Marihuana in man: three years later.

The past 3 years of renewed research on the effects of marihuana in man has added little not previously known about the clinical syndromes produced by the drug. The major advance has been a quantification of dose in relation to clinical phenomena, and a beginning of an understanding of the drug's metabolism. The crucial clinical experiments in regard to the social questions about marihuana, such as the possible deleterious effects from chronic use, cannot be answered by laboratory experiments. These must be settled by close observations made on those who experiment on themselves. It should be possible, within a relatively short time, to determine whether marihuana has any medical utility, but the future would appear to be no more promising than the past in this regard. The mechanisms by which marihuana alters mental functions are not likely to be answered in man, nor even answered soon by animal studies. As marihuana may be unique among drugs in that more experimentation has been accomplished in man than in animals, it may be necessary to look to additional animal studies to provide leads for pertinent future studies in man.

Marihuana and temporal disintegration.

High oral doses of marihuana extract, calibrated for content of 1 (-)-Delta(1)-tetrahydrocannabinol, significantly impaired the serial coordination of cognitive operations during a task that required sequential adjustments in reaching a goal. This disintegration of sequential thought is related to impaired immediate memory.

Physostigmine: improvement of long-term memory processes in normal humans.

Nineteen normal male subjects received 1.0 milligram of physostigmine or 1.0 milligram of saline by a slow intravenous infusion on two nonconsecutive days. Physostigmine significantly enhanced storage of information into long-term memory. Retrieval of information from long-term memory was also improved. Short-term memory processes were not significantly altered by physostigmine.

Comparative evaluation of research diagnostic criteria for schizophrenia.

Criteria for establishing a diagnosis of schizophrenia have been proposed by several different authors. This study compared six different research diagnostic criteria (RDC) in a series of 166 patients who received a clinical diagnosis of schizophrenia in a multicenter study. The alternative criteria differed in the proportion of clinical diagnoses that were confirmed, with the Washington University (Feighner) criteria accepting only 26%. The criteria also disagreed concerning which particular patients qualified for the diagnosis. The Washington University and New York RDC disagreed 50% of the time, and some other disagreement rates were even higher. More evaluative research is needed before arbitrary criteria are permitted to redefine the concept of schizophrenia.

Excretion of MHPG in normal subjects: implications for biological classification of affective disorders.

Exretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured repeatedly in 17 normal subjects. The amount of MHPG excreted over a 24-hour period was fairly stable over a period of three consecutive 24-hour samplings, but stability was rather poor over subsequent periods of several weeks, suggesting that execretory patterns are not traits. A normal range of MHPG excretion was estimated to be 900 to 3,500 micrograms/24 hr. This range covers the majority of persons with affective disorders whose excretion patterns have been measured, although comparisons of absolute values between laboratories must be made cautiously. Further, substantial changes within this range may occur in normal subjects with no accompanying change in affect. A slight but definite diurnal pattern of excretion was found, with a peak at the period of 1600 to 1800 hours. No clear relationship to MHPG excretion to state of physical activity, recent consumption of foods or beverages, or prevailing affective state was defined in those subjects living under normal conditions. While MHPG excretion may yet prove useful for categorizing depressed patients and predicting response to drugs, any inferences drawn regarding the pathogenesis of affective disorders must be guarded.

Subtypes of depression based on excretion of MHPG and response to nortriptyline.

We investigated the relationship between urinary excretion of MHPG and the clinical response of 17 depressed patients to nortriptyline hydrochloride. Plasma concentrations of nortriptyline were monitored to assure optimal doses. Patients were classified as having "low" or "normal-high" excretion of MHPG based on one to five 24-hour urine specimens. Hamilton Depression Rating Scale scores were not reduced significantly more among the nine low excreters as compared with the eight normal-high excreters. However, when a true bimodal distribution of MHPG excretion was created by comparing only the six lowest excreters with the six highest excreters, the low group improved significantly more than the high group. This differential response to nortriptyline somewhat supports the notion that MHPG excretion may predict response to specific tricyclics. Collecting urine for MHPG determination in depressed patients is not easy; the variability of excretion within patients is considerable, and the range of MHPG excretion closely parallels that in normal persons. The clinical utility of this procedure is still to be determined.

Marihuana and setting.

Marihuana or placebo cigarettes were smoked by 12 subjects in two environments, one "favorable" and one "neutral". The object was to determine the contribution of setting to the effects reported from the drug. Two quantifiable self-report measurements, the linear euphoriant scale and the card-sort version of the Addiction Research Center Inventory (marihuana and hallucinogen scales), were the major reporting criteria. Analyses of variance consistently demonstrated strong effects for subjects and drug but not for the environmental conditions. Reports of marihuana effects may be assumed to be highly colored by psychological differences in the mental set of subjects, or biological variations in their responses to the drug. The actual environment in which the drug is taken seems to play little, if any, role.

Physostigmine in mania.

