The Wada test

"A perfectly bilateral machine or organism could not perform left-right discriminations, which much include scanning in a preferred (e.g. left-to-right) direction and distinguishing between such letters as d and b, p and q and such words as saw and was, such organisms could only make mirror-image responses to mirror-image stimuli..." (J.L. Bradshaw, 1983)

The right hemisphere is biased toward global processing and the left for local processing. Robert Sperry listed the following specializations for the right hemisphere: rhythm, spatial awareness, Gestalt (the whole picture), imagination, daydreaming, color, dimension. This supposedly describes the creative right brain of many left-handed artists. The left hemisphere, which controls the right hand - typically the dominant hand for writing the name - and which has a higher ratio of grey to white matter than the right hemisphere, specializes in verbal-linguistic and analytic functions.

Many techniques have been developed in the field of left-right brain research, but the Wada test must be one of the most dramatic and conclusive experiments. During a surgical procedure where the large arteries leading to the brain are exposed, injection of drugs into the bloodstream will selectively anesthetize one hemisphere. The Wada test is not performed very often, but it might be used before major brain surgery to determine which hemisphere is dominant for language.

From Human cerebral asymmetry, J.L. Bradshaw writes,

"Wada (1949) first developed the procedure known as the Wada test: an injection of the barbiturate sodium amytal (amobarbital) into one (left or right) of the common carotid arteries that supplies its ipsilateral hemisphere. A temporary loss of function is produced on the affected side of the brain: a flattening of the EEG, along with hemiparesis, hemianesthesia, and hemianopsia. It is in effect a reversible hemispherectomy, permitting tests of higher mental functions in the other hemisphere. If the drug is injected into the dominant hemisphere, there is usually total and abrupt cessation of speech. In view of the slight but definite risk accompanying the insertion of the needle or catheter into the carotid artery, the Wada test is employed only when absolutely necessary, and consequently such patients usually have more or less severe existing abnormalities of cerebral function. Moreover, since the unilateral suppression lasts only five to ten minutes and the experience itself is probably disturbing to the patient, usually all that can be determined is which hemisphere is specialized for speech production. Typically, the upraised contralateral arm and leg fall to the bed with a flaccid paralysis a few seconds after the injection. If the injected hemisphere is nondominant for speech, there is an abrupt and more or less total cessation of speech shortly after the injection; it lasts until recovery from the hemiparesis is well advanced. The patient makes characteristic dysphasic responses (perseveration, misnaming, mixing up the sequence of numbers and of days of the week, etc.) for several minutes before speech returns to normal. The Wada test has shown that dextrals have clear left hemisphere language dominance in over 90 percent of the cases, and sinistrals in 70 percent of cases. The effects of unilateral ECT are similar to those of unilaterally injected sodium amytal." (J.L. Bradshaw, 1983)

Depression of the left hemisphere with the Wada technique is associated with a depressive catastrophic reaction and for most people the traumatic loss of speech. Depression of the right hemisphere with sodium amytal leads to a euphoric or manic response.


Reference

Bradshaw, J. L. and N. C. Nettleton (1983). Human cerebral asymmetry. Prentice-Hall, New Jersey.

BOL-148

BOL-148 is the 2-brom derivative of LSD. There is a Bromine (Br) in place of Hydrogen at position 2.

From molecules

In spite of its close structural relationship to LSD, BOL-148 has no psychedelic effects. Among the LSD analogs, BOL-148 is especially important because it indicates that substitution at the 2-position changes the activity of the whole molecule, as outlined by the studies below.

In 15 healthy males, doses of 75-110 ug/kg BOL-148, which 100X exceed an effective dose of LSD, caused no change in pupillary dilation, patellar reflex, or blood pressure (H. Isbell, 1959). BOL-148 did not alter the behavior of 6 individuals with schizophrenia, when given at 10X the dosage of active LSD, although for BOL-148 these doses may have been too low to observe any effect. One mg BOL-148 twice a day for 2 weeks, or 5 mg for 3 days had no evident effect on their psychoses (W.J. Turner, 1958).

