ 372.9, intravenous 28.6/42.47.

Thompson et al. (1971) under contract to the National Institute of Mental Health have recently carried out extensive studies in rats, dogs and monkeys in order to define the range of toxicity of the drug. The group used synthetic Delta 9 and A' THC and a crude marihuana extract (CME) of carefully define composition. Delta 9 THC was more potent than Al THC. CME was less potent than a similar quantity of A' THC.

Acute toxicity was studied using intravenous, intraperitoneal and oral routes of administration in rats. An LD50 similar to that reported by Phillips et al. (1971) was found by the intravenous route (20 mg/kg of THC) and intraperitoneal route (400 mg/kg) but higher values were noted with oral administration (1140 mg/kg). Interestingly, the LD50 for males was 1400 mg/kg while for females it was 700 mg/kg by the oral route. The minimal lethal dose orally was between 225 and 450 mg/kg.

An LD50 was not attainable in monkeys and dogs by the oral route. Enormous dose levels (over 3000 mg/kg of Delta 9 THC) were administered without lethality to most animals. A dose of about 1000 mg/kg THC was the lowest dose which caused death in any animals The completeness of intestinal absorption of THC at these high doses is unknown. Behavioral changes in the survivors included sedation, huddled posture, muscle tremors, hypersensitivity to sound and hypermobility.

The cause of death in the rats and mice subsequent to oral THC was profound central nervous system depression leading to dyspnea, prostration, weight loss, loss of Fighting reflex, ataxia, and severe fall in body temperature which led to cessation of respiration from 10 to 46 hours after single dose oral administration. No consistent pathological changes were observed in any organs. The cause of death when it rarely occurred in the higher species did not appear to be related to the same mechanism as in the rats.

Using intravenous administration, the acute one dose LD50 for Delta 9 THC was 100 mg/kg in dogs and 15.6 to 62.5 mg/kg in monkeys depending on concentration of the solution. The minimal lethal intravenous dose for dogs, also depending upon concentration, was 25 to 99 mg/kg and for monkeys 3.9 to 15.5 mg/kg.

In contrast to the delayed death observed in rats after oral administration, lethality in rats, dogs and monkeys after intravenous injection occurred within minutes after injection. When sublethal amounts were injected, central nervous system depression with concomitant behavioral changes similar to those observed after oral doses were observed. However, their onset was more rapid and the intensity of effect more severe with anaesthesia, and convulsions noted after injection. The monkeys and dogs that survived the intravenous injection of THC recovered completely within five to nine days.

The only consistent pathological changes were noted in the animals which succumbed. Pulmonary changes including hemorrhage, edema, emphysema and generalized congestion were found and death resulted from respiratory arrest and subsequent cardiac failure. The investigators presumed one mechanism possibly accounting for these findings was due to the concentration of the THC solution and its insolubility in water. Presumably, when these highly concentrated solutions mixed with the blood, the THC precipitated out of solution. The precipitated foreign material then formed aggregates (or emboli) that were filtered out in the lung capillaries causing a physical blockage of pulmonary blood flow.

Subsequently, intravenous studies were repeated using Delta 9 THC emulsified in a sesame oil-Tween 80-saline vehicle at 15 mg/ml or 40 mg/ml. The emulsions were administered at a uniform rate of 2 ml/15 sec. Doses administered were 1, 4, 16, 64, 92,128, 192 and 256 mg/kg. All monkeys injected with 92 mg/kg or less survived and completely recovered from all effects with two to four days. All monkeys injected with 128 mg/kg or more succumbed within 30 minutes for all but one (180 minutes).

Histopathological changes found in the lungs of the deceased monkeys were like those described after the, previous intravenous experiment. All the monkeys that died exhibited severe respiratory depression and bradycardia within five minutes after the injection. Respiratory arrest and subsequent cardiac failure occurred within minutes. Behavioral changes preceding death were salivation, prostration, coma and tremors.

Behavioral and physiological changes described clinically in the surviving monkeys followed a consistent developmental sequence and were roughly dose related in severity and duration. Onset was 15 minutes following injection and duration was up to 48 hours. Huddled posture and lethargy were the most persistent changes. Constipation, anorexia and weight loss were noted. Hypothermia, bradycardia and decreased respiratory rate generally were maximal two to six hours post injection. Tremors with motion but not at rest were believed to be caused by peripheral muscle inadequacy.

In summary, enormous doses of Delta 9 THC, All THC and concentrated marihuana extract ingested by mouth were unable to produce death or organ pathology in large mammals but did produce fatalities in smaller rodents due to profound central nervous system depression.

