Psychopharmacology of Calea zacatechichi A Dream Plant

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Journal of Ethnopharmacology 18 (1986) 229-243 Elsevier Scientific
Publishers Ireland Ltd

PSYCHOPHARMACOLOGIC ANALYSIS OF AN ALLEGED
ONEIROGENIC PLANT: CALEA ZACATECHICHI

LILIAN MAYAGOITIA. Jose-Luis Diaz and Carlos M. CONTRERAS

Departamenta de Psicobiologia y Cunducto, Instituto Mexicano de
Psiquiatria, Antiguo

Camino a Xochimilco 101, San Lorenzo Huipulco Tlalpan 14370 and
Departamento de

Fisiologia. Instituto de Investigaciones Biomedicas, Universidad
Nacional
Autonoma de

Mexico, Apartado Postal 70228. Ciudad Universitaria, Coyoacan 04510
(Mexico, D.F.)

(Accepted October 8. 1986)

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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 Mixtec 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 administration.

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

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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

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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.

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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.

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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.

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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

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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.

References

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