Pharmacological and Toxicological Study of Maytenus ilicifolia Leaf Extract Part II-Clinical Study (Phase I).

Maytenus ilicifolia is a plant widely used in South American folk medicine as an effective anti-dyspeptic agent, and the aim of this study was to evaluate their clinical and toxicological effects in healthy volunteers in order to establish its maximum safe dose. We selected 24 volunteers (12 women and 12 men) between 20 and 40 years of age and put them through clinical/laboratory screening and testing to ascertain their psychomotor functions (simple visual reaction, speed and accuracy, finger tapping tests). M. ilicifolia tablets were administered in increasing weekly dosages, from an initial dose of 100 mg to a final dose of 2000 mg. The volunteers' clinical and biochemical profiles and psychomotor functions were evaluated weekly, and they also completed a questionnaire about any adverse reactions. All subjects completed the study without significant changes in the evaluated parameters. The most cited adverse reactions were xerostomia (dry mouth syndrome) (16.7%) and polyuria (20.8%), with reversal of these symptoms without any intervention during the study. The clinical Phase I study showed that the administration of up to 2000 mg of the extract was well tolerated, with few changes in biochemical, hematological or psychomotor function parameters, and no significant adverse reactions. Copyright © 2017 John Wiley & Sons, Ltd.

Preclinical toxicological assessment of a phytotherapeutic product--CPV (based on dry extracts of Crataegus oxyacantha L., Passiflora incarnata L., and Valeriana officinalis L.).

Associations of plants have been widely used, for centuries, in Ayurveda and in Chinese medicine and have been increasingly acknowledged in Western medicine. The objective of this study is to assess the level of toxicity of an association of three plants: Crataegus oxyacantha, Passiflora incarnata, and Valeriana officinalis (CPV extract). This association was administered to rats, mice, and dogs, both acute and chronically for 180 days. The tests used in the acute experiments were: observational pharmacological screening, LD(50), motor coordination and motor activity. Chronic tests carried out were: weight gain/loss and behavioral parameters in rats and in mice; estrus cycle, effects on fertility, and teratogenic studies in rats and of mutagenic features in mice, in addition to the Ames test. The following parameters were assessed in dogs: weight gain/loss, general physical conditions, water/food consumption and anatomopathological examination of the organs subsequent to the 180 days of treatment. All of the results were negative, showing that CPV administered in high doses and over a long period of time presents no toxicity, suggestive of the fact that this is an association devoid of risk for human beings.

Use of alcohol among the inhabitants of the 107 largest cities in Brazil--2001.

Alcohol is part of the history of humanity, seemingly as a result of countless factors including the easy production of alcoholic beverages in practically all regions of the world. The authors studied aspects of the use of and the dependence on alcohol in Brazil, through a household survey conducted by Centro Brasileiro de Informações sobre Drogas Psicotrópicas (CEBRID). A total of 8,589 interviews were held in 107 of the largest cities in Brazil, all of them with more than 200 thousand inhabitants. The study was planned to gather information within the household environment about a stratified probabilistic sample obtained in three selection phases: 1) the censitaire sectors for each municipality, 2) a systematic randomized sampling, and 3) drafting a respondent by lot in each household to provide information. Approximately 11.2% of the subjects were concerned with their own consumption of alcohol. The signs/symptoms of the syndrome of dependence evident in a greater percentage were the desire to stop or reduce the use of alcohol and to stop or reduce resorting to alcoholic beverages more often than desired, as reported by 14.5 and 9.4% of the respondents, respectively. The regions in Brazil with the highest percentage of dependents were the North (16.3%) and the Northeast (19.9%). According to the estimates obtained in the survey, 5.2% of the teenagers were concerned about the use of alcohol. The estimates obtained in this survey reveal a need to implant specific preventive programs for the problem of alcohol, especially for the very young.

Decrease in tobacco use among Brazilian students: a possible consequence of the ban on cigarette advertising?