The non-fatal consumption of 3000 mg/kg A THC by the dog and monkey would be comparable to a 154-pound human eating approximately 46 pounds (21 kilograms) of 1%-marihuana or 10 pounds of 5% hashish at one time. In addition, 92 mg/kg THC intravenously produced no fatalities in monkeys. These doses would be comparable to a 154-pound human smoking at one time almost three pounds (1.28 kg) of 1%-marihuana or 250,000 times the usual smoked dose and over a million times the minimal effective dose assuming 50% destruction of the THC by smoking.

Thus, evidence from animal studies and human case reports appears to indicate that the ratio of lethal dose to effective dose is quite large. This ratio is much more favorable than that of many other common psychoactive agents including alcohol and barbiturates (Phillips et al. 1971, Brill et al. 1970).

PHYSIOLOGICAL EFFECTS

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.

EFFECTS ON MENTATION AND PSYCHOMOTOR PERFORMANCE

Characteristically, intoxication with psychoactive materials effect psychomotor and mental functions. It is apparent from the subjective assertions of users and a wide range of experimental studies that marihuana is no exception (Clark and Nakashima , 1968; Clark et al., 1970; Dornbush and Freedman, 1971; Hollister and Gillespie, 1970; Manno et al., 1970; Mayor's Committee, 1944; McGlothlin et al., 1971; Melges et al., 1970; Meyer et al., 1971; Weil and Zinberg, 1969; Weil et al., 1968; Volavka et al., 1971; Galanter et al., 1972; Kiplinger et al., 1971; Mendelson et al., 1972; Dornbush et al., 1971).

Psychomotor tasks which have been tested include tapping speed, handwriting and free-hand writing and free handdrawing, simple and complex reaction time, pursuit rotor and tracking tasks and continuous performance tests. Cognitive tasks frequently tested are simple arithmetic problems, serial addition or subtraction, fine judgment tasks, 'digit-symbol substitution test, digit-code memory, reading comprehension, speech or verbal out-put, forward and backward digit spans, goal directed complex serial subtractions and additions to reach a set end sum, and short-term or immediate memory functions.

In general, Kiplinger et al. (1971) have clearly demonstrated that the degree of impairment is dose related and varies in degree during the period of intoxication exerting its maximal effect at the peak intoxication.

Naive subjects commonly demonstrate greater decrement in performance than experienced users but report less subjective effect (Weil et al., 1968). Experienced users appear to better compensate to the effect of the drug especially for ordinary performance at lower doses (Clark and Nakashima, 1968; Clark et al., 1970; Crancer et al., 1969; Jones and Stone, 1970; Meyer et al., 1971; Weil and Zinberg, 1969; Jones, 1971; Mendelson et al., 1972). Performance of simple or familiar tasks (i.e. simple reaction time) during intoxication is minimally effected. However, on unfamiliar or complex tasks (i.e., complex reaction time), performance decrements occur (Weil and Zinberg, 1969; Dornbush et al., 1971; Moskowitz et al., 1970).

Performance decrements are further enhanced when verbal tasks are performed during delayed auditory feedback (Kiplinger et al., 1971). Also marked individual differences in performance are noted between similar subjects. (Clark and Nakashima, 1968; Clark et al., 1970; Manno et al., 1970; Kiplinger et al., 1971). A cyclical waxing and waning of the intensity of the intoxication and concomitant performance occurs periodically (Clark et al., 1970; Melges et al., 1970).

Finally, when subjects concentrate on the task being performed at "normal social high," objective evidence of intoxication is not apparent and the individual may perform better than when drug free (Rodin and Domino, 1970; Mendelson et al., 1972).

Obviously, these observations raise practical doubts regarding the intoxicated individuals' ability to function at jobs requiring memory, concentration, and organization of thinking.

THE INTOXICATED MENTAL STATE

Several investigators have suggested that shortterm memory is the mental function most significantly affected by marihuana and contributes to the subtle alterations of mental functioning noted. Generally an impairment of recent or short term memory is demonstrated (Abel, 1970,1971; Dornbush et al., 1971; Menges, 1970-71; Tinklenberg, 1970; Clark et al., 1970; Weil et al., 1968). Thus, mental tasks requiring immediate information acquisition (Abel, 1971) and/or retrieval (Weil et al., 1968) are effected.

Abel (1971) recently showed that marihuana blocks the acquisition process involved in the storage of new interferes with the retrieval of already stored information. Decrements are produced in decisions requiring recent memory or sustained alertness (Clark et al., 1970) ; conversation (Well et al., 1968) ; calculations, or reading which requires retention, coordinating and indexing sequential information termed temporal disintegration (Melges et al., 1970, 1971).

