Stanley Glick

Copyright © 1995-1996, Paul De Rienzo, Dana Beal
and Members of the Project

All Rights Reserved

CHAPTER 7: Stanley Glick

In 1986, Howard Lotsof again approached the National Institute of Drug Abuse (NIDA) and asked them to put Ibogaine to the hardest test. Have your doctors, he said, give it to subjects you pick, double-blind.

“We don’t really believe you,” they replied, “and anyway you have to demonstrate it in the animal model.”

“Animals are animals and people are people,” he objected. But he realized the work would have to go forth, and he set out to do it. First Lotsof would have to get Ibogaine, and none of the European pharmaceutical giants would sell him any, unless he got European patents. So while he obtained patents in fourteen countries other than the United States, he made the trip to Libreville so he could manufacture his own Ibogaine.

When he finally got his first Ibogaine nine months later, Howard began working on data for attenuating the alcohol dependency syndrome. Here he was venturing beyond his original ’62-’63 trials, so he contracted with a professor through a graduate student at McGill in Montreal to check out Ibogaine’s effect on alcoholic rats. The professor turned the real work over to the same graduate student– who turned out to be simply incapable of performing the analysis to recognize the trend that was clear in his experimental data.

“This kid could have published the first scientific paper showing ibogaine’s efficacy. Instead, he went with me to the bank, where I withdrew every cent I had and gave it to him. Then he said, ‘You know, you really fucked me over.’ Fortunately, our contract specified that I owned the data from his experiment. When I looked it over, the attenuation of alcohol consumption was clear. This guy was simply unwilling to see it.”

Howard filed the patent (U.S. #4,857,523) for attentuation of alcohol dependency s yndrome, July 18, 1988. It was granted the next year, August 15, 1989.

Upon getting supplies, Howard had fired off a sample to Drug Testing Program of the College on Problems of Drug Dependency at the National Institute of Health in Maryland. In January of ’88 he got back a letter from Dr. Arthur E. Jacobsen, the Chairman of the Program, reporting that the Dr. James H. Woods of the University of Michigan Medical School in Ann Arbor had determined Ibogaine was not a substitute narcotic. 69

Using in vitro (in glass, i.e., not in living animals) preparations of the brains of rats and the brain stems of mice, Woods showed Ibogaine “did not exhibit significant opioid activity.”

Howard next furnished Ibogaine to researchers in the Pharmacology Department at Erasmus University, Rotterdam. E.D. Dzoljic, Charlie Kaplan and M.R. Dzoljic developed a method of injecting it into the ventricles (little spaces) of rat’s brains, so that they would get the effects of regular IV or interperitoneal adminstration with a thousandth of the usual amount. For them fifty grams was like fifty kilos.

In ’88, the Dutch group was the first to publish a full paper, Effect of Ibogaine on Naloxone-percipitated Withdrawal Syndrome in Chronic Morphine Dependent Rats. Live rats were addicted by implanting them with morphine pellets, then t hrown into withdrawal with naloxone (the morphine “blocker” developed in the ’60s, prototype of today’s longer-acting naltrexone). By injecting Ibogaine into3 the brain (intercerebroventricularly) fifteen minutes before the naloxone, withdrawal was lessened, especially signs related to locomotion (rearing, digging, jumping)–as well as head-hiding, chewing, teeth-chattering, writhing and salivation–which showed withdrawal was being blocked. The rats also had less desire to hide and to escape; the only sign that increased was penile-licking(!). Kaplan and the Dzoljics noted studies showing Ibogaine simultaneously stimulates sleeping (acetylcholine) and fight-or-flight (nor-adrenalin) brain pathways.

Now in the world of pharmaceutical giants, NDA International was an amoeba among whales (“Three officers and nine lawyers,” quips Norma). It was Norma, Howard and Bruce Sakow, a commercial screen writer who was their first investor (“I’ve known Howard since the eary ’70s,” says Sakow. “When I put my money in I thought I was throwing it away. I didn’t think he would get as far as he has.”)

Lotsof ran out of money in 1989, after he had contracted with Dr. Stanley Glick, head of the Department of Pharmacology and Toxicology at Albany College of Medicine, to test whether Ibogaine would depress long-term intake of morphine in rats.

