Category: Psychedelic Drugs

 Scripps Research Institute scientists have shown for the first time that the neurotransmitter serotonin uses a specialized signaling pathway to mediate biological functions that are distinct from the signaling pathways used by hallucinogenic substances. The new findings could have a profound effect on the development of new therapies for a number of disorders, including schizophrenia and depression.

The study was published in the October 6, 2010 issue of the Journal of Neuroscience.

Serotonin has tremendous influence over several brain functions, including the control of perception, cognition, sleep, appetite, pain, and mood and mediates these effects through interactions with receptors located throughout the central and peripheral nervous systems.

"Our study shows that while both serotonin and hallucinogens act at the serotonin 2A receptor, serotonin utilizes a very specific pathway and its actions are independent of those produced by hallucinogens," said Laura Bohn, an associate professor on the Florida campus of The Scripps Research Institute. "Future drug discovery efforts to identify lead compounds for treatment of depression may consider focusing upon those that only engage that pathway. This work may also lend insight into the mechanisms that underlie the hallucinations that occur in schizophrenia."

This may be particularly important, Bohn said, for the treatment of depression because traditional therapies, which focus on elevating serotonin levels, can sometimes produce serious side effects such as a serotonin syndrome. This syndrome is often accompanied by hallucinations, and is especially serious when antidepressant treatments such as selective serotonin reuptake inhibitors (SSRIs) are mixed with monoamine oxidase inhibitors (MAOIs).

The scientists' current study supports a long-standing hypothesis that hallucinations may arise from the metabolites formed from elevated serotonin levels. Since there is a difference in the way the two neurotransmitters signal, this may represent a means to preserve the effects of serotonin while preventing the adverse side effects caused by the metabolites.

Serotonin Versus Hallucinogens

The study, coauthored by Cullen Schmid, a graduate student in the lab, showed that serotonin signals through the serotonin 2A receptor by recruiting a regulatory protein called β-arrestin2, and that the actions of serotonin at the receptor are far different than those produced by hallucinogenic N-methyltryptamines, a class of naturally occurring substances found in several plants and in minute amounts in the human body and which includes the abused drug, DMT. The study found that the N-methyltryptamines activate the serotonin 2A receptor independently of β-arrestin2.

Both serotonin and the N-methyltryptamines produce what is known as a head twitch response in animal models, which indicates that the serotonin 2A receptor has been activated. Any interruption in the exclusive serotonin pathway prevents that behavioral response to serotonin, but has no effect on N-methyltryptamine-induced head twitches, indicating a distinct divergence in the signaling pathways utilized by these two neurotransmitters.

"Despite the fact that they activate the same receptor, serotonin leads to the assembly of a number of proteins associated with the receptor that the metabolites of serotonin do not produce," Bohn said. "But whether the lack of this complex formation is why compounds like DMT lead to hallucinations is not clear."

Bohn continues to investigate these and other questions.

In addition to Bohn, the study, "Serotonin, But Not N-Methyltryptamines, Activates the Serotonin 2A Receptor via an β-Arrestin2/Src/Akt Signaling Complex in Vivo," was authored by Cullen L. Schmid of The Ohio State University Neuroscience Graduate Studies Program and Scripps Research.

The work was supported by the National Institute on Drug Abuse of the National Institutes of Health.

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Journal Reference:

1. C. L. Schmid, L. M. Bohn. Serotonin, But Not N-Methyltryptamines, Activates the Serotonin 2A Receptor Via a β-Arrestin2/Src/Akt Signaling Complex In Vivo. Journal of Neuroscience, 2010; 30 (40): 13513 DOI: 10.1523/JNEUROSCI.1665-10.2010

Health and social services are facing a new challenge, as many illicit drug users get older and face chronic health problems and a reduced quality of life. That is one of the key findings of research published in the September issue of the Journal of Advanced Nursing.

UK researchers interviewed eleven people aged 49 to 61 in contact with voluntary sector drug treatment services.

"This exploratory study, together with our wider research, suggest that older people who continue to use problematic or illegal drugs are emerging as an important, but relatively under-researched, international population" says lead author Brenda Roe, Professor of Health Research at Edge Hill University, UK.

"They are a vulnerable group, as their continued drug use, addiction and life experiences result in impaired health, chronic conditions, particular health needs and poorer quality of life. Despite this, services for older drug addicts are not widely available or accessed in the UK."