With newly developed drugs and low doses of known drugs, there is frequently a problem in deciding whether the drug has an effect on the EEG. Generally where there is no EEG effect, no drug effect is expected. There is evidence of the contrasting pharmacological effects of LSD and BOL-148 on the EEG. While LSD affects the EEG in doses of 100 ug/kg, BOL-148 in doses of 100+ ug/kg are reported to be without effect on the EEG. BOL-148 did not cause any sign of the fast electrical activity or alerting behaviour seen with injections of LSD in cats, even when doses of up to 100 ug/kg of BOL-148 were used intraventricular, to avoid the blood-brain barrier (P.B. Bradley, 1956). BOL-148 is reported to produce no EEG changes in Macaca mulatta, in high dose ranges 110-175 ug/kg (R.R. Monroe, 1961). Saline gave the same response as 1000 ug/kg BOL-148 in cats with permanently implanted EEG electrodes (E. Eidelberg, 1965). In rabbits, 500 ug/kg BOL-148 failed to produce EEG alerting for longer than 15 minutes (A.K. Schweigerdt, 1966). These studies indicate a lack of effect of BOL-148 across a range of species.

BOL-148 has a very slight change in molecular structure compared to LSD, but it has none of the behavioral effects of LSD. LSD caused behavioral arousal in cats whereas BOL-148 produced mild sedation, when the two drugs were administered intraventricularly (P.B. Bradley, 1956). In rabbits, LSD enhances eyeblink conditionining, whereas BOL-148 had a neutral effect (J.A. Harvey, 2003). No affective changes in Papio papio were observed after BOL-148 in doses of 2-4 mg/kg (M.D. Fairchild, 1980).

Table 3 below shows the questionnaire responses for LSD and several LSD derivatives. LSD is the most potent drug, and caused the most positive responses on the questionnaire. BOL-148 is on this table, and there were few positive responses on the questionnaire at doses of 80 ug/kg, or 50 times the active dose LSD. This shows a lack of effect of BOL-148 as reported by human volunteers.

From LSD congeners and other human hallucinogens

There is some evidence that BOL-148 pre-treatment protects against LSD psychosis. Studies in rabbit have shown that BOL-148 1 mg/kg had no direct temperature effect - as LSD does - but prevented the pyretogenic actions of LSD (A. Horita, 1958). In humans, BOL-148 did not function as a direct LSD antagonist since intravenous injections of BOL-148 at the height of a LSD trip did not cancel the LSD effects, but pre-treatment with BOL-148 in nonpsychotic humans did produce tolerance to the LSD reaction, though the tolerance-producing effect of BOL-148 for equal weights of LSD is much less, approximately 1/30 that of LSD and the attenuation of the LSD reaction observed after pre-treatment with BOL-148 is still less than that which occurs after pre-treatment with LSD. (H. Isbell, 1959)

In an experiment with 10 men, pretreatment with BOL-148 for 5 days (1 mg BOL-148 three times daily) significantly attenuated LSD 0.5-1.5 ug/kg psychosis. As shown in Table 3 (below), blood pressure, pupil size and number of positive responses to questionnaire were reduced during LSD challenge 5 days after BOL-148 pretreatment (Isbell, H. 1959).

From LSD congeners and other human hallucinogens

Some assays have indicated similarities between LSD and BOL-148. For example, LSD and BOL-148 were found to have the same affinity for beta-adrenergic receptors (A. Dolphin, 1978), and were equally effective as MAO and acetylcholinesterase inhibitors in histochemical analysis of rat brain (T.R. Shanthaveerappa, 1963). However it is important to keep in mind that these samples did not involve the whole organism. More research in needed into the general significance of the 2-position for the pharmacological and EEG effects of LSD.

There is one report from 1957 indicating that BOL-148 may function as a hallucinogen in high doses. Two normal volunteers experienced psychic effects when BOL-148 was administered intravenously to total doses of 18 and 22 mg, or equivalent to ~200 LSD doses.

