Turn On, Tune Out: the Medicinal Use of Hallucinogens By Robbin Zirkle Introduction Growing up during the turn

of the millennium means a number of things for my generation that were not relevant to those before us. Greater access to technology and global markets aside, this is the first time in human history that the Western populace has concerned itself with the connection between an intrinsic concern with the human psychological condition and new pharmaceutical technology. With the increase in diagnoses of psychological maladies, such as depression and bipolar affective disorder, drug companies have developed a battalion of combative drugs to deal with such disorders. As is the case with any technological revolution, there has been a response to these pharmaceuticals that deals with alternative treatments for psychological disorders. In the main, these alternatives generally use harmless herbs and supplements. There is now evidence to demonstrate, however, that hallucinogenic drugs may be used to effectively treat psychological disorders, particularly depression and bipolar affective disorder. This area of alternative medicine is breaking into the realm of scientific study and is inherently interesting, especially for a twenty-year-old college student who lives her life well within the confines of conventionality. The idea of currently-illegal hallucinogen being utilized to treat dangerous psychological problems is a positive one, and challenges everything that public educators taught my generation about drugs. The presence of psychological problems is relevant to human societies due to its effects on citizens, but utilizing drugs that humankind has labeled as harmful for positive aims

2 transforms how we perceive self-care and redefines social attitudes toward hallucinogens. If hallucinogens are deemed to be effective in treating depression and bipolar affective disorder, then humans may be faced with a number of ethical dilemmas dealing with the appropriateness of employing such drugs for treatment of people on a mass-scale. Experiences with hallucinogens are varied and, as the literature demonstrates, are not always negative. Popular Press Popular literature on the topic of using hallucinogens to treat psychological disorders seems to be focused upon educating readers about a subject with which they may or may not be familiar. Two articles published in the New York Times within the last ten years indicate that the time may be right for another stab at researching the potential benefits of hallucinogenic drugs. In contrast to traditional psychological pharmaceuticals which cause serotonin to linger in gaps between brain cells, hallucinogens work as serotonin agonists, which amplify the sensitivity of different brain systems. Generally speaking, these processes produce sights, sounds and feelings that have no basis in reality (1). Despite the stigma of drug use, both articles cite numerous accounts of improved symptoms of psychological disorders, ranging from obsessive-compulsive disorder to anxiety to post-traumatic stress disorder (PTSD). A Johns Hopkins medical school study examined the effects of psilocybin (a psychoactive ingredient found in some mushrooms) on psychological distress, such as depression. The Johns Hopkins study found that participants experienced illuminations and life-changing revelations that greatly improved their lives and relationships, even a year later (2).

3 Another study led by Dr. Roland Griffiths examined the effects of the hallucinogen psilocybin on healthy people with no psychological disorders in comparison to drugs such as Ritalin. This study determined that participants reactions to psilocybin and Ritalin were so similar that monitors could not tell what had been administered. A 14-month follow up with participants revealed that most of the psilocybin subjects once again expressed more satisfaction with their lives and rated the experience as one of the five most meaningful events of their lives (2). Other reports have revealed that patients with terminal illnesses who are given LSD report less pain and fear, while peyote (extracted from cactus) can help alcoholics stay sober. The influence and traditional medicines of Native Americans in particular have been essential to studying peyote, as some tribes utilize this drug for spiritual purpose and nothing else; a study involving Dr. Dennis McKenna found that alcoholics who took hallucinogens in a ritualistic context often stopped drinking and had higher blood levels of serotonin (1). The scientific community has begun to seriously consider the uses of hallucinogens in treating these psychological disorders. In April 2010, the largest conference on psychedelic science in the United States in forty years was held. At this conference, researchers gathered to discuss studies of psilocybin and other psychedelics for treating depression in cancer patients, obsessive-compulsive disorder, end-of-life anxiety, post-traumatic stress disorder and addiction to drugs or alcohol (2). The spirit of this conference provides sharp contrast to attitudes toward hallucinogens in the 1960s, which became taboo when enthusiasts exaggerated their benefits and claimed psychedelic drugs were a cure-all.

