Tuesday, 11 August 2009

The Ecstasy and the Agony

The Ecstasy and the Agony
Matt Palmquist

MDMA holds promise as part of a therapy that helps post-traumatic stress patients confront and extinguish their fears. But ecstasy's recreational reputation has slowed research.

For people suffering from post-traumatic stress disorder — an anxiety condition that develops in the wake of extreme psychological stress or fear — often the only way forward is to confront the very memory that triggers the disorder. While group and cognitive therapies have shown promise, exposure-based therapies have become increasingly popular and successful. Exposure means confronting a distressing memory (a near-death experience, the loss of a loved one or a sexual assault, for example) to emotionally process it in a safe clinical environment — either through imagined scenarios or real-life exposure to reminders of trauma. The therapy is intended to help the patient "re-learn" a non-debilitating response to a trigger of fear. It's a phenomenon known as extinction learning.

Even with this approach, about 40 percent of patients continue to experience some level of post-traumatic stress after therapy. To reduce that number, scientists have been investigating a range of drug therapies in recent years to improve exposure therapy, which is not intended to "erase" a patient's memories but rather to help them process the painful stimulus as merely a memory, and not an event that will happen — or threaten them — again. The therapy requires patients to confront their anxieties, but researchers believe medication — including MDMA — can help by making the patient feel safer, more in control, more able to process emotions and less evasive or dispirited.

Earlier this year, a pair of Norwegian scientists published a paper in the Journal of Pharmacology titled "How could MDMA help anxiety disorders? A neurobiological rationale." Authors Pål-Ørjan Johansen and Teri Krebs, who are based at the Norwegian University of Science and Technology and receive funding from the Research Council of Norway, propose that the substance 3,4-methylenedioxymethamphetamine — also known as MDMA or as the street drug ecstasy — holds significant therapeutic promise for patients with post-traumatic stress disorder. As they write, "MDMA [ecstasy] has a combination of pharmacological effects that ... could provide a balance of activating emotions while feeling safe and in control."

To learn more about their studies of MDMA and post-traumatic stress disorder, Miller-McCune conducted an e-mail interview with the two researchers in Norway. They responded jointly.

Miller-McCune: Could you provide an overview of the ideas behind exposure therapy and how MDMA works to quell anxiety in that context?

Krebs & Johansen: A lot of people wonder: How is it possible that a few doses of MDMA, in combination with psychotherapy, could have lasting benefits for anxiety? Doesn't it just make people feel happy for a few hours? Aren't most psychiatric medications taken daily for a long time? There is a common misconception that psychotherapy is a really long process of vaguely defined "talking" and that it probably isn't that effective anyway. Actually, exposure therapy (in particular "prolonged exposure therapy," as developed by Dr. Edna Foa at the University of Pennsylvania) is short-term, structured, based on scientific behavioral principles of conditioning and extinction, and validated by many controlled studies. For most patients, exposure therapy has clinically significant effects on anxiety after a few hours, and for PTSD, exposure therapy has demonstrated long-term positive results after 10 to 12 hourlong weekly therapy sessions.

If MDMA could facilitate exposure, then it is entirely understandable that MDMA-augmented therapy could have lasting long-term effects on PTSD symptoms, after a few four- to six-hour therapy sessions with MDMA, within a course of short-term therapy. This needs to be demonstrated repeatedly in clinical trials, but it is biologically plausible. In the last 10 years, there has been a large amount of research on the molecular mechanisms of fear extinction with an objective of making exposure therapy easier, faster or more effective.

The main point that we want to get across: Fear extinction in exposure therapy requires a balance of activating emotions while feeling safe and in control. MDMA has effects that combine together many of the proposed mechanisms for enhancing fear extinction. Interestingly, MDMA appears to both facilitate exposure as well as augment extinction learning. Therefore, more research on these aspects of MDMA is clearly appreciated.

M-M: How was the therapeutic potential of MDMA first discovered? And what made you begin to think of using MDMA in this therapeutic context?

K & J: MDMA was first synthesized by Merck back in 1912, but it was never tested on humans. It was rediscovered in the late 1960s, and the therapeutic potential was immediately recognized by chemist Alexander Shulgin. Shulgin introduced MDMA to physicians who used MDMA to augment psychotherapy in the early '80s.

