Ayahuasca: alkaloids, plants & analogs
Section 1 :
Harmala alkaloid pharmacology
Based on lethality studies of rabbits and protozoa, Gunn 1935 found harmaline twice as active as harmine and tetrahydroharmine to be about three times less active than harmaline.
Given orally, 300 mg of racemic THH produced similar effects to 100 mg of harmaline. This was evaluated, by Naranjo, once in one volunteer. Oddly this seems to be its only published bioassay with details.
Calloway has claimed in correspondence that it was "active" when smoked but included no details concerning either its activity or the dosage.
Naranjo 1967 gave harmaline as the hydrochloride and determined it was hallucinogenic above 1 mg/kg iv or 4 mg/kg orally. [Harmine required about twice this.]
- Onset was around one hour after oral and almost immediate when iv.
- Harmaline produced more lethargy and withdrawal than harmine but both caused visual changes.
- Paresthesias of hands, feet or face accompanies onset followed by a feeling of numbness. Feeling is most pronounced if injected and was likened by some subjects to anesthesia.
- Pressure in head, discomfort in the chest, or enhancement of sensations such as breathing or blinking.
- Nausea was reported in 18 or 30 subjects and sometimes led to intense vomiting.
- Usually associated with dizziness or general malaise.
- Elements common to other hallucinogens such as distortion of bodily images, distortion of forms, changes in perception of depth or in facial expressions were rarely if ever present. Color enhancements and breathing images were also not observed.
- Harmaline left the environment essentially unchanged.
- Usually the visual phenomenon was limited to images superimposed on walls or ceilings or seeing imagined scenes simultaneously with the unchanged perception of the surroundings.
- Rapid lateral vibration in the visual field. Over half of the subjects reported buzzing noises.
- Musical perception was unchanged but some noises became pronounced and considered bothersome.
- Double or multiple contours in objects, especially if moving or if seen peripherally.
- Closed eye imagery was abundant; most were vivid and brightly colored. Red-green or orange contrasts predominated.
- Long dream-like sequences were more common with harmaline than with mescaline.
- Harmaline did not produce the aesthetic or empathetic qualities of mescaline but concern with religious or philosophical problems was frequent. Subjects consistently could identify β-carbolines as distinct from mescaline.
- [No synaesthesias or alterations of the sense of time were reported.] "The typical reaction to harmaline is a closed-eye contemplation of vivid imagery without much further effect than wonder and interest in its significance, which is in contrast to the ecstatic heavens or dreadful hells of other hallucinogens."
Naranjo reported an amelioration of neurotic symptoms in 8 out of 30 subjects.
- Extreme passivity and withdrawal were noted with minimal desire for communication.
- Most subject given harmaline lay down for 4 to 8 hours during which they felt relaxed with no inclination to move or talk.
- Naranjo felt that harmaline produced more images than mescaline and these showed a more realistic quality. Many subjects felt that certain of the scenes they witnessed had actually happened with them as a disembodied observer, seeing them in a different time and place.
- Harmaline caused a definite increase in the alpha wave and a decrease in the beta wave. Naranjo felt that production of the double images was a retinal effect.
- Harmaline was indicated as acting as a stimulant on the midbrain reticular formation. Its direct action of the brain cortex seems to be more that of a depressant.
The state produced by harmaline: lethargy, immobility, closed eyes and generalized withdrawal from the environment, accompanied by alertness to mental processes and activation of fantasy.
Pennes & Hoch 1956 (Using psychiatric patients and harmine supplied by K.K. Chen at Eli Lilly):
They used both naturally derived material from B. caapi and synthetic HCl.2H2O .
Dosages were given as the hydrochloride salt and ranged from:
Oral: (11 patients) 20-960 mg
Subcutaneous: (6 patients) 40-70 mg
Intravenous: (11 patients) 100-300 mg
Slight drowsiness was a common effect.
Bradycardia and hypotension occurred in all doses of intravenous harmine limiting dosages to 300 mg or less. [A reduction of 18 beats per minutes and 16 mm of systolic pressure were average. Recovery was in about 30 minutes.]
Harmine was not reported to be hallucinogenic if taken orally or subcutaneously. It was given orally in dosages up to 960 mg.
