 |
 |
|
|
|
From the
Journal of Ethnopharmacology 18 (1986) 229-243
Eleavier Scientific Publishers Ireland Ltd
Summary
Calea zacatechichi is a plant used by the Chontal Indians of Mexico to
obtain divinatory messages during dreaming. At human doses, organic
extracts of the plant produce the EEG and behavioral signs of somnolence
and induce light sleep in cats. Large doses elicit salivation, ataxia.
retching and occasional vomiting. The effects of the plant upon cingulum
discharge frequency were significantly different from hallucinogenic-
dissociative drugs (ketamine. quipazine, phencyclidine and SKF-10017). In
human healthy volunteers, low doses of the extracts administered in a
double-blind design against placebo increased reaction time end time-lapse
estimation. A controlled nap sleep study in the same volunteers showed
that Calea extracts increased the superficial stages of sleep and the
number of spontaneous awakenings. The subjective reports of dreams were
significantly higher than both placebo and diazepam, indicating an
increase in hypnagogic imagery occurring during superficial sleep stages.
Introduction
Dreams are important in mesoamerican cultures. They are believed to occur
in a realm of suprasensory reality and, therefore, are capable of
conveying messages (Lopez-Auatin. 1980). The use of plant preparations in
order to produce or to enhance dreams of a divinatory nature constitutes
an ethnopharmacological category that can be called "oneiromancy" and
which justifies rigorous neuropharmacological research.
There are several plants used in Indian communities of Mexico to obtain
divinatory messages from dreams. Several puffball mushrooms (Lycoperdon
spp.), wrongly reported as hallucinogens (Ott et al., 1975), are eaten
fresh by Mazatec Indians before going to bed in order to dream (Diaz,
1975. 1979). Nahuatl Indians from the Sierra de Puebla use an as yet
unidentified species of Salvia, known by the name of Xiwit, for the same
purpose (Tim Knab, pers. commun.). The plant known as Bakana to the
Tarahumara Indians, which has been reported to be an analgesic,
antipsychotic and divinatory agent(Bye. 1979), was later found to be
employed for dreaming during night sleep (William Merrill, pers. commun.).
Finally, Calea zacatechichi Schl. (Compositae) is used in the same context
by the Chontal Indians of Oaxaca.
C. zacatechichi is a plant of extensive popular medicinal use in Mexico
(Diaz. 1976). An infusion of the plant (roots. leaves and stem) is
employed against gastrointestinal disorders, as an appetizer. cholagogue,
cathartic. antidysentry remedy, and has also been reported to be an
effective febrifuge. With other aromatic Compositae, dry C. zacatechichi
is used as insecticide (Diet, 1975). There is also some information
concerning psychotropic properties of this plant that require further
clarification (Schultes and Hofmann, 1973).
The pioneer study on the appetizer properties of zacatechichi, conducted
at the Institute Medico Nacional of Mexico, mentioned some psychoactive
effects (Sandoval, 1882). MacDougall (1968) reported that a Chontal
informant knew that the leaves of the plant were to be either smoked or
drunk as an infusion to obtain divinatory messages. Subsequent interviews
with MacDougall's informant and active participation in ceremonial
ingestion revealed that the plant is used for divination during dreaming
(Diaz, 1975). Whenever it is desired to know the cause of an illness or
the location of a distant or lost person, dry leaves of the plant are
smoked, drunk and put under the pillow before going to sleep. Reportedly,
the answer to the question comes in a dream. A collection of interviews
and written reports concerning the psychotropic effects of these;
preparations on 12 volunteers has been published (Diaz. 1975, 1979). Free,
reports and direct questioning disclosed a discrete enhancement of all
sensorial perceptions, an increase in imagery, mild thought discontinuity,
rapid flux of ideas. and difficulties in retrieval. These effects were
followed by somnolence and a short sleep during which lively dreams were
reported by the majority of the volunteers. These preliminary observations
suggested that the psychotropic effects of the plant were similar to those
interesting from ethnobotanical. psychological and neuropharmacological of
the "cognodysleptic" drugs, whose prototype is marihuana (Cannabis
saliva)(Diaz, 1979). The possible effects upon dreaming are the most
perspectives.
C. zacatechichi is a shrub measuring 1-1.5 m in height. The plant has many
branches with oviform and opposite leaves (3-5 cm long and 2-4 cm wide).