4 Despite hesitation from some conservative individuals, this research is happening, though it is currently regulated heavily by the United States government. Scientists must acquire licenses from the Drug Enforcement Agency to use hallucinogens in clinical trials. Because of the varied reactions of different individuals to hallucinogens, researchers and review boards developed guidelines for the environments in which such drugs are administered. Research is largely funded by private organizations, especially nonprofits such as the Heffter Research Institute and the Multidisciplinary Association for Psychedelic Studies (MAPS). Dr. George Greer also stated that, ''If hallucinogens ever find their way into mainstream medicineand I am convinced they willthey will never be handed out like ProzacPeople will need guidance. These are not drugs you administer every day (1). Regardless of all of the red tape surrounding hallucinogen research, scientists believe that their research is valuable and will one day be useful in the field of medicine. Rick Doblin, the executive director for MAPS, notes that Theres this coming together of science and spirituality.Thanks to changes over the last 40 years in the social acceptance of the hospice movement and yoga and meditation, our culture is much more receptive now, and were showing that these drugs can provide benefits that current treatments cant (2). Indeed, it seems that the time is right for science to examine alternatives previously unplumbed. Professional Reviews Reviews of available literature delve into the discovery of the causes of some psychological disorders involving serotonin as well as project into the future to suggest where humans should to look toward treating mental diseases. Much of the knowledge regarding psychological disorders is dependent upon the identification of serotonin, which is responsible

5 for modifying behavior in the human body. In 1949, Maurice Rapport identified a vasoconstrictive substance that he had isolated with his colleagues as indolealkylamine 5-HT. In another independent study, Vittorio Erspamer identified enteramine in 1946, another substance determined to be 5-HT. In 1954, Gaddum and Hameed examined the effects of 5-HT on a number of tissues and observed that it caused contractions of the uterus, duodenum and colon of rats, the uterus, duodenum and jejunum of rabbits, and the uterus, duodenum, jejunum and ileum of guinea pigs, and also caused vasoconstriction of the perfused rabbit ear (4, p.1584). The technique used, bioassay, is a sensitive process that enables scientists to identify amine in tissue extracts. In 1953, at the National Heart Institute, it was proposed that 5-HT was formed from tryptophan, by hydroxylation followed by decarboxylation; after this demonstration, scientists worked furiously to fully characterize the enzymes involved in this process, including tryptophan hydroxylase, 5-HTP decarboxylase, monoamine oxidase (MAO), and aldehyde dehydrogenase and aldehyde reductase (4). Later work demonstrated that an enzyme named tryptophan hydroxylase is responsible for controlling the formation of 5-HT in the brain, and influences the rate of 5-HT synthesis. Studying the role of free tryptophan in human blood and its competition against amino acids, insulin and carbohydrates opened the door for discovering its influence on 5-HT synthesis. Grahame-Smith proposed in 1971 that 5-HT function was controlled in part by MAO, concluding that measuring cerebral 5-HT concentration was not an adequate assessment of functionality, which he later discovered could lead to behavioral changes.

6 All of these discoveries worked toward the eventual examination of the relationship between 5-HT, LSD, and the human mental state. Gaddum eventually discovered that LSD had an antagonistic action on the effect of 5-HT in both the rat uterus bioassay system and in the rabbit ear preparation (4). At this point (circa 1979), scientists knew that LSD produced psychedelic effects, but work from both Stoll and Gaddum concluded that these effects could be due to action on 5-HT. Gaddums clinical study with Vogt involved animal and human testing (note: self-testing) in addition to extensive observations in the United Kingdom. In 1964, Feldberg demonstrated that 5-HT (4) had the potential to raise body temperature. These studies of 5-HT took place primarily because of the presence of psychiatric disorders in human populations. After it was proposed that 5-HT could be linked to mood, many scientists were concerned with therapeutic drugs to alleviate the symptoms of some psychological disorders. There is an abundance of published literature regarding bipolar affective disorder (BAD). Although, as mentioned, some scientists have considered the effectiveness of LSD in influencing 5-HT, the cannabinoids tetrahydrocannabinol (THC) and cannabidiol (CBD) have been considered in treating BAD. Through a survey of literature, it becomes clear that BAD is poorly controlled by current prescribed drugs, with side effects ranging from limited effectiveness to causing reproductive issues to rapid mood cycling. Anecdotal accounts of cannabis use combined with pharmacology hint that THC and CBD may have the ability to stabilize moods. Additionally, there is a strong correlation between individuals affected by BAD and lifelong substance abuse, which in some cases has been reported to alleviate depression and mania, despite adverse effects.