Figures from the USA suggest that the number of people over 50 seeking help for drug or alcohol problems will have risen from 1.7 million in 2000 to 4.4 million by 2020. And the European Monitoring Centre for Drugs and Drug Addiction estimates that the number of people aged 65 and over requiring treatment in Europe will double over the same period.

The nine men and two women who took part in the study had an average age of 57. All were currently single and their homes ranged from a caravan, hostel or care home to social housing.

Key findings from the study — by the Evidence-based Practice Research Centre at Edge Hill University and the Centre for Public Health at Liverpool John Moores University — included:

• Most started taking drugs as adolescents or young adults, often citing recreational use, experimenting or being part of the hippy era. Child abuse and the death of a parent were also mentioned.
• Some started taking drugs late in life due to stressful life events like divorce or death. Meeting a drug using partner was another trigger. One man started taking drugs later in life to shock his drug taking partner into stopping and ended up developing a drug habit himself.
• First drug use varied from magic mushrooms, LSD, amphetamines and cannabis to heroin and methadone. Alcohol and smoking often featured alongside drug use.
• Some increased their drug use over time, while others had periods when they tried to reduce or even abstain from drugs. All but two of the participants were taking methadone, either as maintenance or as part of a reduction strategy in order to give up drugs.
• A number of the participants said they were trying to use drugs responsibly and it was felt that their age and the influence of drug treatment services were factors in this. They also appeared more aware of the need to maintain their personal safety, based on previous experiences.
• Most recognised that their drug use was having detrimental and cumulative effects on their health, as they had developed a range of chronic and life-threatening conditions that required hospitalisation and ongoing treatment.
• Physical health conditions included: circulatory problems such as deep vein thrombosis, injection site ulcers, stroke, respiratory problems, pneumonia, diabetes, hepatitis and liver cirrhosis. Malnutrition, weight loss and obesity also featured, as did accidental injuries due to falls and drug overdoses.
• Common mental health problems included memory loss, paranoia and changed mood states, with anxiety or anger also featuring.
• All wished they hadn't started taking drugs and would advise young people not to. A few were keen to give up, but others felt it was too hard. One man described his drug use as "disgusting and squalid" while another said that the older he got the worse his drug use got and that it was a "crazy" situation.
• All were single or divorced and drug use was a common factor in relationship breakdowns. Most lived alone, with three relying on carers who were also drug users. Pets were often important for some, providing companionship as well as a sense of responsibility and structure to their day.
• Drug use was often associated with chaotic lifestyles and relationships and some reported periods of imprisonment.
• Participants were positive about the support they received from voluntary drug services, but had mixed experiences of primary and hospital care. Some felt stigmatised by healthcare professionals, while others received compassion and acknowledgement of their drug use.

"Our population is aging and the people who started using drugs in the sixties are now reaching retirement age," says Professor Roe.

"It is clear that further research is needed to enable health and social care professionals to develop appropriate services for this increasingly vulnerable group. We also feel that older drug users could play a key role in educating younger people about the dangers of drug use."

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Journal Reference:

1. Brenda Roe, Caryl Beynon, Lucy Pickering, Paul Duffy. Experiences of drug use and ageing: health, quality of life, relationship and service implications. Journal of Advanced Nursing, 2010; DOI: 10.1111/j.1365-2648.2010.05378.x

 In the first human study of its kind to be published in more than 35 years, researchers found psilocybin, an hallucinogen which occurs naturally in "magic mushrooms," can safely improve the moods of patients with advanced-stage cancer and anxiety, according to an article published online September 6 in the Archives of General Psychiatry.

Patients enrolled in the study at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (LA BioMed) demonstrated improvement of mood and reduction of anxiety up to six months after undergoing treatment, with significance reached at the six-month point on the "Beck Depression Inventory" and at one and three months on the "State-Trait Anxiety Inventory." A third screening tool, the "Profile of Mood States," identified mood improvement after treatment that approached but did not reach significance.

"We are working with a patient population that often does not respond well to conventional treatments," said Charles S. Grob, MD, an LA BioMed principal investigator who led the research team. "Following their treatments with psilocybin, the patients and their families reported benefit from the use of this hallucinogen in reducing their anxiety. This study shows psilocybin can be administered safely, and that further investigation of hallucinogens should be pursued to determine their potential benefits."

Researchers conducted extensive investigations of psychedelic drugs in the 1950s and 1960s and found promising improvements in mood and anxiety, as well as a diminished need for narcotic pain medication among advanced-stage cancer patients. The research was abandoned in the early 1970s in the wake of widespread recreational usage that led to stiff federal laws regulating hallucinogens.