To find out, Glick trained his rats to self-inject about 75 milligrams (mg.) of morphine a day, enough to feel pleasure but not enough to be addicted. He took them off morphine on weekends: These were “casual user” rats. Each time a rat would press a l ever, they’d get .04 mg. per kilo (mg/kg) of body-weight.

Ibogaine in doses ranging from 2.5 to 80 mgs. was given either before and after the morphine on day one of the experiment. Immediately, 5 mg. of Ibogaine cut morphine intake 40 percent; 10 mg. cut it in half; 20 mg., 60 percent; and 40 mg. cut it to on e-tenth of what it was at the beginning of the experiment. But since Ibogaine causes behavioral immobility, in the first twenty-four hours water intake was also severely depressed by the time the dose reached 40 mg./kg.

What grabbed Glick’s attention was the after-effect. Ibogaine goes out of the body in a few hours, but doses of 40 to 80 mg./kg. depressed intake up to several weeks! Moreover, after several weekly treatments, this after-effect kicked in with some rats who were initially resistant. Not only that, this after-effect was not aversive (a simple conditioned negative response) because it happened whether Ibogaine was given before or after the morphine on day one of the experiment.

Although Ibogaine was shown in 1956 to double the painkilling effect of morphine, that only happens for the few hours that both are in the body. Ibogaine couldn’t be an antagonist,
because the rats would just have bar-pressed more morphine. Anyway, most researchers thought indole-alkaloids aren’t supposed to interact with the morphine pathways at all. Glick speculated that either a long-lasting Ibogaine metabolite or some lesi oning of the brain might be involved.

Now under the terms of their contract, Dr. Glick had to send Lotsof a preliminary report. But researchers don’t like to circulate anything before formal publication in a scientific journal; and to Glick’s embarrassment, he says, Lotsof “sent the data to two dozen people around the world!” Glick was relieved when Lotsof couldn’t pay him the rest of the money. That allowed him to break the contract, but continue Ibogaine research with his regular block grants from NIDA.

His next experiment (summarized inInteractions between Ibogaine, an potential anti-addictive agent, and morphine: an in vivo microdialysis study , with I.M. Maisonneuve and R.W. Keller, Jr.) used probes set in the skulls of living rats to colle ct minute amounts of a neurotransmitter called dopamine (DA), to track the effect of Ibogaine on the morphine high.

Dopamine makes your “pleasure centers” do their thing; when one neuron fires off dopamine to the next neuron, it feels good. It also triggers locomotion. In Parkinson’s disease the dopamine
system shuts down, causing paralysis.

Cocaine produces a surplus of DA in the intersynaptic space by occupying a slot on the protein “transporter” that carries DA back into the neuron for re-use. Morphine, nicotine, and booze increase the neuronal firi ng rate. Amphetamine increases DA release directly. But take away your usual drug (except for marijuana, which keys into a completely different network atop the brain) and you’ll feel listless, anhedonic (no pleasure) and even the pangs of acute withdrawal.

The common denominator effect of all these drugs is chronic DA surplus in the mesocortical or mesolimbic system, i.e., where dopamine pathways project either into the pre-frontal cortex (decision-making), or a little bulb called the nucleus accumbens (sexual pleasure, movement). or further back in the occiput, into the striated cortex, the striatum (visualization). In the standard model of addiction, visualization in the striatum (a) triggers craving in the nucleus accumbens, (b) which sets up a dopiminergic cascade of further visualizations and cravings that finally trip the dopamine switch in the pre-frontal cortex, (c) initiating drug-taking.

Glick, Maisonneuve, et al. sought to determine first, what Ibogaine alone does to extra-cellular DA and its metabolites, DOPAC (3,4 dihydroxyphenacetic acid) and HVA (homovanillic acid)? Next, how does morphine by itself, 5 mg. and 30 mg., effect all three regions? Finally, what does Ibogaine pre-treatment nineteen hours prior to 5 mg. of morphine [by which time the Ibogaine–with a “half life” in the body of one hour, according to Dhahir–is certainly gone] do to the dopamine release and behav ioral change that normally come with a 5 mg. per kilogram dose of morphine?