7 As of 2005, The literature search revealed no systematic studies of the therapeutic use of cannabis or cannabinoids in BAD, although there are several anecdotal reports (3, p.293). A 1996 study demonstrated that marijuana had an antidepressant effect and individuals with BAD found it more effective than their standard antidepressant drugs. Ashton et al. (2005) concluded that in anecdotal reports: cannabis was not taken for the high sought by recreational users and it is possible that its effects are different when taken in subeuphoric doses for medical reasons.The effects are most probably due to cannabinoids present in cannabis smoke, including 9THC, CBD and possibly others, which have been less studied. Patients accounts and the advances in the understanding of cannabinoids physiology suggest that they may have a therapeutic potential in BAD. This statement is significant because it reflects an attitude toward cannabis that is not popularized through western media. Furthermore, it introduces the scientific basis for the therapeutic properties of cannabis. The major psychoactive agent in cannabis is THC, an agonist of cannabinoid receptors present in the brain, spinal cord and peripheral nerves (3). Activation of these receptors inhibits adenylate cyclase and decreases the production of cAMP. The result is inhibition of neuronal depolarization, decreased action potential generation and hence reduced impulse propagation (3, p.297). Patients, especially those with Multiple Sclerosis, using THC pharmaceutically have noted mood improvement and increased well-being, as well as improved symptoms. In contrast to THC, CBD binds minimally to these receptors and is generally nonpsychoactive. Bisogno also demonstrated CBDs ability to block the reuptake of anandamide.

8 CBD has been reported to function as an anticonvulsant effective even with patients with uncontrolled secondary generalized epilepsy. The absorption of THC and CBD when taken orally is slow and unpredictable, with peak effects not occurring for two to six hours. Medicinal research has developed other modes of administration, including sublingual spray. Additionally, THC and CBD are slowly released from fatty tissues over the course of five to seven days. It is entirely feasible to administer cannabis for use pharmaceutically, especially considering its antidepressant effects and anticonvulsant actions. These assertions except chronic recreational use of cannabis, which often is accompanied by tolerance and dependence thereof, but overall, it is believed that cannabis can effectively treat BAD.

Primary Literature Salvinorin A: A potent naturally occurring nonnitrogenous opioid selective agonist 1. The psychoactive plant salvia divinorum has a pharmacological profile that makes it a unique agonist. 2. If the psychoactive plant salvia divinorum does indeed have a pharmacological profile that makes it a unique agonist, it may be a novel psychotherapeutic compound that can be used to treat diseases manifested by perceptual distortions (6, p.11934) such as schizophrenia, dementia and bipolar disorders by modulating human perception. 3. Researchers screened Salvinorin A using a panel of mostly cloned human receptor transporters. They then screened the same molecular targets with prototypic LSD at the

9 same concentration, 10 M. They did this by first using radio ligand binding assays and different concentrations of test compounds spanning a 10,000-fold dose range. Functional assays at 5-HT receptors were performed using a KOR ( opioid)-cell line. Cells were split and incubated overnight in a serum-free medium, which was replaced the next day with a manmade medium containing isobutylmethylxanthine. After fifteen minutes of incubation, the cAMP content was determined. Tests were performed with brain receptors and cloned receptors. 4. Results indicated that Salvinorin A inhibited only [3H]-bremazocine-labled KORs and did not significantly inhibit binding to cloned human receptors or any of the 48 other molecular targets screened (6, p.11936). Scientists determined that Salvinorin A was a potent agonist in a guinea pigit is the first naturally occurring opioid, whereas LSD inhibits most biogenic amine receptors. Scientists also observed that Salvinorin A had no detectable affinity for the 5-HT2A serotonin receptor and did not activate [said receptors] (6, p.11936). Furthermore, docking of salvinorin into hydrogen bonds indicates that it is compatible with different binding sites of receptor models in different modes. Furthermore, Salvinorin A was determined to be a potent KOR agonist. 5. The data provided indicates that Salvinorin A is a KOR agonist but does not necessarily affect serotonin uptake. Furthermore, the evidence indicates that activates KORs and may potentially influence perception disorders such as those mentioned at the beginning because the KOR is a target for psychotomimetic agents. As for whether or not Salvinorin A is in fact the first nonalkaloid opioid subtype-selective drug (6,

10 p.11934), it is a matter of history; it clearly falls into this category, but it is difficult to say whether or not it is unique. Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later 1. Individuals who participated in a previous double-blind study regarding the psychological effects of psilocybin have long-term meaningful after-effects. 2. If this hypothesis is correct, then it is reasonable to say that traditional hallucinogens such as psilocybin have the ability to positively influence individuals lives, and these influences are long-term. Additionally, if this hypothesis is correct, it could call into question whether it is advisable to re-initiate therapeutic trials with classical hallucinogens. 3. The thirty-six participants for this study were recruited using flyers; all were medically and psychiatrically healthy and were unexposed to hallucinogens. Researchers collected demographic information about participants such as age, education, employment and involvement in spiritual activities. The study compared the effects of psilocybin and methylphenidate hydrochloride that had been administered orally in either two or three eight-hour drug sessions spaced two months apart. Researchers used the NEO Personality Inventory, Positive and Negative Affect ScaleExpanded Form, Quality of Life Inventory raw score, Mysticism Scale, Spiritual Transcendence Scale, Faith Maturity Scale12 item version, and the Functional Assessment of Chronic Illness TherapyNonIllnessSpiritual Well-Being Scale to measure personality, affect, quality of life and spirituality at the time of screening as well as two months after each session and at the

