Category: Psychedelic Drugs

Researchers have found that genetic factors may play an important role in a person’s use, misuse or dependence of illicit drugs like marijuana, stimulants, opiates, cocaine and psychedelics.

In the July issue of the journal Psychological Medicine, Virginia Commonwealth University researchers, in collaboration with researchers from Norwegian Institute of Public Health and University of Oslo in Norway, reported the results of a population-based study of twin pairs that showed that genetic factors influence the illicit drug use in Norway, a country with significantly low levels of psychoactive substance use disorder.

“Prior twin studies of illicit drug use and abuse have all been conducted in Anglophonic countries, specifically the United States and Australia, with high levels of such use. This is the first study of a non-English speaking country with much lower rates of drug use – yet results are similar – drug use and abuse or dependence is quite heritable,” said lead author Kenneth S. Kendler, M.D., a professor of psychiatry and human genetics in VCU’s School of Medicine.

The team examined the role of genetic and environmental factors in the progression of psychoactive substance use and abuse.

Approximately 1,400 young adult twin pairs from the Norwegian Institute of Public Health Twin Panel were interviewed and assessed for their lifetime use of illicit drugs, including marijuana, stimulants, opiates, cocaine and psychedelics. Researchers defined the significant lifetime use of illicit substances as use 10 or more times.

Previous theories have suggested that genetic factors might be of less importance in influencing drug use in societies where drugs were not widely available. According to Kendler, the results of this study are inconsistent with this theory.

“In addition to prior findings, the results of this investigation indicate that genetic factors are likely to be important risk factors for psychoactive drug use and misuse in many parts of the world,” he said.

This work was supported in part by grants from the National Institutes of Health, the Norwegian Research Council, the Norwegian Foundation for Health and Rehabilitation, The Norwegian Council for Mental Health and the European Commission.

Kendler collaborated with Steven H. Aggen, Ph.D., in the department of psychiatry at VCU; and Kristian Tambs, Ph.D., and Ted Reichborn-Kjennerud, M.D., who are affiliated with the Division of Mental Health and Institute of Psychiatry, Norwegian Institute of Public Health; and University of Oslo Norway.

Hamilton, ON – It was the drug of choice on university campuses, the drug that spawned psychedelic culture as well as countless jail sentences and fines, but LSD actually has respectable roots—roots that a McMaster University researcher is uncovering.

"Far from being fringe medical research, trials of LSD were once a legitimate branch of psychiatric research," explains Erika Dyck, a doctoral researcher in the Department of History at McMaster. "LSD produced a "model psychosis," meaning people who took the drug exhibited symptoms of illnesses such as schizophrenia. Doctors used this as a new method for studying mental illness."

In a recent issue of the Canadian Journal of Psychiatry, Dyck traces the history of LSD—and its eventual withdrawal from medical research. LSD, or d-lysergic acid diethylamide, first appeared in scientific literature in 1943. For nearly a decade, it gave psychiatrists insight into the experi-ences of schizophrenic patients and showed potential as a cure for alcoholism.

In the 1960s, as the media increasingly associated the drug with love-ins, anti-war demonstrations and the counterculture, governments intervened to criminalize LSD, restricting and then terminating medical research into its potential therapeutic effects.

Now, therapeutic uses of psychedelic drugs are resurfacing. Research groups in the United States are currently examining the usefulness of MDMA, or "ecstasy," in treating pain in medical conditions such as Parkinson's disease and cancer.

This makes Dyck optimistic that LSD may become a valid area of research again. "Many illegal drugs are used in medical settings. Scientists who studied LSD made important contributions to psychiatry, and found it helped many people cope with mental illness."

Dyck discovered another interesting fact while researching LSD: The term "psychedelic", it turns out, was a Canadian invention – coined in Weyburn, Sask. in the 1950s.

The paper is available online at www.cpa-apc.org/Publications/Archives/CJP/2005/june/InRevDyck.asp.

McMaster University, named Canada's Research University of the Year by Research InfoSource, has world-renowned faculty, and state-of-the-art research facilities. McMaster's culture of innovation fosters a commitment to discovery and learning in teaching, research and scholarship. Based in Hamilton, the University has a student population of more than 23,000, and an alumni population of more than 115,000 in 128 countries.