Acutely (i.e., right away) Ibogaine decreased DA in the striatum, increased it in the pre-frontal cortex, had no effect in the nucleus accumbens.* But the metabolite DOPAC increased in all three areas; HVA increased in the striatum and nucleus accumbens.

On the other hand, the lower five mg. dose of morphine kicked up DA and its metabolites in all three regions; while 30 milligrams increased not dopamine but the metabolites. [On the graph it looks like the entire increase shifts into metabolites.]

After Ibogaine pre-treatment, 5 mgs. of morphine failed to raise DA levels in the three regions. Instead there was a rise in metabolites similar to 30 mgs. of morphine with no Ibogaine pre-treatment, (except in the neo-cortex, where DOPAC stayed flat and HVA increase was de layed and smaller).

Likewise, 5 mgs. of morphine by itself inhibited motor activity for 40 minutes, followed by a burst of excitement. But in pre-treated rats there was no excited period, just an inhibitory phase (of two hours) much like 30 mgs. of morphine (three hrs). Was a long-lasting metabolite of Ibogaine potentiating the morphine, so that a 5 mg. dose had the same effect as a 30 mg. dose? Or was a neurotoxic effect damaging some DA neurons while increasing firing of the remaining ones? The second possibility seemed ruled out by Dhahir’s ’71 study, in which rats treated for thirty days with 10 to 30 mg./kg. of Ibogaine showed no neuronal damage.

With 5 mgs. of morphine, increased motor activity matched a rise in striatal dopamine (80 % of DA receptors are in the striatum). Glick concluded that the30 mg./kg. dose somehow additional opioid sites were being activated, blocking striatal DA release.

With Ibogaine treatment, DA release was also down. Since Glick found the same morphine level (5 mg./kg.) in the control group, this meant neither Ibogaine nor a longlasting metabolite was prolonging morphine half life. Morphine was still firing off DA, but it was turning into metabolites DOPAC and HVA instead of hanging out. Glick did know that by preventing a DA surplus in the nucleus accumbens, Ibogaine could decrease morphine’s “reinforcing effect.”

Glick’s group followed this up with the most complex set of tests yet, trucking in radioactive samples (radio-ligands) of Ibogaine and its closest relatives to find whether the reduction of morphine intake was specific to Ibogaine, or if ’60s psychedelic researchers had missed a general effect of a number of indole-ring compounds. Glick chose Ibogaine HCI, ibogamine, tabernanthine, corinaridine, harmaline HCI, harmane HCI, and harmine HCI.

Published later as Mechanisms of action of Ibogaine and Harmaline cogeners based on radioligand binding studies , the experiments aimed to answer three questions: Was Ibogaine locking into one of the opiate receptors? Does the hallucinogenic effect involve the serotonin (5 HT) receptors? And third, iboga and harmala alkaloids produce tremor (slight shaking)–how? For comparison purposes, drugs were used with known affinities for thirty different kinds of brain receptor including dopamine, se ratonin, adrenalin and opiates, but also GABA, cannabinoid, CI (since Ibogaine HCI is a chloride salt), benzodiazapine (BZD) and several others.

There were some big surprises. Lack of affinity for serotonin receptors showed that iboga and harmala indolealkalamines–even though they share an indole ring–are fundamentally different from the LSD series. As for tremor, it wasn’t happening in the GABA receptor; nor was chloride uptake being blocked at the BZD (valium) receptor. Instead all the harmala and iboga compounds were conductively–i.e, neuro-electrically–firing via the sodium channels.

But the real find was that all the iboga compounds–and none of the harmala ones–had a transient affinity for the KAPPA-opiate receptor. But only transient–one rinse of the homogenized brain tissue used in the experiment freed it up for any competing chemical. By comparison, buprenorphin, which cannot be blocked by naloxone once it is administered, gives up its hold on opiate receptors most reluctantly. Ibogaine’s long-lasing effect doesn’t come by locking out opiates. It does just enough to block wi thdrawal 95 percent, but leave the addict something to overcome. Once again it was shown to be neither a substitute narcotic nor an antagonist (blocker).

Glick was now completely hooked on Ibogaine research. He converted one-third of his lab to his own mini-Staten Island project, spending a few hundred thousand in NIDA block grants.