"In man small doses of bromo-LSD are said to produce none of the bizarre psychic effects noted with LSD but this is not the case when bromo-LSD is administered intravenously in large doses. Thus, when constant intravenous infusions of bromo-LSD were given to normal subjects, both experienced psychic changes, which became more severe as the infusion continued and persisted for 3 to 4 hours after the infusion was stopped. No hallucinations were noted but there were feelings initially of drowsiness, depression, anxiety, and apprehension followed by feelings of irritation, restlessness, and tenseness, and later, intensely disagreeable sensations of unreality and depersonalization, inexplicable feelings of strangeness and mild confusion." (R. Schneckloth, 1957)

A relatively large body of work exists on human studies with BOL-148, making it one of the most well characterized LSD analogs. BOL-148 shows that structure-activity relationships can be quite revealing about the mechanism of action of LSD, since substitution at the 2-position can change the activity of the whole molecule. Another important research finding related to BOL-148 research is that LSD does not induce a psychosis by creating a relative deficiency of 5-HT within the brain. BOL-148 has been shown to have more anti-5-HT activity than LSD in vitro and in vivo, thus if LSD worked by blocking 5-HT neurotransmission, BOL-148 would be expected to be a more potent hallucinogenic drug, but BOL-148 is inactive on many accounts.


References

BRADLEY P. B. and A. J. HANCE. (1956). The effects of intraventricular injection of d-lysergic acid diethylamide (LSD 25) and 5-hydroxytryptamine (serotonin) on the electrical activity of the brain of the conscious cat. J.Physiol. 132, 50-1P.

Dolphin, A., A. Enjalbert, J.P. Tassin, M. Lucas and J. Bockaert (1978). Direct interaction of LSD with central "beta"-adrenergic receptors. Life Sci. 22, 345-352.

Eidelberg E., M. Long and M. K. Miller. (1965). Spectrum analysis of EEG changes induced by psychotomimetic agents. Int.J.Neuropharmacol. 4, 255-264.Fairchild M. D.,

D. J. Jenden, M. R. Mickey and C. Yale. (1980). EEG effects of hallucinogens and cannabinoids using sleep-waking behavior as baseline. Pharmacol.Biochem.Behav. 12, 99-105.

Harvey J. A. (2003). Role of the serotonin 5-HT(2A) receptor in learning. Learn.Mem. 10, 355-362.

HORITA A. and J. H. GOGERTY. (1958). The pyretogenic effect of 5-hydroxytryptophan and its comparison with that of ISD. J.Pharmacol.Exp.Ther. 122, 195-200.

ISBELL H., E. J. MINER and C. R. LOGAN. (1959). Relationships of psychotomimetic to anti-serotonin potencies of congeners of lysergic acid diethylamide (LSD-25). Psychopharmacologia. 1, 20-28.

ISBELL H., E. J. MINER and C. R. LOGAN. (1959). Cross tolerance between D-2-brom-lysergic acid diethylamide (BOL-148) and the D-diethylamide of lysergic acid (LSD-25). Psychopharmacologia. 1, 109-116.

MONROE R. R. and R. G. HEATH. (1961). Effects of lysergic acid and various derivatives on depth and cortical electrograms. J.Neuropsychiatr. 3, 75-82.

SCHNECKLOTH R., I. H. PAGE, F. DEL GRECO and A. C. CORCORAN. (1957). Effects of serotonin antagonists in normal subjects and patients with carcinoid tumors. Circulation. 16, 523-532.

Schweigerdt A. K., A. H. Stewart and H. E. Himwich. (1966). An electrographic study of d-lysergic acid diethylamide and nine congeners. J.Pharmacol.Exp.Ther. 151, 353-359.

SHANTHAVEERAPPA, T. R., K. NANDY and G.H. BOURNE (1963). Histochemical studies on the mechanism of action of the hallucinogens D-lysergic acid diethylamide tartrate (lsd-25) and D-2-bromo-lysergic acid tartrate (bol-148) in rat brain. Acta Neuropathol. 3, 29-39.

TURNER W. J. and S. MERLIS. (1958). Chemotherapeutic trials in psychosis. III. 2-Brom-d-lysergic acid diethylamide (BOL 148). Am.J.Psychiatry. 114, 751-752.