11 14-month follow-up. After administering the drug to the participant during sessions, monitors rated participant behavior and mood using a 5-point scale throughout the remaining session. After the drug subsided, participants completed two questionnaires assessing subjective drug effects (5, p.623). Two months after the session, participants completed the Persisting Effects questionnaire which measures changes in attitude and behavior, and also answered three questions regarding how meaningful their session was. At the 14-month follow-up, participants were asked to complete Retrospective Questionnaires and completed an open-ended clinical interview. For ease of analysis, measures of personality, affect, quality of life and spirituality were converted to T-scores, with anything below 45 considered low and above 55 considered to be high. Researchers compared data on the Persisting Effects Questionnaire from sessions, 2-month follow-ups and 14-month follow-ups. Pearsons correlations were calculated to compare the total scores on the Mysticism Scale, Spiritual Transcendence Scale, Faith Maturity Scale, and mean overall score on the Measure of Actualization Potential Questionnaire. Pearsons correlations were also calculated between volunteers ratings of personal meaning and spiritual significance at the 14-month follow-up and data obtained on session days. Intensity of drug effects was also analyzed. 4. Analysis of personality, affect, quality of life and spirituality indicated that volunteers were generally well-adjusted, outgoing, open and high in spirituality (5, p.624), with low neuroticism and high actualization potential and spiritualism. Psilocybin participants indicated significant experience elevations in comparison to individuals who

12 received methylphenidate. Two months later, psilocybin session participants gave higher ratings of their positive attitudes, mood, social effects and behavior, and the fourteen-month follow-up followed suit. Scientists also discovered that intensity contributed non-significant effects and did not influence spiritual significance in particular. Furthermore, at the 14-month follow-up there were no reports of persisting perceptual phenomena sometimes attribute to hallucinogen use or of recreational abuse of hallucinogens. Overall, all participants appeared to continue to be well-adjusted, high-functioning and productive members of society (5, p.629). 5. Griffiths concludes that while there was a strong correlation between different human traits such as openness and spirituality, there is no strong correlation between these traits and the sustained effects of psilocybin. He goes on to conclude that when psilocybin was administered under supportive conditions, even a year later participants found their experiences to be satisfying and meaningful. This hints that psilocybin might be used in a therapeutic setting. Though these results clearly indicate a positive experience in participants, it is unclear how this might connect to treating psychological distress therapeutically. Griffiths suggests rigorous scientific investigations (5, p.631) that I believe might corroborate such a conclusion. Analysis After surveying the relevant literature from the popular press, professional reviews and primary studies, I learned that hallucinogens have huge pharmacological potential, particularly in a world that seems to be increasingly preoccupied with self-diagnosis. On the level of popular press, it was clear that writers were most interested in changing attitudes toward

13 hallucinogens in the public. More than one time, I read a cautionary line about contemporary studies rejecting the free-spirited drug use of the 1960s. I believe that this is necessary, especially in regard to older people and younger people rather than those who are middleaged. Older people lived in a world where people were wary of drugs, especially hallucinogens, and young people, particularly my generation, have been pelted with Just Say No campaigns since childhood. These attitudes contrast with those of middle-aged people who are more accustomed to drug use and who are, quite frankly, less uptight about it. Each of the popular press articles seemed to survey a separate study. Scientists Test Hallucinogens for Mental Ills, written in 2001, discusses potential studies and those conducted overseas and identifies the red tape set up by the Federal Drug Administration, while Hallucinogens Have Doctors Tuning In Again looks at a single Johns Hopkins study. After glancing over the specifics of these studies, it is clear to me that Scientists Test Hallucinogens for Mental Ills is set upon a more solid scientific foundation with more support than Hallucinogens Have Doctors Tuning In Again, which uses one primary study. My one qualm with the popular press was my feeling that Hallucinogens Have Doctors Tuning In Again misrepresented the Johns Hopkins study led by Griffiths. The story begins with anecdotal evidence provided by Clark Martin and claims that his depression miraculously lifted after being exposed to psilocybin. This study was used in this report and I discovered that all participants in that study were given a clean bill of health; I feel that the New York Times misrepresented Martins experiences in an attempt to win over people who might be wary of the potential of hallucinogens such as psilocybin.