Next Glick studied Ibogaine and D-amphetamine (remember “dexies”?), since amphetamine produces dopamine surplus via the most straightforward route (increased release, versus increased neuronal firing rate on morphine, etc.). Rats will inject amphetamine directly into the nucleus accumbens. Also, lesioning there decreases amphetamine-induced DA release and hyperactivity.

Nineteen hours after the pre-treatment, dopamine levels were back to nor-mal; but both metabolites (DOPAC, HVA) were still down. When D-amphetamine was given, DA levels were doubled in both the nucleus accumbens and striatum of pre-treated rats, while metabolites decreased. Pre-treatment also increased locomotion across a broad range of doses, and after the first hour, made it peak sooner.

How, if pre-treatment doubled DA release, and DA causes the pleasure that makes drugs addictive, could Ibogaine interrupt amphetamine abuse? The answer lies in the well-known unpleasant ” wasted” feeling produced by too much amphetamine. As Glick said later in Interactions of ibogaine and D-amphetamine: in vivo microdialysis and motor activity in rats (with I.M. Maisonneuve and R.W. Keller, Jr.), released DA activates other autoreceptors, so that one too-hig h dose can produce an averse reaction to subsequent low doses.

How? Glick proposed Ibogaine might do this by sensitizing the neurons, or via his elusive “long-lasting Ibogaine metabolite.”

Next Glick’s group went back to measure, more exactly, what happens with dopamine and behavior when morphine is given one hour, nineteen hours, one week and one month after Ibogaine pre-treatment. As explained in Acute and Prolonged effects of Iboga ine on brain dopamine metabolism and morphine-induced locomotor activity in rats , they first recorded the effects of morphine on locomotion. Then, instead of teasing traces of DA and its metabolites from between the neurons with dialysis, this time they killed the rats and determined total DA tissue content.

The first mystery solved was how DOPAC and HVA are depressed nineteen hours after pre-treatment: within an hour of Ibogainization, dopamine fell a whopping 54 % in the pre-frontal cortex, 51% in the nucleus accumbens, and 42 % in the striatum (where 80 % of DA receptors reside). Nineteen hours later, DOPAC was still at 85% of normal in the nucleus accumbens and 83% in the striatum; the pre-frontal cortex was normal. Aweek after Ibogaine, striatial DOPAC was still 90 % of normal. (Glick was so surprised he checked this finding twice.) After a month, everything was normal.

Now Ibogaine itself inhibits motor activity, but only during the first hour. A week after Ibogaine Glick’s rats were more active, which indicates the initial DA drop wasn’t a result of simple lesioning–say of the nucelus accumbens. But even after a week, Ibogaine (40 mg./kg.) depressed morphine’s behavioral stimulation, except at the high dose of 30 mg./kg. Since his second study (Interactions between Ibogaine and Morphine) found expected DA release was depressed in the striatum, but not the nucleus accumbens (which is thought to govern movement), Glick could only speculate the absence of stimulation might result from striatally-induced morphine rigidity. [The alternative explanation–inhibition of visualization in the triggering of craving–is harder to check out in rats. But he was also inclined to see visualizations as an undesirable side effect of Ibogaine therapy.] At one month later, the inhibition of morphine effect finally wore off.

Yet if the second study recorded no 50 % DA release, and only moderate metabolite increase (HVA), where was the dopamine going? Ibogaine action on voltage-dependent sodium channels could release a little, and block re-uptake a bit, but that doesn’t account for 50 %! Perhaps DOPAC decrease at nineteen hours could result from new DA being diverted into storage pools. But to fully explain it, Glick was left either with his elusive, and now very long-lasting, metabolite or “persistent neuronal change.”

Finally, Maisonneuve and Glick tried out Ibogaine on cocaine. Repeating the combo of micro-dialysis and measurement of behavioral stimulation, they found that cocaine challenge (i.e., fresh administration) nineteen hours after pre-treatment boosted and lengthened the usual DA release in the nucleus accumbens, and to a lesser extent, in the striatum. Behavioral stimulation was increased only in the second hour, but that might be because the rats were not yet habituated to cocaine. They could only begin to be habituated in the second hour, when the motor enhancement corresponds to the first point of the cocaine “crash,” where the user typically becomes uncomfortable and hyperstimulated.