Pennes & Hoch reported a "semidelirioid or confusional state",
- Nausea and vomiting.
- Slow, coarse, spontaneous tremor of extremities ("extrapyramidal" appearance).
- Humming and buzzing noises (no voices).
- "Waviness" of the environment.
- "Sinking" sensations.
- Subjective sense of bodily vibration.
- Subjective numbness (reduced sensitivity to touch and pinprick).
Harmine and harmaline both show primarily inhibition of MAO-A but at the concentrations ingested in ayahuasca they also inhibit MAO-B. However, this latter inhibition is competitive and both compounds show lower affinity for MAO-B than does tyramine and thus are easily displaced by it.
Udenfriend (et al. 1958) showed harmaline to be an extremely potent and reversible MAOI. Pletscher (et al. 1959) found this to be true also of methoxy-harmanes, harmine and tetrahydroharmine using mouse brain in vivo (murine brain). MAO inhibition in rat brain resulting from harmaline lasted 12-16 hours. Harmine lasted around 8 hours. [This is in rats not humans.]
Harmaline and harmine cause bradycardia and hypotension when given iv. Both prevent or reverse hypotensive and sedative effects of reserpine.
Small doses of harmine can slightly increase blood pressure.
Harmine blocks or depresses ganglionic and myoneural transmission and stimulates intestinal contractions in vivo.
Both harmine and harmaline promoted uterine contractions.
Harmine and harmaline have been observed to show antihelmintic action on ascarid worms and various harman derivatives are also active against protozoa.in vitro (trypanosomes and amoebas)
Gershon & Lang: "The chief central effects of [harmine] are an anxiety type response in normal man and an activation of psychotic processes in schizophrenic subjects."
Harmaline nullifies conditioned avoidance-escape behavioral reflex.
Ho 1977 felt that unsaturation was required for strong psychotomimetic activity of β-carbolines.
Saturated compounds were more potent inhibitors of serotonin uptake in vitro than were the unsaturated ones. (Using a synaptosomal suspension from mouse brains.
Tetrahydro-β-carbolines were more potent inhibitors of serotonin uptake than of norepinephrine or dopamine uptake, according to Buckholtz 1979.
- Lessin et al. 1967:
|Compound||in vitro||in vivo||A|
A = 5HT reuptake in platelets in vitro (tryptamine=1)
in vitro used the mitochondrial fraction of guinea pig liver homogenates.
in vivo evaluated brain homogenates from mice treated with the test compound.
Harmine is an active MAOI with mouse brain (in vivo) but was reported to have no MAOI activity with mouse liver. It was also shown to demonstrate little liver MAO inhibition with beef liver but completely inhibited 5HT oxidation by beef brain. A similar disparity was reported in rats.
It is believed that there are two types of MAO in beef brain with an affinity for harmine; one with a low affinity and another stronger one. In beef brain, harmine shows noncompetitive inhibition of tyramine oxidation but in pork brain shows competitive inhibition.
There appears to be no relationship between MAO inhibition and tremor production. The reduction of dopamine function by harmine has been found to be directly related.
While repeated administration of harmaline causes a decrease in the levels of striatal dopamine and homovanillic acid; a single administration of harmaline had no affect on striatal dopamine 1 or 2 hours after injection.
Harmine has no effect on the activity of tyrosine hydroxylase, dopa decarboxylase or dopamine-β-hydroxylase. (At levels of up to 100 mM.)
Harmaline was also found to interfere with the conversion of injected L-dopa to striatal DA and HVA in the thalamus and striatum but it did not interfere with the conversion of 5HTP to 5HT.
In intact cats (at 5 mg/kg iv) "harmaline induces a fine generalized tremor at 8-12/sec." It is "usually synchronous in antagonistic muscles and is periodically interrupted by tonic contractions lasting 1-10 sec."
Rhythmic discharges at 8-12/sec in the inferior olive generated synchronous climbing fiber responses in Purkinje cells associated with an almost complete suppression of simple spike activity."
Rhythmic activity at 6-12/sec in the form of bursts or interrupted trains of unit discharge was recorded from the cerebellar cortex, the inferior olive, the fastigal nucleus, the bulbar reticular formation and the vestibular nuclei."
harmaline would seem to exaggerate the normal rhythmic properties of the olivary cells."