In 2000, cigarette advertising was banned from the Brazilian media [LEI N degrees 10.167, de 27 de dezembro de dezembro. (2000). http://www.planalto.gov.br/ccivil_03/Leis/L10167.htm]. Nevertheless, not enough surveys have been carried out to measure the impact of the prohibition. The objective of the present survey was to compare the use of tobacco by primary and secondary school students in 1997 and 2004, that is, before and after the ban on tobacco advertising in Brazil. Two surveys were conducted (in 1997 and 2004) using the same methodology, with a target population of primary (from the fifth grade on) and secondary public schools in ten different Brazilian capitals. The sampling was done by conglomerates, stratified, and obtained in two stages. In total, 15,501 students were surveyed in 1997, and 21,712 in 2004. The questionnaire was adapted from an instrument developed by WHO, anonymous, self-administered, and applied collectively in the classroom. In a comparison of the two surveys (1997 and 2004) tobacco lifetime use (used any psychotropic drug at least once in their life) decreased significantly in seven out of ten capitals surveyed. The 11-12 year old age group experienced the largest decrease in tobacco lifetime use. There was a decrease in lifetime use for males in nine capitals, and in eight capitals for females. A decrease was also observed in heavy tobacco use also in eight capitals. In conclusion there was a significant decrease in tobacco consumption among the surveyed students, suggesting that the decrease is related to changes in public policy in Brazil over the surveyed period.

A comparison of plants utilized in ritual healing by two Brazilian cultures: Quilombolas and Kraho Indians.

The present study deals with two ethnobotanical surveys carried out in two different segments of the Brazilian population: the first among the Krahô Indians living in Tocantins State, a Cerrado region, and the second one among the descendants of former black slaves, the Quilombolas, living in Mato Grosso State. Both populations use plants which may have effects on the central nervous system (CNS) in their ritual healing ceremonies. Field work was performed during two years by one of the authors (E. Rodrigues) utilizing methods from botany and anthropology. Information was obtained on a total of 169 plants which were utilized in the preparation of 345 prescriptions for 68 ailments seemingly of the CNS, classified as tonics, analgesics, anorectics, hallucinogens, and anxiolytics. The taxonomic families of plants used, the more common therapeutic indications and types of healing rituals are discussed.

Plants with possible psychoactive effects used by the Krahô Indians, Brazil.

OBJECTIVE: In spite of the richness of the Brazilian biodiversity, no phytomedicines have been developed from this flora with the purpose of being used in psychiatric treatments. The objective of the present study was to document the use of plants with possible psychoactive effects in rituals performed by the Krahô Indians, who live in the cerrado savannahs biome in the central region of Brazil. Also, the present data were compared with the data obtained during a review of the literature on the use of psychoactive plants by 25 Brazilian indigenous groups. METHOD: The study was carried out during two years of fieldwork during which anthropological and botanical methods were employed. RESULTS: Seven local shamans were interviewed and they indicated 98 formulas, consisting of 45 plant species that appear to have psychoactive properties and were used in 25 different treatments. Some of the psychoactive properties were "prevention of madness", "stimulant effect", "tranquilizing effect", "prevention of tremors", "longer sleeping period", "open mind" and "induction of sleep". This article also describes the review of literature, which recorded 58 plants that may have psychoactive effects used by 25 Brazilian Indian cultures. CONCLUSION: The treatment of psychological/psychiatric disorders based on the plants used by the Krahô Indians is very rich. It is also observed among other Brazilian indigenous groups. Future phytochemical and pharmacological studies on these plants may develop new medicines to treat psychiatric disorders.

Household survey on drug abuse in Brazil: study involving the 107 major cities of the country--2001.