In Interactions between ibogaine and cocaine in rats: in vivo microdialysis and motor behavior , Maisonneuve and Glick noted the effect would be the same as a higher-than-intended dose of cocaine–anxiety-producing, ergo, aversive. Just like amphetamine. Of course, how Ibogaine pre-treatment could increase DA release with amphetamine while blocking DA re-uptake with cocaine, was as big a mystery of how pre-treatment could work at all when Ibogaine is completely out of the body after nineteen hours.

Glick now leaned toward the “long-lasting metabolite” hypothesis. If he could find it, and patent it, it would do everything Ibogaine does sans psychedelic effect. And as Dr. Marvin Snyder of NIDA told a NEWSDAY reporter in the summer of 1990: “We’re n ot looking at any drugs with psychedelic effects [for treatment of drug dependency].”

To be fair, as a veteran NIDA grantsman, Glick was aware Ibogaine had powerful adversaries in high places. He was aware Ibogaine had been plugged in the first draft of a 1989 Senate Judiciary Report on new medications for drug dependen-cy, but was drop ped from the final draft because Dr. Thomas Kosten and another doctor from Yale wrote a letter objecting that it’s an “herbal.” (Actually, Howard now gets synthetic 99.7 percent pure Ibogaine from Omnichem in Belgium.)

The centerpiece of the report? Buprenophine, which doesn’t work that well, and is addictive…but was developed by Kosten and Herb Kleber. So where Glick told NEWSDAY in 1990 that “lying on your back for two days would be a small price to pay” if Ibo gaine worked, by October 16, 1991, he told the ALBANY TIMES-UNION, “It is doubtful Ibogaine could ever be marketed because of its psychoactive properties and the muscle tremor.” He opined that they’d probably wait ten years to develop a synthetic. Glick needed NIDA grants to do anything, and Herb Kleber was Deputy Drug Czar.

To Lotsof and his supporters, the visualization or “waking REM” (Rapid Eye Movement, as in dreaming) effect was integral to Ibogaine’s efficacy. Howard says this phase, which only lasts four-to-five hours, enables the addict to dredge up all kinds of traumatic material while in a “neutral cognitive state,” and is essential to their “maturing out of addiction.” Certainly, there’s no way to learn how important waking REM is by studying rats, mice or monkeys.

“Originally our critics told us no medication can get at the deep psychological roots of addiction,” says Howard. “Well, you certainly can’t affect those roots without getting at them.

“They want crops without plowing up the ground… rain without thunder and lightning. They want the Ocean without the awful roar of its many waters.”

Gradually, though, Lotsof has become reconciled with Glick. In February 1990, when he got more good news from Jacobsen of the Committee on Problems of Drug Dependence, he made certain Glick was first to know. Drs. Aceto, Bowman and Harris of the Medic al College of Virginia had performed research showing that Ibogaine does not cause significant physical dependence. Here was independent confirmation Ibogaine had at least one characteristic of a true addiction interrupter.

On April 30, 1991, Dr. Stanley Glick gave a one-hour lecture, with slides, at Mt. Sinai Hospital–as a courtesy, since personnel there had been instrumental in introducing him to Lotsof in 1986. As a courtesy, Howard, Bob Sisko and Dana Beal were all i nvited. They sat there as Glick presented an overwhelming profusion of charts, graphs and statistics, a slick show on his phase of the Staten Island Project. But his principal findings were simple:

*Ibogaine is neither a substitute narcotic nor a crude mechanical blocker like naltrexone.

*Iboga, but not other indoleakalamines, temporarily bind to the KAPPA-opiate receptor, enough to ameliorate withdrawal but not enough that the addict feelsno withdrawal whatsoever.

* Ibogaine depressed morphine intake in all but one of twelve rats who were not addicted, but were self-injecting for pleasure. Ibogaine decreases, but does not extinguish, pleasure response.

* Through the same mysterious mechanisms Ibogaine boosted amphetamine and cocaine effect in a way that could be anxiogenic, “aversive” in addicts upon first trying coke or amphetamines after treatment.

When the hour was up, and Glick was done, Howard Lotsof walked up to him and said: “Listening to your presentation, viewing your data, I felt like I was present when Enrico Fermi initiated the first nuclear reaction under the Stadium at the University of Chicago.”

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