 A naturally occurring hallucinogen advocated by some clinicians as a potent anti-addiction drug has been rigorously studied for the first time, confirming its ability to block alcohol craving in rodents, and clarifying how it works in the brain. The new research findings about the drug Ibogaine open the way for development of other drugs to reverse addiction without Ibogaine's side effects, potentially adding to the small arsenal of drugs that effectively combat addiction.

Derived from a West African shrub, Ibogaine has been championed for years by a cadre of clinicians and drug treatment advocates impressed with its ability to reverse withdrawal symptoms and craving for alcohol and various drugs of abuse. It has been used outside of the U.S. to treat addiction by American and other clinicians. But its side effects, including hallucinations, which made it popular in the 1960s drug culture, and evidence of toxicity to certain nerve cells in rodent studies have discouraged careful studies of its clinical potential against drug and alcohol addiction. The FDA has not approved use of Ibogaine in the U.S.

Scientists at UCSF's Ernest Gallo Clinic and Research Center have now shown definitively in experiments with mice and rats that Ibogaine does reduce alcohol consumption, and they have determined that it does so by increasing the level of a brain protein known as glial cell line-derived neurotrophic factor, or GDNF. In a separate study, they demonstrated that GDNF by itself decreases alcohol consumption.

The research is being published in the January 19 issue of The Journal of Neuroscience.

"By identifying the brain protein that Ibogaine regulates to reduce alcohol consumption in rats, we have established a link between GDNF and reversal of addiction — knowledge of a molecular mechanism that should allow development of a new class of drugs to treat addiction without Ibogaine's side effects," said Dorit Ron, PhD, UCSF associate professor of neurology and also principal investigator at the Gallo Center. Ron is co-senior author of the paper with Patricia Janak, PhD, UCSF assistant professor of neurology and also principal investigator at the Gallo Center.

In their research, the scientists first carried out classic behavioral studies showing that Ibogaine reduced alcohol consumption. They induced the rats to consume alcohol in daily drinking sessions and then demonstrated that their drinking declined precipitously when they received Ibogaine. The drug was administered either by injection or directly into the same brain region where GDNF levels were shown to increase.

The research also showed that Ibogaine was quite effective in preventing relapse, or "falling off the wagon" — the vulnerability of recovered alcoholics or addicts to return to uncontrolled drinking or drug use when exposed to the drug of abuse months or even years after breaking the habit.

In this analysis, the researchers provided alcohol to rats until they had become "experienced" daily drinkers. They then withheld alcohol for two weeks, which normally leads to greatly increased drinking when when alcohol is again available. When they administered Ibogaine, they found that the heightened craving and consumption was significantly reduced.

"The discovery that Ibogaine reduced binge drinking after a period of abstinence was an exciting finding for us because this is the type of behavior in alcoholics for which very few effective drugs exist," Janak said.

The scientists confirmed in a cell model that Ibogaine stimulated GDNF activity. Finally, they showed that a known inhibitor of GDNF blocked Ibogaine's ability to decrease alcohol craving in the rats, suggesting a direct link between Ibogaine's desirable actions and GDNF.

"If we can alter the GDNF pathway, we may well have a new treatment against alcohol and drug addiction without the unwanted side effects of Ibogaine," Ron said.

Colleagues in the research and coauthors on the paper are postdoctoral fellows Dao-Yao He, PhD, Nancy N.H. McGough, PhHD; Ajay Ravindranathan, PhD; Jerome Jeanblanc, PhD; Marian Logrip, BA, UCSF neurology graduate student; and Khanhky Phamluong, BA, research associate, all at the Gallo Center.

The research is supported by funds provided by the State of California through UCSF for medical research on alcohol and substance abuse, and by the Department of Defense.

A mouse study reported in this week's Science magazine shows that three drugs, each acting on a different chemical transmitter in the brain, all produce the same schizophrenia-like symptoms by acting on a single "master molecule" in the brain.

The findings, reported by researchers at Rockefeller University with collaboration from three pharmaceutical and biotech companies, provides, for the first time, a cellular model detailing how this crucial protein, known as DARPP-32, interacts with multiple neurotransmitter systems to produce behavior.