The prevalence of the use in Brazil of illicit drugs, as well as of alcohol and tobacco, was determined. Further, illicit use of psychotropic medicines, and anabolic steroids were also surveyed. This study was carried out in 107 Brazilian cities with more than 200,000 inhabitants aged 12-65 years. The sampling design adopted was that of sampling per aggregates in three stages: first, the census sectors were selected; second, homes were selected among the sectors; finally, in each home, a respondent was selected in a manner independent of the interviewer. There were 8589 persons interviewed. The questionnaire utilized was that of the SAMHSA (Substance Abuse and Mental Health Services Administration) which was translated and adapted for Brazilian conditions. The lifetime use of alcohol in the 107 major cities of the country was 68.7%, which was close to numbers observed for Chile at 70.8% and the USA at 81.0%. Yet, tobacco lifetime use was 41.1% of the total, which is lower than the prevalence observed in the USA (70.5%). The data on the lifetime use of marijuana in Brazil (6.9%) approximated the findings for Colombia (5.4%), however, being much lower than that observed in the USA (34.2%) and the United Kingdom (25.0%). The prevalence of lifetime use of cocaine was 2.3%, well below the levels for the USA with 11.2% of the total population. The abuse of inhalants was 5.8% of the total, greater than that found in Colombia (1.4%) and about four times less than that in the United Kingdom with 20.0%. Among the medicaments, stimulants had a 1.5% prevalence of lifetime use, and that of benzodiazepines had similar percentages in Brazil (3.3%) and in the USA (5.8%). In this survey, only four individuals reported lifetime use of heroin, which was equivalent to about 0.04% of the sample and much lower than that in the USA with 1.2% and in Colombia reaching 1.5%. These findings will allow the implementation of public policies fitted to the situation with psychotropic drugs in Brazil.

[Use of psychotropic drugs in Brazil: household survey in the 107 biggest Brazilian cities--2001]. / Uso de drogas psicotrópicas no Brasil: pesquisa domiciliar envolvendo as 107 maiores cidades do país--2001.

The objective was to estimate the prevalence of the use of drugs, alcohol, tobacco and the use of non-medical psychotropics. This study enclosed the 107 biggest cities in Brazil; sample: ages between 12 and 65 years. Sampling in three periods: tax sectors; household and the respondent. Were interviewed 8,589 people. The lifetime use of the alcohol was 68.7%, closer to 70.8% in Chile. The lifetime use of the tobacco was of 41.1%, lower than USA (70.5%). The lifetime use of the marijuana was of 6.9% closer to Colombia (5.4%) and lower than USA (34.2%). The lifetime use of the cocaine was 2.3%, lower than USA (11.2%). The lifetime use of solvent was of 5.8%, much lower than the United Kingdom (20.0%). The stimulants have had 1.5% of lifetime use and the anxiolytics with 3.3%. These findings will allow the implantation of adjusted public politics to our reality in the field of the psychotropics drugs.

Factors influencing the aggressiveness elicited by marihuana in food-deprived rats.

1. Aggressive behaviour was elicited in rats that had been deprived of food for 20 h daily (starved), by chronic administration of Cannabis sativa extract or (-)-Delta(9)-trans-tetrahydrocannabinol.2. The influence of intraperitoneal (i.p.) or oral glucose administration, cold environment, acidosis, and corn, and protein-free diets on this aggressiveness was studied.3. Intraperitoneal injections of glucose (100-1,600 mg/kg) did not alter the aggressiveness induced by marihuana in starved rats; glucose given orally, however, blocked this behaviour.4. Low temperature (14 degrees C) strongly potentiated the aggressive behaviour induced by marihuana in the starved rats.5. Lactic acid in doses capable of potentiating thiopental anaesthesia, failed to alter the marihuana-aggressiveness of starved rats or to facilitate this effect of marihuana in rats fed ad libitum. The same negative results were obtained with ammonium chloride.6. In rats fed ad libitum with protein-free or corn diets, marihuana administered chronically did not elicit aggressive behaviour. However, aggressiveness appeared when rats were fed for only 2 h daily on those diets.7. The results suggest that the stress of hunger (and not hypoglycaemia, acidosis or lack of specific nutrients due to starvation) is the factor that facilitates the development of aggressive behaviour by chronic administration of marihuana.

Cannabis, catecholamines, rapid eye movement sleep and aggressive behaviour.