The leaves show serrated borders, acute endings and a short petiole. They
are rugose and pubescent. The inflorescence is small and dense (comprising
around 12 flowers each) with the pedicels shorter than the heads
(Martinet, 1939). The plant grows from Mexico to Costs Rice in dry
savannas and canyons (Schultes and Hoffmann, 1973). The name of the
species comes from Nahuatl "zacatechichi" which means "bitter grass' and
is the common name of the plant all over Mexico. It is also known with the
Spanish names of "zacate de perro" (dog's grass), "hoja madre" (mother's
leaf) "hoja de dies" (Cod's leaf), and thle-pela-kano in Chontal Diaz,
1975).
Several sesquiterpene lactones had been isolated from the plant. Calaxin
and ciliarin were identified by Ortega et al. (1970), and the
germacranolides, 1B-acetoxy zacatechinolide and l-oxo zacatechinolide, by
Bohlmann and Zdero (1977). Quijano at al. (1977. 1978) identified
caleocromenes A and B and caleins A and B. while Ramos (1979) found
caleicins I and II. Herz and Kumar (1980) isolated acacetin, o-methyl
acacetin, zexbrevin and an analogue, as well as several analogues of
budlein A and neurolenin B, including calein A. C. zacatechichi samples
show differences in chemical composition, which has led Bohlmann et al.
(1981) to suggest that chemical taxonomy may help to reclassify the genus.
Further taxonomic work is required since our Chontal informant
distinguishes between "good" and "bad" varieties according to their
psychotropic properties.
In the present paper we report some properties of zacatechichi extracts
upon cat behavior and EEG, human reaction time, nap EEG, and subjective
experiences.
Materials and methods
Plant collection and extract preparations
"Good" samples of C. zacatechichi were collected under the guidance of the
Chontal informant near Tehuantepec, Oaxaca during November, 1978.
Specimens of this collection were identified by Dr. Miguel Angel Martinet
Alfaro at the National Herbarium of Mexico as C. zacatechichi despite the
Fact that there were minor morphological differences relative to
previously collected material. The samples were identical with collections
made in the area of the isthmus of Tehuantepec.
One kilogram of the dried plant (stem and leaves) was mashed and extracted
with hexane until exhaustion in a Soxhlet apparatus. This fraction was
dried and 308 of an solvent-free hexane extract were obtained. The
remaining material was thoroughly extracted with methanol and the organic
fraction evaporated. This procedure resulted in 86 g of a solvent-free
gummy residue called the methanol extract. Both extracts were separated in
fractions and packed in gelatin capsules for pharmacological experiments.
The dose was estimated in the following manner: the human dose for
divinatory purposes reported by the Chontal informant is "a handful" of
the dried plant. Since the mean weight of many handfuls taken by several
people was 60 g. we decided that the average human dose (HD-1) is around 1
g/kg of dried-mashed material. Therefore, the HD-1 for the hexane extract
was 30 mg/kg, and 86 mg/kg for the methanol extract. In the experiments
with cats. doses of HD-2. -4. -6 and -10 of both extracts were used. The
EEG; effects of C. zacatechichi extracts were compared with those elicited
by phencyclidine (Bio-ceutic Laboratories), quipazine (Miles Research
Products). ketamine (Parke Davis) and SKF-10047 (Smith Kline B French),
and industrial solvent toluene. which can produce the appearance of 6 cps
spike and wave activity in the cingulum of cats. During the appearance of
this electrographic activity. animals show "hallucinatory" behavior (Conteras
et al.. 1979, 1984).
Behavioral toxicology in cats
This first experiment was performed in order to assess the possible toxic
behavioral effects of C. zacatechichi extracts. For this purpose three
male cats (3 kg each) were used. Observations were done from 1300 to 1500
h in a sound-attenuated recording chamber (109 x 76 x 74 cm) with a
triple-glass wall. Each animal was placed in the cage and its behavior was
recorded for 1 h prior to oral administration of a gelatin capsule (25 x 8
mm) containing a zacatechichi extract and 2 h thereafter. Each capsule was
placed inside the mouth and swallowing was forced by giving 2-3 ml of
saline solution. The extracts (methanol or hexane) and doses (HD-1, HD-2.