They also mentioned in-press work as reporting the recording of "rhythmic activity at 7-12/sec in the olivo-cerebello-bulbar system in awake monkeys injected with harmaline."
- De Montigny & Lamarre 1973
Tremorigenic effects appeared (in rabbits) at 2-3 mg/kg for both harmine and harmaline. When dosages of 5-10 mg/kg were used excitation, ataxia and mydriasis accompanied the tremors. Tremors appeared 30-60 seconds after injection and lasted for 10-15 minutes with harmine and no more than 5 minutes with harmaline (both at 5 mg/kg).
Later, tremors were only noticed if animals moved.
In the EMG, the frequency of the tremor in the rabbit was 10-12 cps and showed a waxing and waning pattern. (Ahmed & Taylor 1959 had reported 15-20 cps in mice but also the same waxing and waning.)
- Fuentes & Longo 1971
- Both harmine and harmaline are rapidly absorbed by tissues after ip injection and reach maximal concentration after 30 minutes.
- Harmine and harmaline both modify the EEG increasing frequency and voltage at cortical and hippocampal levels.
- Harmine and harmaline cause excitation, tremors and ataxia in rats and rabbits.
- Harmaline causes a generalized tremor with a frequency of 8-12 seconds in mice, rats, cats, and monkeys. There are differences in the production of tremors by harmine and harmaline.
- Harmaline (ip) induces hypothermia in rats. Intracisternal administration produces a faster reduction in body temperature suggesting a central origin for the effect. While it induces hypothermia in rats, it elevates body temperature in mice and in rabbits (hyperthermia).
- The hypothermic response from harmaline was reported to require the presence of norepinephrine.
- (There appears to be no relationship between the hypothermic action and MAO inhibition.)
- Ho 1977
Harmine is a reversible inhibitor of ATP-MG2+ dependent uptake of epinephrine into isolated rat adrenal vesicles. Harmaline is slightly less effective.
Harmine and harmaline are "inhibitors of membrane (Na+ + K+)-ATPase systems prepared from human erythrocytes, rat brains and squid retinal axon."
- Ho 1977
Harmine's effects on adrenal medullary storage vesicles were similar to reserpine except that harmine demonstrated reversible inhibition rather than irreversible inhibition.
- Green & Slotkin 1973
Harmine and harmaline both showed competitive inhibition of norepinephrine reuptake into rat brain synaptic vesicles. Slotkin et al 1978
Harmaline showed more potent vasopressin-like effects on sodium and water transport than harmine
- de Sousa & Grosso 1978
Harmine & Harmaline both showed a UV-mediated cytotoxic activity against a variety of bacteria. Harmaline showed greater activity in this regard than did harmine.
(THH was not evaluated but 6-Methoxyharmalan showed activity comparable to harmaline whereas 6-Methoxytetrahydroharman was devoid of activity suggesting that the same might hold true for THH.)
- McKenna & Towers 1981
Llinas & Volkind 1973
Mao et al. 1975
Simonson & Charnock 1979
Zetler et al. 1972
β-carbolines appear to be ligands for the known benzodiazepine (Valium) receptors:
See: Lippke 1983 & Morin 1984
Harmine was reported to produce a state of anxiety and excitation in dogs by Gershon & Lang 1962. Harmine & harmaline have been reported to cause excitation, tremors & ataxia in mice, rats, cats, rabbits and also monkeys. [Fuentes & Longo 1971]
Atropine (up to 5 mg/kg) and also Serotonin (up to 20 mg/kg) had no effect on the actions of harmine or harmaline.
L-DOPA was found to be an effective antagonist to the tremors and other symptoms caused by harmine & harmaline at 5-10 mg/kg iv.
L-DOPA was given at 5 mg/kg iv, the effects of the harmala alkaloids disappeared within 5 minutes. This activity was temporary and the effects eventually returned but could be again eliminated by additional administrations of L-DOPA. If 20 mg/kg of L-DOPA was given, there was a complete & lasting abolition of effects and the animals behaved normally except for a slight amount of excitation.
- Fuentes & Longo 1971