1. Previous work from our laboratory has shown that cannabis induces aggressive behaviour in rats that have been deprived of rapid eye movement (REM) sleep. It was suggested that this effect was related to brain catecholamines, with dopamine playing an agonist role and noradrenaline an inhibitory one. The present paper describes new experiments dealing with this subject. 2. Previous REM sleep-deprivation enhanced both delta9-tetrahydrocannabinol (THC)-induced hypothermia and nomifensine effects on aggressive behaviour. 3. A marihuana extract decreased brain dopamine turnover in REM sleep-deprived rats, an effect not observed in non-deprived rats. Noradrenaline metabolism was not altered. 4. Fighting behaviour was elicited in REM sleep-deprived rats treated with 4 different dopamine-beta-hydroxylase inhibitors. 5. Apomorphine, nomifensine and delta9-THC administered to non-deprived rats pretreated with bis(4-methyl-1-homopiperanzinyl-thiocarbonyl) disulphide (Fla-63), induced fighting behaviour. 6. Nomifensine and apomorphine induced fighting in non-deprived rats pretreated with delta9-THC. 7. Clonidine inhibited the fighting elicited in REM sleep-deprived rats by either delta9-THC or Fla-63 pretreatment. 8. The data are discussed in terms of the influence of REM sleep-deprivation (or the stress associated with deprivation) on the response to dopaminergic drugs and cannabis. Taken together they emphasize the participation of brain dopamine and noradrenaline systems in the aggressive behaviour studied.

Effects of chronic administration of (+)-amphetamine on maze performance of the rat.

1. The influence of (+)-amphetamine, given 1 min after each training session, on the performance of 124 rats in a Lashley III maze was measured every 48 hr.2. The first three injections of the drug significantly improved the learning ability of naive rats.3. With prolonged treatment, (+)-amphetamine strongly impaired the maze performance of these rats.4. The chronic administration of (+)-amphetamine to previously trained rats produced the same adverse effect.5. Amylobarbitone sodium given to previously trained rats 30 min before the training sessions completely blocked the adverse effect of (+)-amphetamine.6. (+)-Amphetamine did not produce impairment of performance when given chronically 30 min before training sessions, to previously trained rats.

Effects of marihuana in laboratory animals and in man.

1 The pharmacological potencies of the resins from three different samples of Brazilian marihuana (A, B and C) were determined through corneal areflexia in rabbits, decrease of spontaneous motor activity and induction of catatonia in mice, and decrease of rope climbing performance of rats.2 The Delta(9)-tetrahydrocannabinol (Delta(9) THC) content of the marihuanas, measured by gas chromatography, was 0.82, 2.02 and 0.52%, respectively, for samples A, B and C. Approximately 2% cannabinol was present in samples A and B whereas the content of cannabidiol was approximately 0.1%.3 The petroleum ether extraction of the samples A, B and C yielded, respectively, 12.06, 14.56 and 4.26% of resin.4 In all animal tests resin B was nearly twice as active as resin A, whereas C was the weakest.5 The smoke of the marihuana samples was inhaled by 33 human subjects, under a double-blind standardized procedure. Pulse rate, a time production task and an evaluation of psychological effects were recorded.6 The smoke of 250 mg of sample B provoked disruption of the time production task, increased pulse rate, and induced strong psychological reactions in four of the six subjects who received it. Similar effects, although slightly smaller, were obtained with 500 mg of sample A. On the other hand, 500 mg of sample C did not differ from placebo.7 It is suggested that it is possible by means of animal tests to predict the potency of a marihuana sample in man.8 In parallel experiments, Delta(9)-THC was administered to other human subjects and to laboratory animals in a manner similar to that in which the marihuana samples were administered.9 Comparison of the results between the marihuanas and Delta(9)-THC showed that in man and in the laboratory animals marihuanas A and B induced effects two to four times greater than expected from their Delta(9)-THC content.10 It is suggested that there may be potentiation of the effects of Delta(9)-THC by other substances present in these marihuana samples.