HD-4. HD-10) were randomly assigned and tested only once. Two cats were
observed three times and the third animal twice. Between tests each animal
was allowed to rest for 6 days. Sampling ad libitum (Altmann. 1974) was
used to evaluate the cats' response. Attention was given to abnormal
behaviors such as ataxia, bizarre postures and movements directed to
non-existing objects (Fischer. 1969).
EEG activity in cats
Several common EEG effects to a series of hallucinogenic compounds have
been reported by Winters et al. (1972). A dissociative action in
multi-unitary activity between the reticular formation and basolateral
amygdala and a hypersynchronic rhythm (2-3 cpa) in cortical recording are
the two most characteristic features. Tracheal administration of
neurotoxic industrial solvents produce limbic discharges while cats
display "hallucinatory behavior" (Contreras et al., 1979). The following
experiment was designed to ascertain whether C. zacatechichi extracts
share these neurophysiological actions.
Six adult male cats were stereotaxically implanted with stainless steel
concentric bipolar electrodes in the basolateral amygdala. the septum and
cingulum according to the atlas of Snider and Niemer (1961). Epidural
electrodes were placed on the cortex at the marginal circumvolution. After
surgery the animals were allowed a & 1 week recovery period. Each cat was
used as its own control and the effects of oral administration of
zacatechichi extracts (HD-6) were compared to those of phencyclidine (400
ug/kg i.m.), quipazine (10 mg/kg i.p.), ketamine (6 mg/kg i.m.) and
SKF-10047 (3 mg/kg i.m.). These drugs are dissociative psychodysleptics
and produce 6 cps wave-and-spike activity in cingulum recording in
addition to the characteristic hypersynchronic rhythm (Contreras at al.,
1984). In each experiment, control recordings were taken in addition to t
60 min and + 120 min after drug aministration.
Reaction Time and Time-lapse estimation in humans
Measurement of reaction time to a light flash and the ability to calculate
fixed lapse times in humans allows the identification of hypnotic
compounds (Fernandez-Guardiola et al., 1972). Objective evaluations of
time perception modification by marihuana have been achieved with the same
technique (Fernandez-Cuardiola et al., 1974). From the experiments
performed in cats it appeared that zacatechichi had hypnotic properties.
Therefore, we chose this experimental paradigm to evaluate human effects.
The study was performed in 5 healthy volunteers (3 women and 2 men. ages
23-34) according to the procedure described by Fernandez-Guardiola et al.
(1972, 1974). The subjects were informed about the experiment and the
known effects of the plant and a written consent was obtained. Capsules
containing either a Calea extract (HD-1) or placebo were administered 1 H
before the task in a double-blind randomized design, where neither the
volunteers nor the evaluator knew which substance had been ingested. The
first session did not involve the administration of any substance in order
to habituate the subjects to the experimental manipulations. Physiological
responses recorded included EEG, electromyogram, electrocardiogram, and
galvanic akin response. All sessions were done at the same time period
(1700-1820 h). A complete session consisted of alternated 10-min periods
for reaction-time evaluation and 10-min periods for time-lapse estimation.
In the reaction-time periods. the subjects were instructed to press a
button with their dominant hand as soon as possible after a light wee
dashed. Intervals between consecutive Bashes were of 10-s duration. In the
following 10 min, alternating with the reaction-time periods, the subjects
were asked to estimate the dash intervals by pressing the button each time
they thought the light should have been dashed. The entire test lasted 80
min. Analysis of variance was used to assess results between and within
individuals, the protected "t" and Least Significant Difference tests were
used in paired comparisons.
Sleep recordings in humans
The conventional procedure for EEG recording of sleep (Rechtschaffen and
hales. 1968) was used in a similar double-blind randomized design which.
in this case, included a low dose of an active hypnotic drug (diazepam,
2�5 mg orally). In order to standardize the nap session, all volunteers
were asked to reduce their normal sleep time by 2 h the night before
testing. The extract, diazepam or placebo capsule was ingested 1 H prior
to the recording session (1700-1900 h). The physiological variables
recorded included respiratory and heart rates, number of nap episodes.
total time spent in wakefulness (W). in slow wave sleep stages (SWS stages
I to IV) and in rapid-eye-movement sleep (REM) (Rechtschaffen and Kales,
1968). The respiratory rate was recorded by means of a thermistor located
in the nostril and connected to a polygraph amplifier measuring the air
temperature in each inhalation-exhalation cycle. This is an indirect
method which provides the frequency and amplitude of respiratory rate.