We have been in a kind of plateau the last decade; we need to develop new treatments beyond timid half-modifications of treatment models. ... We have acquired a lot of knowledge about the brain circuits of fear and fear extinction from animals. Recently we have started to move over the hump of being stuck in the same place. By translating principles from research on extinction and animal learning into clinical studies of exposure therapy, new strategies for combining pharmacological and exposure-based treatments have emerged.

M-M: What makes post-traumatic stress disorder a particularly viable condition to target with MDMA? Is it specifically because of the use of exposure therapy in treating the disorder?

K & J: Chronic post-traumatic stress disorder is an often-complex disorder that occurs in response to a traumatic event involving perceived personal threat, such as rape, torture, physical assault or combat. Most pharmacological interventions to PTSD are daily treatments involving long-term mechanisms presumed to correct biochemical abnormalities. In contrast, prolonged exposure therapy is a short-term treatment and, consistent with extinction models of fear inhibition, prolonged exposure therapy leads to long-term improvement. Applying psychotherapy to PTSD has gained substantial support and is today regarded as the treatment of choice. However, not all people benefit from the treatment.

People with PTSD often avoid triggers or reminders of the trauma and feel emotionally disconnected or are unable to benefit from the support of others — likely contributing to the development and maintenance of the disorder. A goal during exposure therapy for PTSD is to recall distressing experiences while at the same time remaining grounded in the present, according to Dr. Edna B. Foa. Emotional avoidance is among the most common obstacles in exposure therapy for PTSD, and within a particular session, a high emotional engagement predicts a better outcome.


As illicit versions of MDMA hit the streets in the early 1980s, becoming especially popular in gay night clubs before spreading in the 1990s to underground music parties known as raves, researchers were also taking a renewed interest in its therapeutic potential, and the World Health Organization's Expert Committee decided to examine studies of the drug as an aid to treatment of a variety of mental afflictions. In 1985, the committee called MDMA an "interesting substance" and concluded: "While the Expert Committee found the reports intriguing, it felt that the studies lacked the appropriate methodological design necessary to ascertain the reliability of the observations. There was, however, sufficient interest expressed to recommend that investigations be encouraged to follow up these preliminary findings."

On July 1, 1985, however, MDMA became the first (and still only) drug classified as Schedule I under a new law that allowed the U.S. Drug Enforcement Agency to place an emergency ban on drugs it deemed dangerous to the public. When the government was sued by a group of psychologists, psychiatrists and researchers, Francis L. Young, an administrative law judge for the U.S. Department of Justice, analyzed the literature and concluded that, prior to its being proscribed, MDMA did have "a currently accepted medical use in treatment in the United States. ... [I]t is not presently being used in treatment because it has been proscribed."

Young went on: "In addition, other psychiatrists have been using MDMA in their practices over the past 10 years. Because MDMA cannot be patented, no pharmaceutical company has had the financial incentive to carry out the extensive animal and clinical tests required by the FDA for approval to market the drug on an interstate basis. Nevertheless, the overwhelming weight of medical opinion evidence received in this proceeding concurred that sufficient information on MDMA existed to support a judgment by reputable physicians that MDMA was safe to use under medical supervision. No evidence was produced of any instances where MDMA was used in therapy with less than wholly acceptable safety."

Although Young recommended that MDMA be placed in Schedule III — allowing it to be manufactured, used on a prescription basis and subject to further research — the DEA maintained its Schedule I ruling. It wasn't until 1993 that the Food and Drug Administration approved clinical trials on the effects of MDMA on human volunteers.

In her seminal work on the drug, Ecstasy: The Complete Guide, New York psychiatrist Dr. Julie Holland notes that the drug acquired its street name largely on the basis of its marketing potential, but that even early users acknowledged its empathetic, therapeutic aspects. "It is widely accepted that the name ecstasy was chosen simply for marketing reasons," she writes. "It is a powerful, intriguing name to attach to a psychoactive substance. The person who named the drug, an alleged dealer who wishes to remain anonymous, had this to say: 'Ecstasy was chosen for obvious reasons, because it would sell better than calling it empathy. Empathy would be more appropriate, but how many people know what it means?'"

M-M: Obviously, the public at large will associate MDMA with the recreational drug ecstasy. How do you distinguish between clinical use of MDMA in a controlled setting and the illicit use of ecstasy at raves or parties?

K & J: MDMA has many potential side effects, most notably increased blood pressure and heart rate, which must be considered when screening and monitoring clinical subjects. As with other pharmaceuticals, it is important to distinguish between the risks of controlled clinical use of MDMA in research and hospital settings, and illicit use of "ecstasy" of unknown purity and dosage taken in potentially unsafe circumstances without medical supervision.