Melges eta]. (1970, 1971) theorizes that episodic impairment of immediate memory produces voids which are filled with perceptions and thoughts extraneous to the organized mental processes. He suggests that this leads to temporal disintegration producing a fragmented and disorganized temporal experience in which past and future time frames are blurred and the present is experienced as prolonged or boundless. Thus, depersonalization occurs as the individual experiences himself temporally in a strange and unreal manner during marihuana intoxication.

UNPLEASANT REACTIONS: "TOO STONED" AND "NOVICE-ANXIETY"

These substantial cognitive and psychomotor effects are probably responsible for many of the acute adverse reactions to marihuana. One, of the most common is the heavy, drugged feeling where the individual feels mentally and physically sluggish so that every motion and thought seems to require extreme effort (Smith and Mehl, 1970). This probably reflects impaired cognitive function and psychomotor retardation from getting "too stoned." This most frequently occurs after oral ingestion of a large dose of drugs or in inexperienced smokers who have, not learned to selftitrate their dose to achieve the desired high.

In these instances, depression, anxiety, fatigue, short-term memory loss, dizziness, nausea, incoordination, palpitations are experienced as generalized discomfort, and ill-being.

"Novice anxiety reactions" or panic reactions account for a majority of acute toxic reactions to marihuana (Baker and Lucas, 1969; Baker-Bates, 1935; Gaskill, 1945; Grossman, 1969; Persyko, 1970; Bialos, 1970; Sonnenreich and Goes, 1962; Sigg, 1963; Dally, 1967; Hamaker, 1891; Marten, 1969; Smith and Mehl, 1970; Walton, 1938).

When dosage, set and setting are optimal the distortion of self (depersonalization) and temporal disintegration (timelessness of the present moment) common to marihuana intoxication is recognized by the individual as time-limited and drug-induced. It is usually experienced as pleasurable. But, if dose, set and setting are not optimal the experience may cause the intoxicated individual to fear that loss of his identify and self control may not end or that he is dying or losing, his mind. Acute, anxiety or panic results (Mel et al., 1970).

Non-drug factors of set and setting play a most important role in these, reactions. Of course, the great variability of individuals makes the effect of marihuana on any specific individual rather unpredictable.

The large majority of these anxiety reactions occur in novices who have intense underlying anxiety surrounding marihuana use such as fears of arrest, of disruption of family and occupational relations and of possible physical and mental dangers. Also, individuals with relatively rigid personality structures, whose values are more in line with those of the "straight"society and have little desire for new and different experiences, appear to experience these, anxiety reactions much more frequently than those, individuals who are members of the "counterculture" (Smith and Mehl, 1970).

In addition, simple episodes of neurotic depression may be observed in these, same types of individuals during periods of unusual psychological stress (Well, 1970). Both of these types of reactions are transient and abate as the drug effects wear off over a few hours. Treatment should consist of gentle but authoritative. reassurance that nothing is seriously wrong and that the drug effects will wear off and the individual will feel normal" again (Smith and Mehl, 1970; Well, 1970).

ACUTE PSYCHOSES

Rare cases of full-blown acute psychotic episodes precipitated by marihuana use are reported in individuals with histories of mental disorder, with marginal psychological adjustments or with poorly developed personality structures and ego defenses (Talbott, 1968; Heiman, 1968; Kaplan, 1971; Pernot, 1969; Keeler, 1968; Defer and Diehl, 1968; Wurniser et al., 1969; Allentuck and Bowman, 1942; Bromberg, 1939; Bromberg, 1934; Curtis and Wolfe, 1939; Hughes et al., 1970; Isbell et al., 1967; Keup , 1970; Keeler, 1967; Talbott and Teague, 1969 Mayor's Committee, 1944).

Marihuana intoxication may hinder the ability of these, individuals to maintain structural defenses to existing stresses, or, alternatively produce a keener awareness of personality problems or existing stresses (Smith, 1968). Psychotherapy and antipsychotic medications are useful in controlling and preventing this reaction (Weil, 1970).

Exceptionally rare reports from North America of nonspecific toxic psychosis or actite brain syndrome have occurred after extremely high drug dose consumption, although such reports are, more common in the eastern countries. These conditions are self-limited and clear spontaneously as the drug effect abates (Weil et al., 1968; Bartolucei et al. 1969 Ames, 1958; Isbell et al., 1967; Mayor's Committee, 1944; Williams et al., 1946).

Finally, marihuana intoxication may trigger delayed anxiety reactions or psychotic episodes in a small percentage of persons who have prior experience with hallucinogenic drugs (Ungerleider et al., 1968; Ungerleider, 1969; Weil et al., 1968; Favazza and Domino, 1969).

In summary, the acute psychomotor-cognitive effects of marihuana intoxication are, interesting academically to gain understanding of normal and abnormal mental function. Also, for practically determining the danger-risk factor for the individual including determination of his functional level personally, vocationally and socially in this society. The effect on personal-social-vocational function is highly individualized and difficult to predict at present.