Data analyses were done by means of factorial analysis of variance
(ANOVA). For paired comparisons, the Student Newman-Keuls test was used.
Dream reports
The psychological effects of Calea extracts were evaluated by the
application of directed questionnaires and analysis of free reports of the
subjective sensations and dreams in all human volunteers after the
reaction-time, nap sessions and the following night. Neither the subjects.
the interviewer nor the evaluator knew whether the individual had taken a
plant extract, diazepam, or placebo. The results were compared by the
binomial test.
Results and discussion
Behavioral toxicology in cats
Some minor behavioral changes were observed with low doses of both
extracts (HD-1 and HD-2). The cats stared for long periods of time and 30
min after the administration of the zacatechichi extracts somnolence and
sleep were frequently observed. The HD-4 and HD-1O doses of the hexane
extract produced ataxia, bilateral contractions of nasal and maxillar
muscles, and stereotyped pendulum head movements. The HD-10 dose also
induced salivation with vomiting occurring about 90 min after
administration. The methanol extract produced ataxia (HD-4) and compulsive
grooming (HD-2). A common toxic effect of both extracts (doses HD4 and
HD-10) was retching and thick salivation. It was not clear if these
effects were elicited by direct central nervous system stimulation or in
response to local gastric irritation caused by some bitter principle of
the plant. This activity was noted by Giral and Ladabaum (1959) and may be
responsible for the appetizer properties of C. zacatechichi. Stare and
pendular head movements can be elicited by several psychoactive drugs such
as toluene (Alcaraz et al., 1977; Contreras et al., 1977), quipazine
(Sales et al.. 1966, 1968) and dopamine agonists (Ernst. 1967). These
effects are. therefore, not specific for any one of the several classes of
psychoactive compounds. Moreover, staring and pendular head movements may
merely be indications of somnolence. In order to analyze more precisely
the neural effects, electrophysiological recordings were taken in
free-moving cats.
EEG activity in cats
Both plant extracts produced similar EEG changes which were very different
from the other drugs used(Fig. 1). The hexane extract induced 3 cps large
voltage rhythms in the cortex, cingulum and septum while the methanol
extract provoked 8 slowing of the EEG rhythm more predominant in
subcortical structures. Somnolence was observed during the appearance of
these changes. A quantitative analysis of frequency of discharge in the
cingulum was performed for all drugs tested (Fig. 2). The hexane extract
produced only minor changes while the methanol extract clearly decreased
the frequency. This response is in contrast to the known psychodysleptic
compounds which produce decreases of 6-7 cps (Contreras:- et al.. 1984).
The results of these experiments show that zacatechichi does not share the
neurophysiological effects of the dissociative psychodysleptics and only
induces the behavioral and EEG signs of somnolence and sleep. The apparent
low toxicity of the plant in these experiments and its history of
ethnobotanical use allowed us to ascertain the hypnotic potency, dream-
inducing effects and other psychotropic properties in human beings.
Reaction time and time-lapse estimation in humans
No differences among the three treatments were found for human rate,
galvanic skin response and EEG recordings. With the methanol extract,
short periods of sleep (stage I) usually appeared between flash intervals,
and the subjects were awakened by the light. Both extracts produced a
statistically significant slowness of reaction-time (Fig. 3): 250 ms with
placebo, 280 ms with hexane extract and 290 ms with methanol extract (P <
0.01). Similarly, the IO-s lapse was overestimated with the zacatechichi
extracts (Fig. 4). The methanol extract increased estimation by 3 s on
average (P < 0.001). Both extracts increased respiratory rate, but this
change was not significantly different from controls.
The characteristic EEG slowness and the increased reaction times of
subjects treated with both extracts suggested that zacatechichi may
contain hypnotic compounds. Moreover, a larger effect was elicited by the
methanol extract suggesting that the active compounds might be found in
the polar fractions. An increase in time-lapse estimation and a weak
respiratory analeptic effects have been reported after marihuana
administration (Fernandez-Guardiola et al., 1974).