It's important to discriminate between medical research and drug policy. One area cannot be used to promote the other, and vice versa. It is inconsistent with traditional medical ethics or outright unethical to block treatment development and research based on drug policy. Drugs with greater potential for dependence and harm than MDMA, such as amphetamines (Adderall) and benzodiazepines (Valium), are widely prescribed for long-term use.

Treatment with MDMA involves only a few doses in combination with psychotherapy taken in a controlled clinical setting with appropriate medical precautions — for example, pre-screening for heart problems. It's also important to note that MDMA is not being considered for daily use or take-home use. In research studies, including in the United States, MDMA has been given to hundreds of healthy volunteers, with no occurrence of serious problems requiring medical attention. There has been a lot of misunderstanding in the past; fortunately a lot of development in this area over the last 10 years has made the climate ready for change.

M-M: From reading your paper, it seems the key role MDMA plays is helping patients overcome "emotional avoidance" of the trauma they experienced in the past. What are the biological reasons that MDMA works so well in this context?

K & J: In order for extinction to begin at all, the PTSD client has to be able to bearably remember and describe the traumatic memory. This is difficult for most PTSD clients. Activation of the fear is required for extinction. Anxiety-reducing pharmaceuticals like benzodiazepines can be counterproductive during exposure therapy (because they can merely suppress the memory for a period of time).

MDMA is found to do several things: It increases the level of oxytocin related to pro-social behavior and bonding, it increases activity in prefrontal brain areas involved in fear inhibition, and it increases the levels of norepinephrine and acetylcholine, which are neurotransmitters involved in emotional arousal and consolidation of emotional memories, including extinction learning. Consistent with fear inhibition models and translational research, we suggest that MDMA co-administered with prolonged exposure therapy will improve the therapeutic alliance, increase emotional processing and lead to enhanced extinction of fear responses.

M-M: Why do you think MDMA's potential in this area has been under-appreciated? Is it because of the negative attention on ecstasy?

K & J: MDMA and treatment research has been caught up with drug policy. However, it is common for new treatments to take a couple of decades to be fully tested and accepted. There is a great deal of interest among clinicians and scientists in the therapeutic potential of MDMA. It has been a silent story for 20 years. Previously, the only published results were open-label case studies. Now we have randomized, placebo-controlled studies.

We will see more research on the possible therapeutic applications of MDMA. It has been under-appreciated that the neurobiological effects of MDMA fit well with the current understanding of emotional learning and evidence-based treatments for anxiety. There has been a lot of research on MDMA, including clinical studies in over 300 healthy volunteers, but almost all research has focused on the possible risks in a recreational setting.


Krebs and Johansen would like to see more basic research on the impacts of MDMA on empathy, positive emotions and trust. That means studies in both animals and humans that more closely examine the acute effects of MDMA on behavior, endocrine levels and brain activity in response to emotional stimuli, particularly during the process of fear extinction wherein people can learn to suppress a reaction to fright by repeatedly confronting, in a safe environment, whatever memory or stimulus spurs their anxiety. But so far, there have only been a few studies, which have taken years to get approval, taking a close look at MDMA's therapeutic benefits.

The Multidisciplinary Association for Psychedelic Studies, a nonprofit group that funds therapeutic trials of MDMA, LSD, psilocybin and marijuana in accordance with FDA, European and international guidelines, has been working since its founding in 1986 to spur research into MDMA therapy. In February 2004, after approval from the FDA and on-site inspections of laboratories, the DEA gave its first consent to a study of MDMA and post-traumatic stress disorder by Dr. Michael Mithoefer, a psychiatrist in South Carolina. The $1 million project wound down last year, after what MAPS called an "outstanding demonstration of the safety and efficacy of MDMA-assisted psychotherapy in subjects with treatment-resistant PTSD."

MAPS has also initiated a study of MDMA-assisted psychotherapy in subjects with both anxiety and advanced-stage cancer at Harvard Medical School's McLean Hospital, led by Dr. John H. Halpern. There is also a study under way in Israel under the direction of Dr. Moshe Kotler, chair of the department of psychiatry at the Sackler School of Medicine at Tel Aviv University and former chief psychiatrist of the Israeli Defense Forces; a similar study has begun in Switzerland. The results of those studies should be released this year, while MAPS is working on initiating additional trials in Canada, Spain, France and Jordan.