Seven men and one woman with primary affective disorder, mania, were given a slow intravenous infusion of physostigmine salicylate. In six patients, mood and thought content changed from mania toward depression as evaluated by either a visual analog mood scale or the Pettersen scale. Two other patients, who were the only predominantly irritable manics in the study, demonstrated little change in their hostility, although one became somewhat depressed. These findings are consistent with earlier reports of suppression of manic symptoms after physostigmine infusion in some but not all patients with mania. The pharmacologic mechanism of physostigmine reversal of manic symptoms may be the direct result of increased cholinergic activity or a result of the effect of increased cholinergic activity on other brain neurotransmitters.

Pituitary response to thyrotropin-releasing hormone in depression.

Plasma thyrotropin (TSH) levels varied relatively little over minutes to days in the same individual not subjected to challenge with thyrotropin-releasing hormone (TRH). Thus, the TSH response to stimulation with TRH is not likely to be confounded by spontaneous changes of comparable degree. Variable numbers of depressed patients showed a blunted response to TRH stimulation of the pituitary, but the exact prevalence of this phenomenon remains to be clearly defined. In any case, the pituitary response to TRH stimulation was not correlated with the prevailing level of depression, nor did this response to an initial TRH challenge predict the degree of clinical change during a 15-day treatment during which three intravenous doses of 600 mug of TRH were given. Depressed patients, as do schizophrenics and normal patients, show diminished TSH responses to repeated challenges with TRH. Whether or not these three groups differ in regard to the rate at which the pituitary response can be abolished remains to be determined.

Vasodilators in senile dementias: a review of the literature.

The rationale for the use of vasodilators in the aged has changed from the attempt to increase cerebral blood flow to the attempt to improve cerebral metabolism. Review of 102 studies of eight vasodilators showed that significantly more controlled studies claimed practical clinical benefit from drugs supposed to improve neuronal intermediary metabolism with secondary vasodilatation than from drugs supposed to have only vasodilator action (P less than .005). Studies of both classes of drugs often suffered from poor study design, inappropriate and inconsistent application of outcome measurements, as well as negative bias due to selection of severely demented subjects. Future studies should be placebo-controlled investigations of drugs with primarily metabolic action, address questions of dose and time response, consistently use appropriate outcome measurement, and concentrate on the elderly in whom cognitive improvement is possible.

Double-blind comparison of alprazolam, diazepam, and placebo for the treatment of negative schizophrenic symptoms.

Fifty-five schizophrenic outpatients with negative symptoms were treated for up to six weeks by the addition of alprazolam (mean dose, 4.2 mg/d), diazepam (mean dose, 40.4 mg/d), or placebo to their ongoing neuroleptic treatment. A repeated-measures analysis of variance with baseline measurements entered as covariates indicated the presence of a significant time X drug interaction effect for the weekly Brief Psychiatric Rating Scale (BPRS) withdrawal/retardation subfactor scores. During the initial weeks of the study, the alprazolam-treated group had lower scores, while the diazepam-treated group had higher scores than the placebo-treated group. However, an end point analysis performed on the final BPRS withdrawal/retardation subfactor scores showed no significant differences among the three groups, nor were beneficial effects observed on any of the BPRS subfactor scores that assess positive symptoms. Plasma alprazolam levels were maintained throughout the study and ranged from 20 to 100 ng/mL. These results suggest that alprazolam had no sustained significant effect on negative schizophrenic symptoms.

Possible associations among plasma prolactin levels, tardive dyskinesia, and paranoia in treated male schizophrenics.

To determine whether there is an association between prolactin (PRL) levels and psychopathology or tardive dyskinesia during neuroleptic treatment, we measured plasma prolactin levels and neuroleptic activity (NA) in 33 chronically treated male schizophrenics. Neuroleptic dose, plasma NA, and PRL were significantly intercorrelated. Plasma PRL levels were also measured in 8 male schizophrenics recently withdrawn from neuroleptics and in 18 normal male controls. In treated patients, but not in controls, PRL levels decreased with age and duration of illness, two variables that we interpreted as indirect measures of neuroleptic exposure. PRL levels in patients recently withdrawn from neuroleptics were lower than in treated patients or controls, which was suggestive of rebound hypoprolactinemia. A prolactin index, calculated as the ratio of PRL levels to NA, was inversely correlated with paranoid symptoms and tardive dyskinesia in younger treated patients. These results lead to speculation that tuberoinfundibular dopaminergic supersensitivity develops in chronically treated schizophrenics and that it is associated with nigrostriatal supersensitivity, manifested by tardive dyskinesia, and paranoid symptoms, which may reflect mesolimbic supersensitivity.

Dopaminergic supersensitivity follows ferric chloride-induced limbic seizures.