Further studies of the aggressive behavior induced by delta9-tetrahydrocannabinol in REM sleep-deprived rats.

The aggressive behavior induced by delta9-tetrahydrocannabinol in pairs of REM sleep-deprived rats was studied in five experiments by measuring dominant and submissive behavioral patterns. When 2 REM-deprived rats received delta9-THC, one of the animals displayed very aggressive postures, while its partner assumed incomplete defensive postures. The intensity of these behavioral postures was dose-dependent. In pairs composed of one REM-deprived rat injected with delta9-THC and one normal or one REM-deprived partner injected with control solution the deprived/drugged rat showed an aggressive posture and catatonia, or a strikingly bizarre behavior, while the control partner displayed typical defensive postures. The behavioral alterations induced in REM-deprived rats by amphetamine, LSD-25, and pentobarbital failed to provoke defense postures in the normal rats paired with them; however, apomorphine partially mimicked the delta9-THC-effects. It is concluded that in REM-deprived rats delta9-THC not only provokes aggressive behavior but also impairs the defensive-submissive behavioral patterns.

Interaction of cannabidiol and alcohol in humans.

Six male and four female healthy volunteers were given oral placebo (glucose capsule and orange juice), cannabidiol (CBD 200 mg capsule and orange juice), alcohol (1 g/kg in orange juice and glucose capsule), and CBD (200 mg capsule) plus alcohol (1 g/kg in orange juice) in a double-blind, crossover, randomized design. Treatments were spaced one week apart. Parameters measured were a finger tap test (motor performance), cancellation and differential aptitude tests (psychomotor performance), a 1-min time production task, subjective effects (66 item adjective-pair semantic differential), and breathalyzer estimations of blood alcohol levels. Compared to placebo, alcohol and alcohol plus CBD, but not CBD alone, produced significant impairments of motor and psychomotor performances, overestimations of time production and subjective responses indicating an accurate self-perception of their intoxication and deficits. The combination of alcohol plus CBD resulted in significantly lower blood alcohol levels compared to alcohol given alone, however, there were few differences observed between the pharmacological effects of the two alcohol conditions. Thus, the inactivity of CBD, a major marijuana constituent, on motor and mental performance and effects also extends to its interaction with alcohol.

6-Hydroxydopamine and the aggressive behavior induced by marihuana in REM sleep-deprived rats.

6-Hydroxydopamine (6OH-DA) pretreatment increased the aggressive behavior induced by marihuana in REM sleep-deprived rats. Brain catecholamine assays revealed that 6OH-DA depleted popamine (DA) and norepinephrine (NE) to a different extent, increasing the DA/NE ratio. Intraventricular injection of NE significantly decreased the aggressive behavior of these animals, whereas control solution or DA injections had no effect. The possible role played by DA and NE in the aggressive behavior induced by marihuana in REM sleep-deprived rats is discussed.

Hypnotic and antiepileptic effects of cannabidiol.

Clinical trials with cannabidiol (CBD) in healthy volunteers, isomniacs, and epileptic patients conducted in the authors' laboratory from 1972 up to the present are reviewed. Acute doses of cannabidiol ranging from 10 to 600 mg and chronic administration of 10 mg for 20 days or 3 mg/kg/day for 30 days did not induce psychologic or physical symptoms suggestive of psychotropic or toxic effects; however, several volunteers complained of somnolence. Complementary laboratory tests (EKG, blood pressure, and blood and urine analysis) revealed no sign of toxicity. Doses of 40, 80, and 160 mg cannabidiol were compared to placebo and 5 mg nitrazepam in 15 insomniac volunteers. Subjects receiving 160 mg cannabidiol reported having slept significantly more than those receiving placebo; the volunteers also reported significantly less dream recall; with the three doses of cannabidiol than with placebo. Fifteen patients suffering from secondary generalized epilepsy refractory to known antiepileptic drugs received either 200 to 300 mg cannabidiol daily or placebo for as long as 4.5 months. Seven out of the eight epileptics receiving cannabidiol had improvement of their disease state, whereas only one placebo patient improved.