"Political and cultural pressures forced an end to these studies in the 1970s," said Dr. Grob. "We were able to revive this research under strict federal supervision and demonstrate that this is a field of study with great promise for alleviating anxiety and other psychiatric symptoms."

The LA BioMed study is the first research publication in several decades to examine the hallucinogen treatment model with advanced-cancer anxiety. Twelve volunteers, ages 36 to 58, with advanced-stage cancer and anxiety were given a moderate dose of 0.2 mg/kg of psilocybin and, on a separate occasion, a placebo. Neither the volunteers nor the researchers monitoring them knew whether they'd been given a placebo or psilocybin.

The two experimental sessions took place several weeks apart in a hospital clinical research unit at Harbor-UCLA Medical Center, where Dr. Grob is a professor of psychiatry. The research volunteers were monitored for the six hours following their dose. The volunteers were encouraged to lie in bed, wear eye shades and listen to music during the first few hours after ingesting the medication or the placebo. They were interviewed after the six-hour session and over the next six months to assess the outcome of the treatment.

This study was funded by the Heffter Research Institute, the Betsy Gordon Foundation and the Nathan Cummings Foundation (with the support and encouragement of James R. Cummings). Infrastructural support for this study was provided via grant M01-RR00425 from the National Institutes of Health for the General Clinical Research Unit at LA BioMed.

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Journal Reference:

1. Charles S. Grob, MD; Alicia L. Danforth, MA; Gurpreet S. Chopra, MD; Marycie Hagerty, RN, BSN, MA; Charles R. McKay, MD; Adam L. Halberstadt, PhD; George R. Greer, MD. Pilot Study of Psilocybin Treatment for Anxiety in Patients With Advanced-Stage Cancer. Arch Gen Psychiatry, Online September 6, 2010 DOI: 10.1001/archgenpsychiatry.2010.116

— A paper to be published this month by University of Hertfordshire researchers about the availability of 'Spice' drugs online will raise new concerns about its mood altering effects.

'Spice' is a brand name for a herbal mix widely sold as an 'incense' or legal substitute for cannabis. It comes under a variety of names according to its 'flavours', such as 'Spice Diamond', 'Spice Gold', 'Spice Silver', 2Spicy', 'Spice of Life', etc, which according to users, are meant to produce subtly different effects.

The research paper, entitled "Psychoactive drug or mystical incense? Overview of the online available information on Spice products," of which Professor Fabrizio Schifano and Dr Ornella Corazza at the University's School of Pharmacy are lead authors, will be published in the International Journal of Culture and Mental Health this month.

The study carried out an eight-language qualitative assessment of information available on Spice products in a sample of about 200 web sites.

It reported that while Spice products appealed to online customers due to its cannabis -like effects, legal status, lack of detection in biological samples and ease of online access, typical online product descriptions of the drug did not mention its strong synthetic properties that seem to account for the psychoactive/hallucinogenic effects of Spice and similar herbal blends.

"Spice is sold as a legal substitute for cannabis and our study has identified a number of websites offering both information and purchase opportunities," said Professor Fabrizio. "Our concern is that very little is known about both human metabolism and toxicity of these compounds. We plan to use this study, the first multilingual review of Spice, to raise awareness among health professionals that the World Wide Web is a new resource for the drug and therefore more information is needed about its effects."

This study is part of a wider web mapping programme, the Psychonaut Web Mapping project, involving a European group of researchers based in seven European countries (UK, Finland, Norway, Belgium, Germany, Italy and Spain).

Two University of Hertfordshire academics are releasing new evidence about the dangers of ‘Spice’ drugs today at the first International Psychonaut Web Mapping Conference in Ancona, Italy.

Professor Fabrizio Schifano and Dr Ornella Corazza from the University’s School of Pharmacy will describe the pharmacological aspects of novel drugs of abuse and provide an overview of ‘Spice’ drugs at the conference which takes place as a result of a two-year European Commission-funded study to implement a regular monitoring of the World Wide Web in respect to novel recreational drugs.

‘Spice’ is a brand name for a herbal mix widely sold as an ‘incense’ or legal substitute for cannabis. It comes under a variety of names according to its ‘flavours’, such as ‘Spice Diamond’, ‘Spice Gold’, ‘Spice Silver’, 2Spicy’, ‘Spice of Life’, etc, which according to users, are meant to produce subtly different effects.