Although reports of anxiety attacks and psychotic episodes are more frequent as marihuana use spreads, they are still exceedingly rare and their incidence appears to be decreasing as use becomes more acceptable to more diverse populations. For example, during the nine-year period of 1961 to 1969, out of 701,057 admissions to Los Angeles County Hospital, located in a, city with very high marihuana use, only three patients required hospitalization for psychic sequelae of marihuana smoking (Lundberg, et al., 1971).

In contrast, many cases are being seen in Vietnam soldiers where a extremely potent material is available and daily stresses are high, but, these probably represent only a small fraction of marihuana, users (Talbott and Teague, 1969; Talbott, 1968; Heiman, 1968).

During the, academic year 1968 and 1969, eight students were seen in the mental hygiene division of a private Eastern University student population (8,500) with acute anxiety reactions (Bialos, 1970). The frequency of marihuana-associated acute adverse, anxiety reactions requiring attention at Boston University Student Health Service (student population 20,000) is between five and seven yearly (Pillard, 1970).

In a recent survey of newly admitted patients to a large mental hospital, marihuana was the direct cause of the hospitalization in only 0.9 per thousand admissions (Keup, 1970).

PERSISTENT EFFECTS AFTER ACUTE DOSE

Investigators have not noted persistent effects after smoking marihuana for periods of more than three to five hours (Fink et al., 1971; Weil et al., 1968; Pillard, 1970).

Users report only minimal hangover effects (Mayor's Committee, 1944; Haines and Green, 1970; McGlothlin et al., 1971) after very heavy use. Feelings of lassitude and heaviness of the head, lethargy, irritability, headaches and loss of concentration are reported especially when associated with lack of sleep (Chopra and Chopra, 1939; Indian Hemp, 1893). This may be related to preliminary data (Rickles et al., 1970) suggesting a subtle increase in REM sleep time primarily seen in the last one-third of the night in individuals who smoked one to two cigarettes per day usually at night for at least a year.

EFFECTS OF MARIHUANA USE ON CONCOMITANT BEHAVIOR

Mendelson et al. (1972), under contract to the Commission, analyzed the effects on behavior of acute marihuana intoxication on an extensive variety of assessine nts including a simple operant task, mood states, individual and group observations before, during and after smoking and clinical psychological evaluations.

Sleep-inducing properties were confirmed. Increased amounts of total sleep were observed in both number and length of shorter and longer blocks of consecutive hours of sleep related to marihuana smoking.

Examination of mood assessments prior, during and after marihuana smoking indicates that the acute effects were a reduction of negative moods (anxiety, hostility, and guilt-shame) and an increase in the positive moods (carefreeness and friendliness). Examinations of the mood prior to smoking revealed that the subjects tended to smoke marihuana when they reported generally positive moods. The effect of the drug was to increase this positive mood. One paradoxical finding was that the subjects also reported feeling more depressed after smoking.

Acute effects of marihuana on cognitive and motor functions were studied with a battery of tests sensitive to brain function (Halstead Category Test, Tactile Performance Test, Seashore Rhythm Test, Finger Tapping Test, Trail Making Test and the Weschler Adult Intelligence Scale). No alterations in performance as a result of acute intake of marihuana were noted in any of these.

The acute effect of marihuana smoking on social behavior was investigated, by observing the individual and his interaction in small groups. The data indicated very strongly that marihuana smoking, in addition to being a subjective drug experience, is also a social activity around which verbal interaction and other types of social behavior are centered.

Although marihuana smoking tended to be, a group activity, subjects did not always engage in verbal communication while smoking. Subjects often were observed withdrawing from the social interaction and then participating in some type of noncommunicative passive activity, such as watching television, listening to music, reading or staring at objects or people. This decrement in total interaction appeared to be a drug effect.

Heavy marihuana users tended to be more withdrawn than the intermittent users, often listening to the stereo and focusing on the personal effects of the drug. The intermittent users tended to watch television which provided group entertainment, thus enhancing the social effects of the drug.

Verbal interaction in formal task-oriented discussion groups diminished when several group members were simultaneously intoxicated. How-ever, groups engaged in problem-solving tasks performed more efficiently because less suggestions and discussion ensued before proposing a workable solution. The groups tended to become more convivial and less task-oriented although none failed to arrive, at the goal. Marihuana did not appear to increase hostility during these sessions and furthermore tended to change the nature of hostile communication from direct criticism to indirect sarcasm.

Assessment of risk-taking behavior revealed that under the influence of marihuana, users tend to become more conservative in the decision making.

In summary, it appears that marihuana does exert subtle effects on measurable components of social behavior and interaction.