Injection of ferric chloride (FC) into the left amygdala of rats produced limbic seizures that lasted at least 3 weeks. In addition, FC-injected animals demonstrated motor impairment, decreased protesting vocalizations, and spontaneous stereotypies during a behavioral examination. An increase in apomorphine-induced stereotypies was also noted, and weekly administration of apomorphine for 3 weeks potentiated the increase in stereotypies produced by FC injection. These behavioral changes were associated with changes in postsynaptic dopamine D2 receptors. In animals injected only with FC, an increase in the [3H]-spiperone Bmax in the left nucleus accumbens and an increase in Kd in the right nucleus accumbens were noted. In FC-injected animals challenged weekly with apomorphine for 3 weeks, increases in the [3H]-spiperone Bmax in both amygdalae, the left nucleus accumbens, and the right nucleus caudatus and increases in Kd in the left amygdala and right nucleus accumbens were noted. Severance of the anterior commissure at the time of FC injection reversed most of these changes in behavior and dopamine receptor binding. Possible mechanisms for these changes are discussed, as well as the implications of these results for research on limbic dysfunction and psychopathology.

Site-specific drug delivery to CNS: old and new.

Delivery of drugs to specific sites in the CNS represents an essential therapeutic challenge. Extradural administration of opiates successfully delivers drugs to the CNS. The levodopa-carbidopa combination achieved some degree of site-specific delivery by pharmacological methods. Antibiotics have been administered through cannula directly into ventricles. Invasive methods offer the greatest degree of site-specificity.

Choline chloride effects on memory in the elderly.

Choline chloride (2 g QID) and placebo were administered to 10 subjects over age 60 in a placebo-drug placebo design. Subjects first took placebo for 7 days, followed by choline for 21 days and finally took placebo for another 21 days. Memory tests were given at the end of both placebo periods and twice during choline administration. Choline did not significantly affect performance on a test of memory storage, a test of retrieval from memory or on the digit span test. In addition, a correlational analysis showed that the difference between memory performance during choline administration and during placebo administration was not significantly related to baseline memory performance. These results, together with results of previous studies indicate that choline is not an effective agent for improving memory in nondemented elderly patients.

Psychopharmacology: the bridge between psychiatry and biology.

The current enthusiasm for biologic approaches to psychiatric problems stems from the practical applications of clinical psychopharmacology. Effective drugs led to more efficient and humane treatment of patients with such disorders. Still, our present drugs leave much to be desired. As we have learned more about how they may ameliorate various types of mental disorders, we generate hypotheses about the possible causes of the disorders we treat. Thus we try to lift ourselves by our bootstraps; drugs generate hypotheses that one hopes will lead to better drugs. Although at times progress seems to be agonizingly slow, if we consider the great progress of the past 35 years one cannot be less than enthusiastic about the prospects for the next three decades. It has been my good fortune to have been connected closely with the developments of the past, a few of which have been discussed in this personal odyssey. It will be the good fortune of my younger colleagues to see the future realization of many of our hopes for better treatment and understanding of psychiatric disorders.

No circadian effect on nortriptyline kinetics in man.

Kinetics of a single 100-mg dose of nortriptyline were studied in 10 normal men who took this dose at 9 A.M. in the morning and on another occasion at 9 P.M. Only minimal differences in kinetic parameters were observed, none enough to be of any clinical consequence. A rather high first-pass metabolism of the drug was evident by high plasma concentrations of 10-hydroxynortriptyline. It is thus unlikely that the recent custom of giving single daily doses of tricyclic antidepressants in the evening excludes regimens with more favorable drug kinetics.

Interactions in man of delta-9-tetrahydrocannabinol. II. Cannabinol and cannabidiol.

Oral doses of delta-9-tetrahydrocannabinol (THC) 20 mg, combined with placebo or with 40 mg dses of cannabinol (CBN) and cannabidiol (CBD), were given to volunteers. The combination of THC with CBN produced no detectable changes in the quality, intensity, or duration of the effects of THC alone. The THC-CBD combination tended to delay onset and prolong effects of THC, while making them somewhat more intense. Even this interactive effect was slight, providing no reason to abandon the current practice of basing doses of marihuana for clinical studies solely on THC content.

Chronopharmacology of amitriptyline.

Side effects of decreased salivation and sedation were more marked when a single dose of amitriptyline was taken orally in the morning than in the evening. These dynamic differences were due to alteration in kinetics. Absorption of the drug was more rapid in the morning, although other kinetic parameters, especially total bioavailability, were unchanged. Thus, in the case of this drug, chronopharmacologic differences were due to a change in rate of absorption. The present practice of giving a single dose of drug in the evening is justified on the basis that it induces fewer side effects without a loss in therapeutic efficacy.

Action of delta-9-tetrahydrocannabinol. An approach to the active metabolite hypothesis.

The active metabolite hypothesis, that delta-9-tetrahydrocannabinol (THC) must be converted to its 11-hydroxy metabolite before it becomes active, was tested in a study of subjects chosen as rapid and slow hydroxylators of drugs on the basis of antipyrine and phenylbutazone plasma disappearance rates. Although the sample of subjects showed the customary wide variations in effects experienced after an intravenously administered dose of THC, it was impossible to correlate either the speed of onset, total intensity, or duration of these effects with speed of hydroxylation of drugs. Although 11-hydroxy-THC has unquestioned activity indistinguishable from THC itself, it need not necessarily be solely responsible for the pharmacologic activity of THC.