According to initial results of the Psychonaut Web Mapping study on Spice carried out by Dr Corazza, the drug is accessible to children and young people, as there are no or very limited controls on any of the websites selling the drug.

This coupled with the fact that most of the new psychoactive compounds, including Spice, are unknown to health professionals, and very little information is available on the international medical database, monitoring of information about it on the Web is crucial.

“These results are alarming, particularly as Spice drugs are among the “three legal highs” that the Home Secretary, Alan Johnson has said will be banned by the end of the year,” said Dr Corazza. “It seems that legal restrictions and bans cannot be the only answer to the rapid diffusion of the new psychoactive compounds, which are much wider and more rooted in society.”

Professor Schifano, who has carried out extensive research into deaths from drug abuse and the link between the availability of these drugs on the Web, will also reveal new evidence about the potential of misuse of some well-known prescribing drugs.

A clinical report from Dresden supports the impression that "Spice Gold" is strongly addictive. In the current edition of Deutsches Ärzteblatt International, Ulrich S. Zimmermann, from Dresden Technical University, and his colleagues describe a young man who developed physical withdrawal symptoms after regular consumption of this designer drug, accompanied by a dependence syndrome.

Since 22 January 2009, "Spice Gold" has been subject to the German Narcotics Law. This means that production, free trade and possession are forbidden — but initially for only a year. There will be a permanent regulation at the end of the year. More information about "Spice Gold" is currently being collected. The authors' case report is a scientific contribution to this discussion.

When he came to the hospital, the patient had been consuming "Spice Gold" daily for eight months. Because of the loss of activity, he had rapidly increased the daily dose from 1 g to 3 g. He felt continuous craving for the drug and this caused him to carry on consuming it, in spite of the cognitive impairment it caused him. This led him to neglect his duties at his workplace and he was now threatened with unemployment.

He had already been forced to be abstinent for a time, because of a bottleneck in supplies, and this had triggered typical withdrawal symptoms, such as internal unrest, tremor, palpitations, headache, nausea, vomiting, depression and desperation. These symptoms had abruptly disappeared when he started consuming spice once again. He suffered similar symptoms during drug withdrawal in hospital.

The authors interpret the symptoms as indicating a typical withdrawal disease, very probably due to the admixture of synthetic cannabinomimetics.

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Journal Reference:

1. Zimmermann, U S; Winkelmann, P R; Pilhatsch, M; Nees, J A; Spanagel, R; Schulz, K. Withdrawal Phenomena and Dependence Syndrome After the Consumption of 'Spice Gold'. Deutsches Ärzteblatt International, 2009; 106(27) DOI: 10.3238/arztebl.2009.0464

 A hallucinogenic compound found in a plant indigenous to South America and used in shamanic rituals regulates a mysterious protein that is abundant throughout the body, University of Wisconsin-Madison researchers have discovered.

The finding, reported in the Feb. 13 issue of Science, may ultimately have implications for treating drug abuse and/or depression. Many more experiments will be needed, the researchers say.

Scientists have been searching for years for naturally occurring compounds that trigger activity in the protein, the sigma-1 receptor. In addition, a unique receptor for the hallucinogen, called dimethyltryptamine (DMT), has never been identified.

The UW-Madison researchers made the unusual pairing by doing their initial work the "old-fashioned," yet still effective, way. They diagrammed the chemical structure of several drugs that bind to the sigma-1 receptor, reduced them to their simplest forms and then searched for possible natural molecules with the same features. Biochemical, physiological and behavioral experiments proved that DMT does, in fact, activate the sigma-1 receptor.

"We have no idea at present if or how the sigma-1 receptor may be connected to hallucinogenic activity," says senior author Arnold Ruoho, chair of pharmacology at the UW-Madison School of Medicine and Public Health. "But we believe that the National Institute on Drug Abuse (NIDA) may be interested in biological mechanisms underlying psychoactive and addictive drug action."

In addition to being a component of psychoactive snuffs and sacramental teas used in native religious practices in Latin America, DMT is known to be present in some mammalian tissues, and it has also been identified in mammalian blood and spinal fluid. Elevated levels of DMT and a related molecule have been found in the urine of schizophrenics.

Ruoho speculates that the hallucinogen's involvement may mean that the sigma-1 receptor is connected in some fashion to psychoactive behavior. When his team injected DMT into mice known to have the receptor, the animals became hyperactive; mice in which the receptor had been genetically removed did not.

"Hyperactive behavior is often associated with drug use or psychiatric problems," says Ruoho. "It's possible that new, highly selective drugs could be developed to inhibit the receptor and prevent this behavior."