The persistence of hyperresponsiveness to apomorphine in rats following REM sleep deprivation and the influence of housing conditions.

The hyperresponsiveness to apomorphine disappears after REM sleep deprivation of rats; the time course of the disappearance was investigated. When REM sleep-deprived (REMd) rats were caged individually during the recovery period the increase in ambulation and in stereotyped behaviour elicited by apomorphine subsided within 8-24 h; on the other hand, the exaggerated aggressiveness persisted up to 64 days. However, when the deprived rats were allowed to recovery in groups of 3 per cage the increase in aggressiveness subsided after 4 days. Since individual housing of non-deprived rats for 4--11 days increased the apomorphine-aggressiveness steadily, 'isolation' probably summed with REM deprivation in facilitating the effects of apomorphine on aggressive behaviour. The results also suggest that the dopaminergic systems implicated in aggressive behaviour are sensitized by REM deprivation for a longer period than those subjacent to ambulation and stereotype.

Effects of cannabidiol on behavioral seizures caused by convulsant drugs or current in mice.

In mice, running, clonic and tonic convulsions and lethality were assessed following transcorneal (electroshock) current or convulsant drugs, each administered alone and after cannabidiol (CBD) pretreatment. CBD prevented tonic convulsions caused by a convulsant current (CC) 99.99, and by the convulsant dose (CD) 99.99 values of gamma-aminobutyric acid (GABA) inhibitors, 3-mercaptoproprionic acid (3MPA), picrotoxin (PIC), isonicotinic acid hydrazine (INH), pentylenetetrazol (PTZ) and bicuculline (BIC). Rankorder potencies, based on the antitonic ED50 of CBD, were: 3MPA greater than PIC = current = PTZ = BIC. Further, CBD prevented 3MPA-induced lethality, but failed to prevent the occurrence of the other behavioral endpoints of the above treatments. CBD also failed to prevent convulsions and lethality caused by the CD 99.99 of strychnine, a glycine antagonist. The differential effects of CBD suggest that the cannabinoid acts to inhibit seizure spread in the CNS by an action on GABA, but not glycine, mechanisms.

Preliminary note: dangerous use of anticholinergic drugs in Brazil.

To better evaluate the non-medical use of anticholinergic substances in Brazil, a review of the local literature was performed. Synthetic compounds such as triexyphenidyl (Artane), benactizine (Asmosterona), dicyclomine (Bentyl) as well as Datura sp. tea were reported as being used by first and second grade students and by street children of several Brazilian cities. In several cases the percentage of youngsters indulging in such use was higher than the percentage found for cocaine, barbiturates, cough syrups and amphetamine-related drugs. Several cases of patients seeking treatment for dependence or for acute psychotic symptoms were also described.

Preliminary finding: consumption of benzodiazepines in Brazil during the years 1988 and 1989.

This work investigates consumption of benzodiazepines in Brazil during the years 1988 and 1989, using the following sources of information provided to the Brazilian Ministry of Health by institutions that deal with benzodiazepines: (a) benzodiazepine stocks recorded at the beginning and end of each year; (b) Brazilian (internal) production of benzodiazepines; (c) imported and exported amounts of benzodiazepines; (d) amounts employed in the manufacture of brand-name products and in the making of prescription formulas. The records a, b and c furnished the 'calculated consumption', of benzodiazepines, in kilograms. The d records, on the other hand, directly furnished the 'informed consumption', also in kilograms. The data obtained were also expressed in terms of defined daily doses (DDDs)/1,000 inhabitants/day, considering the informed consumption and the Brazilian population. As for the DDDs/1000 inhabitants/day, they were found to be 23.03 and 18.48 for the years 1988 and 1989, respectively. A striking discrepancy was detected between the calculated and the informed consumption figures, the latter having exceeded the former by 2096 kg in 1988 and by 4909 kg in 1989. Diazepam was the primary drug responsible for this difference. Such results may suggest that an illicit, unrecorded trade of benzodiazepines is occurring in Brazil.