14 The professional reviews provided a survey of discoveries over the last fifty years regarding psychological disorders, specifically those involving serotonin, and the therapeutic effects of cannabis. I learned a great deal about the history in these fields as well as the different ways in which drugs can influence serotonin receptors, and how these relationships effect human behavior. These surveys didnt seem to misinform the reader, at least not to my knowledge. The information embedded in Cannabinoids in bipolar affective disorder: a review and discussion of their therapeutic potential is integrated seamlessly, but a review of its scientific sources indicate that it rests upon a sound base. While Gaddum and LSD: the birth and growth of experimental and clinical neuropharmacology research on 5-HT in the UK was only a survey of contributions that scientists in the United Kingdom made to neuropharmacology, I found that it was helpful in providing general knowledge, even if it was rather narrow, and was clearly founded upon a large number of scientific sources. On the level of primary literature, I learned a great deal about specialized science and different methods of conducting experiments. The Salvinium A study provided me with an indepth look at how scientists study activity on different receptors and how different drugs affect behaviors. In contrast, the psilocybin study was conducted almost entirely with observations and questionnaires, though drugs were administered to participants. I conclude that both types of science are valuable to expanding human knowledge, though I can definitely recognize that I understand qualitative studies such as Griffiths psilocybin study more than the Salvinium A study. My issues with the literature that I read was the lack of accessibility in primary literature and sometimes in professional reviews, as well as the oversimplification of complicated

15 concepts and studies in the popular press. It is clear that science is presented to professionals in a manner that is incomprehensible for nonscientists, or people with general rather than specialized knowledge. As I pointed out in New York Times article, Hallucinogens Have Doctors Tuning In Again, research was misrepresented and over-sentimentalized for the sake of winning over the public. I also believe that in both of these popular press articles, the red tape set up by the United States government was overlooked. I believe that describing the legal limitations of these studies might have won over conservative readers rather than inaccurate accounts of science. I learned a great deal about what it means to be human while reading these publications because they illustrate how humanity changes over time. It is important to recognize that hallucinogen research is not relevant to western society simply because of research for the sake of research. The revolution of alternative medicine and therapy for psychological disorders makes finding more effective pharmaceuticals necessary. I would argue that humankind is more preoccupied with its own psychology more now than ever in history, and thus, moderating the effects of disorders is completely relevant to our world. The problem with this core question, as with all of them, is that there is no one right answer. I believe that what is unique about this question is that what it means to be human is always changing under the influence of society; our intellectual movements, our politics, our sense of self is always changing. I believe that at this moment in history, hallucinogen research is relevant because it may change the course of which we are as a species and where we are going.

16 Conclusion Hallucinogen research is important to answering the question of what it means to be human for a number of reasons. First, it demonstrates how little we know about the potential usability of substances that we label as dangerous. Second, it gives humankind the opportunity to transform the purpose of such substances into something positive and therapeutic rather than harmful or recreational. Third, it gives humans another path to explore, ideally for the sake of knowledge, but realistically, to revolutionize the pharmaceutical industryat least in theory. These studies are as relevant as are they interesting: hallucinogen research has the potential to influence progress in the future, and I would like to believe it will do so positively. Who knows what new technologies and data we will extract from this work? At this juncture, the sky is the limit. What, therefore, should we do? Clearly, we should continue such research in controlled and supportive environments that are regulated by large bodies such as the FDA. Furthermore, we should not allow fear that resounds from decades past to prevent progress, but allow it to guide research and revitalize social attitudes.

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Works Cited Popular Press (1) Blakeslee, Sandra. Scientists Test Hallucinogens For Mental Ills. The New York Times 13 Mar. 2001: F7. (2) Tierney, John. Hallucinogens Have Doctors Tuning In Again. The New York Times 11 Apr. 2010: A1. Professional Reviews (3) Ashton, C H, et al. Cannabinoids in bipolar affective disorder: a review and discussion of their therapeutic potential. Journal of Psychopharmacology 19.3 (2005): 293-300. (4) Green, A R. Gaddum and LSD: the birth and growth of experimental and clinical neuropharmacology research on 5-HT in the UK. British Journal of Pharmacology 154.8 (2008): 15831599. Primary Literature (5) Griffiths, R R, et al. Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later. Journal of Psychopharmacology 22.6 (2008): 621-632. (6) Roth, Bryan L., et al. Salvinorin A: A Potent Naturally Occurring Nonnitrogenous Opioid Selective Agonist. Proceedings of the National Academy of Sciences of the United States of America 99.18 (2002): 11934-11939.