Sleep recordings in humans
Since the experiment just discussed did not allow an analysis of sleep
stages, the possibility of sleep and dream modifications by zacatechichi
was tested in a nap study conducted in the same human volunteers. Heart
rate, total time and frequency of each stage of sleep did not change with
any treatment in comparison to placebo (Fig. 5). However. it was found
that the frequency of W and SWS-IV stages were significantly modified by
treatments (W F(3,32)= 5.28, P < 0.01; SWS-IV F(3,32) = 3.35.
P<0.05). Post-hoc paired comparisons showed that, upon onset of sleep, the
methanol extract and diazepam increased significantly the frequency of W
stages (P < 0.05) when compared to placebo. In contrast, methanol extract
and diazepam decreased significantly (P < 0.05) the number of SWS-IV
stages. The other stages of sleep were not significantly modified by
treatments. SWS-I and SWS-II showed a alight increase in comparison to
placebo and, in contrast, SWS-III and REM stages decreased slightly.
Respiratory rate was significantly modified by treatments (F(3,400)=
79.92, P < 0.005). Paired comparisons showed that the methanol extract
increased (P < 0.05) when compared to all other treatments (Fig. 6).
Although this small increase may lack physiological relevance, it does
suggest a pharmacological effect upon respiratory rate. These results
support the idea that zacatechichi extracts, particularly the methanol
fraction, contain compounds with activity equivalent to sub- hypnotic
diazepam doses. Ingestion of the plant produces a light hypnotic state
with a decrease of both deep slow-wave sleep and REM periods. The question
of the ethnobotanical use and open trial reports of dream enhancement was
studied in the following section by the evaluation of subjective reports
during the sleep study.
Dream reports
The quantitative results concerning hypnagogic imagery and dreams are
summarized in Table 1. Data from the reaction-time and the nap sessions
end the following night were pooled. Significantly more dreams (P < 001,
in comparison to placebo) were reported after the methanol extract.
Similarly, the number of dreams reported during naps was significantly
higher following the administration of the plant extracts than with
diazepam (P < 0.01). It can be appreciated that, although not significant,
the number of dreams reported was greater after the ingestion of Calea
extracts than placebo. A more detailed analysis of dream content is shown
in Table 2. The number of subjects that did not remember dreaming was
always greater after placebo and diazepam administration and. conversely,
the individuals that reported more than one dream per session were always
the ones treated with zacatechichi extracts. The dreams reported by
subjects ingesting Calea extracts, were of a shorter content (measured by
the number of lines written in the report). Spontaneous reports of
emotions and nightmares were not different among the four treatments.
Nevertheless, with the methanol extract more colors during dreaming were
mentioned .
These results show that zacatechichi administration appears to enhance the
number and/or recollection of dreams during sleeping periods. The data are
in agreement with the oneirogenic reputation of the plant among the
Chontal Indians but stand in apparent contradiction to the EEG sleep-
study results. It is well known that dreaming activity is correlated to
the REM or paradoxical phase of sleep (Aserinsky and Kleitman, 1953) and
it could be expected that a compound that increases dream would also
increase REM stage frequency or duration, as it has been shown to occur
with physostigmine (Sitaram et al., 1978). In contrast, zacatechichi
increases the stages of slow wave sleep and apparently decreases REM
sleep. This also occurs with low doses 12-10 mg) of diazepam (Harvey,
1982). Despite this similarity in EEG effects, diazepam decreases dreaming
reports (Firth, 1974) while zacatechichi extracts enhances them. Such
discrepancy may be explained by the fact that dreaming and imagery are not
restricted to the REM episodes but also occur during slow wave sleep (SWS
I and II) as lively hypnagogic images (Roffwarg et al., 1962). Such images
are reported as brief dreams and are known to be enhanced by marihuana
(Hollister, 1971). All this suggests that Calea zacatechichi induces
episodes of lively hypnagogic imagery during SWS stage I of sleep, a
psychophysiological effect that would be the basis of the ethnobotanical
use of the plant as an oneirogenic and oneiromantic agent.
Acknowledgments
The authors wish to express their gratitude to Dr. Alfredo Ortega for
advice in the preparation of the plant extracts.
This document Copyright Journal of Ethnopharmacology 18.
� � TeachingPlants.com - 2004 - All rights reserved. �