The study revealed an additional neurologic link by confirming that the sigma-1 receptor and some compounds that bind to it inhibit ion channels, which are important for nerve activity. Work by many researchers — including some from UW-Madison — initially showed this relationship in earlier studies.

Some studies have also linked the receptor to the action of antidepressant drugs, and National Institutes of Health (NIH) scientists recently found that it appears to serve as a "chaperon," helping proteins to fold properly.

The Wisconsin researchers found that DMT is derived from the naturally occurring amino acid tryptophan and is structurally related to the neurotransmitter serotonin. This finding, Ruoho says, illustrates the mantra often used in the biological processing of natural molecules: Nothing goes to waste.

"Our findings support the idea that biochemical alterations of molecules such as tryptophan can produce simple compounds such as DMT that may target other regulatory pathways served by sigma-1 receptors," he says.

DMT may also reflect the presence of an even larger family of natural compounds that arise from other structurally related amino acids that may further regulate the receptor, Ruoho adds.

"It may well be that these different, naturally derived chemical forms regulate the sigma-1 receptor in tissue and organ-specific ways," he says.

— In a follow-up to research showing that psilocybin, a substance contained in "sacred mushrooms," produces substantial spiritual effects, a Johns Hopkins team reports that those beneficial effects appear to last more than a year.

Writing in the Journal of Psychopharmacology, the Johns Hopkins researchers note that most of the 36 volunteer subjects given psilocybin, under controlled conditions in a Hopkins study published in 2006, continued to say 14 months later that the experience increased their sense of well-being or life satisfaction.

"Most of the volunteers looked back on their experience up to 14 months later and rated it as the most, or one of the five most, personally meaningful and spiritually significant of their lives," says lead investigator Roland Griffiths, Ph.D., a professor in the Johns Hopkins departments of Psychiatry and Behavioral Sciences and Neuroscience.

In a related paper, also published in the Journal of Psychopharmacology, researchers offer recommendations for conducting this type of research.

The guidelines caution against giving hallucinogens to people at risk for psychosis or certain other serious mental disorders. Detailed guidance is also provided for preparing participants and providing psychological support during and after the hallucinogen experience. These "best practices" contribute both to safety and to the standardization called for in human research.

"With appropriately screened and prepared individuals, under supportive conditions and with adequate supervision, hallucinogens can be given with a level of safety that compares favorably with many human research and medical procedures," says that paper's lead author, Mathew W. Johnson, Ph.D., a psychopharmacologist and instructor in the Johns Hopkins Department of Psychiatry and Behavioral Sciences.

The two reports follow a 2006 study published in another journal, Psychopharmacology, in which 60 percent of a group of 36 healthy, well-educated volunteers with active spiritual lives reported having a "full mystical experience" after taking psilocybin.

Psilocybin, a plant alkaloid, exerts its influence on some of the same brain receptors that respond to the neurotransmitter serotonin. Mushrooms containing psilocybin have been used in some cultures for hundreds of years or more for religious, divinatory and healing purposes.

Fourteen months later, Griffiths re-administered the questionnaires used in the first study — along with a specially designed set of follow up questions — to all 36 subjects. Results showed that about the same proportion of the volunteers ranked their experience in the study as the single most, or one of the five most, personally meaningful or spiritually significant events of their lives and regarded it as having increased their sense of well-being or life satisfaction.

"This is a truly remarkable finding," Griffiths says. "Rarely in psychological research do we see such persistently positive reports from a single event in the laboratory. This gives credence to the claims that the mystical-type experiences some people have during hallucinogen sessions may help patients suffering from cancer-related anxiety or depression and may serve as a potential treatment for drug dependence. We're eager to move ahead with that research."

Griffiths also notes that, "while some of our subjects reported strong fear or anxiety for a portion of their day-long psilocybin sessions, none reported any lingering harmful effects, and we didn't observe any clinical evidence of harm."

The research team cautions that if hallucinogens are used in less well supervised settings, the possible fear or anxiety responses could lead to harmful behaviors.

These studies were funded by grants from NIDA, the Council on Spiritual Practices, and the Heffter Research Institute.

Additional researchers who contributed to this work include Matthew W. Johnson, Ph.D. and Una D. McCann, M.D. of the Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine; psychologist William A. Richards of the Johns Hopkins Bayview Medical Center; and Robert Jesse of the Council on Spiritual Practices, San Francisco.