The scientists demonstrate that DARPP-32 acts like the thin neck in an hourglass, through which all signals taken into a nerve cell must pass and be processed, producing a wide variety of biochemical reactions. In this case, three different drugs of abuse, LSD, PCP ("angel dust") and amphetamine, work on three different neurotransmitters, serotonin, glutamate, and dopamine, respectively. All three drugs, which are classified as psychotomimetics or psychostimulants, are processed within the DARPP-32 hourglass neck through the same pathway, thus producing very similar physiological symptoms.

"For the first time, we can explain through a molecular model why these drugs all produce the same kind of behavioral symptoms," says the study's first author, Per Svenningsson, M.D., Ph.D., a research assistant professor in the Laboratory of Molecular and Cellular Neuroscience, headed by Paul Greengard, Ph.D.

Clinically, the study does not suggest that DARPP-32 is the root cause of schizophrenia, but it does provide new avenues in which to treat the disease, says Greengard, Vincent Astor Professor at Rockefeller and the study's principal investigator.

By experimentally blocking the function of one of the 205 amino acids that make up DARPP-32, the research team was able to abolish the effects of the drugs, all of which have long been known to produce schizophrenia-like behavior in both mice and humans.

"This is remarkable because it shows that a single amino acid on a single protein, by being altered, can abolish the effects of these psychotomimetic drugs on behavior," says Greengard, who shared the 2000 Nobel Prize in Medicine or Physiology for his work on neurotransmitters and DARPP-32. "The research certainly indicates new targets for the development of antipsychotic drugs."

The study also answers a long-standing debate in psychiatry as to which neurotransmitter is primarily responsible for schizophrenia, says Greengard, because researchers have known that drugs like LSD, PCP and amphetamines, which act on different transmitters, create the same psychoses as seen in schizophrenia.

"It turns out everyone was right, because each of these drugs work on a common pathway regulated by DARPP-32," says Greengard.

Previous research by Svenningsson and Greengard also has demonstrated that DARPP-32 regulates the actions of medications such as Prozac, to treat depression, as well as drugs of abuse such as cocaine, opiates and nicotine.

"We have begun to believe that DARPP-32 is really a master molecule that integrates information coming in from all parts of the brain and is involved in mediating and regulating the actions of many, many neurotransmitters," says Greengard.

The investigators knew that, like many such proteins, DARPP-32 can be activated by the addition of a phosphate molecule (a process called "phosphorylation") or by removal of a phosphate molecule ("dephosphorylation") on specific amino acid sites.

In the findings reported in Science, the Rockefeller team found that DARPP-32 was phosphorylated or dephosphorylated at three sites by the studied psychotomimetics, in a pattern that worked together to inhibit an enzyme downstream of DARPP-32 called protein phosphatase-1 (PP-1). PP-1 helps regulate its own series of biochemical reactions that lead to physiological responses.

In order to understand the precise functional importance of these three phosphorylation sites, the scientists created a series of "knockin" mice, in which each of these sites on the DARPP-32 protein were mutated. The behavioral responsively to LSD, PCP and amphetamine were thereafter compared between these mutant mice and normal mice. It turned out that single mutations in the amino acid sequence of DARPP-32 virtually abolished the behavioral actions of the psychotomimetics.

Schizophrenia-like symptoms such as repetitive movements and sensory perception defects induced by the psychotomimetics were strongly attenuated in two of the three different mutant mouse lines, implicating a critical involvement of two distinct, but interacting, phosphorylation sites of DARPP-32 in the actions of LSD, PCP and amphetamine, says Svenningsson.

Ongoing research is aimed at further understanding how DARPP-32 can process a wide variety of neurotransmitters that affect behavior, he says. "This master molecule seems to be involved in many behaviors, including those related to mood and the way we perceive the world," says Svenningsson.

Co-authors of the study, funded by the National Institutes of Health, include researchers from Rockefeller University (Robert Carruthers and Ilan Rachleff), Eli Lilly and Company (Eleni Tzavara, David McKinzie, George Nomikos), Lexicon Genetics, Inc. (Sigrid Wattler and Michael Nehls) and Intra-Cellular Therapies (Allen Fienberg). Fienberg also is affiliated with Rockefeller University.