But it's not all progress. MAPS' first study of MDMA's effects on post-traumatic stress disorder began in Spain in February 2000, but the study was halted in May 2002, in spite of sustained positive media attention throughout the country. As the doctor who led the study, Jose Carlos Bouso, wrote to the Spanish Medical Journal: "In May 2002, a news article appeared in the newspaper El Pais informing the public about the realization of that trial. The next day, our research team received an inspection from the General Direction of Pharmacy and Sanitary Products (Dirección General de Farmacía y Productos Sanitarios) belonging to the State of Madrid ... on May 13, 2002, the manager of the Hospital Psiquiatrico de Madrid decided to disassociate the Hospital from the study. Since then, because we have no other hospital in which to finish the study, the study cannot be restarted yet and it is now interrupted." Before the trial's close, six subjects had been treated without any lingering side effects, and there were hints of the program's efficacy.

In their interview with Miller-McCune, Krebs and Johansen said: "The biological basis of empathy and positive emotions is currently very interesting for neuroscientists. Many scientists would like to study MDMA, in humans and laboratory animals, but they are unsure how to approach this. We hope that our rationale will provide a framework for future studies and a nice reference for grant authorities. It's a promising treatment, being developed internationally, including at Harvard Medical School. Our overall goal is to reduce fear and increase acceptance around the concept of therapeutic use of MDMA."

Hallucinogenic Drugs in Psychiatric Research and Treatment:Perspectives and Prospects

Hallucinogenic Drugs in Psychiatric Research and Treatment:
Perspectives and Prospects
Rick J. Strassman, M.D.
The Journal of Nervous and Mental Disease, Vol. 183, No. 3, pp. 127-138.
©1995 Williams & Wilkins

Clinical research with hallucinogens has resumed after a generation's hiatus. To place these new studies in context, this article reviews the history of hallucinogens' use and abuse, discusses their pharmacological properties, and highlights previous human studies. Research with Iysergic acid diethylamide and related hallucinogens with thousands of patients and control subjects was associated with acceptable safety when subjects were carefully screened, supervised, and followed up. Data were generated regarding hallucinogens' psychopharmacology, overlap with endogenous psychoses, and psychotherapeutic efficacy. Current American and European studies emphasize systematic psychopharmacology, in addition to psychotherapy protocols. Human hallucinogen research will help define unique mind-brain interfaces, and provide mechanistic hypotheses and treatment options for psychiatric disorders. It is critical that human hallucinogen research in the l990s make use of state of the art methodologies, or consensually define when modifications are required. Training and supervisory issues also must be explicitly addressed.

Hallucinogenic substances found in fungi, plants, and animals have been used on all continents, and in a wide variety of cultures, both highly advanced and preliterate (Dobkin de Rios, 1984). Mescaline, from the peyote cactus, has been used in clinical research protocols from the 1890s to the present (Mitchell, 1896). The thousand-times more potent effects of LSD-25 were discovered in 1943 by Albert Hofmann, 5 years after its synthesis (Stoll, 1947). The beginning of modern "biological psychiatry" can be said to have started as much with the appreciation of LSD's "psychotogenic" effects as the contemporaneous discovery of the one-thousandth as potent "antipsychotic" effects of chlorpromazine.
The study of hallucinogenic drugs in humans was, and remains, important for several reasons. First, they elicit a multifaceted clinical syndrome, affecting many of the functions that characterize the human mind, including affect, cognition, volition, interoception, and perception. Characterizing hallucinogens' properties will enhance understanding of important mind-brain relationships, particularly relevant in this, the Decade of the Brain. Second, naturally occurring psychotic syndromes share features with those elicited by these drugs. Understanding effects and mechanisms of action of hallucinogens may provide novel insights and treatments into endogenous psychoses. Third, increasing use and abuse of hallucinogens over the last several years, particularly LSD, by young adults may produce a similar spate of adverse psychiatric sequelae seen with the first wave of their illicit use in the 1960s. Treatment of these adverse effects consume scarce public resources and safe, selective, and efficacious treatments of acute and chronic negative effects of these drugs are needed. Finally, the enhancement of the psychotherapeutic process, sometimes in treatment refractory patients, reported by early studies, has relevance to current emphasis on time-limited psychotherapeutic interventions.

Many terms have been used to describe the effects of these drugs, including psychedelic (mind manifesting), psychodysleptic (disturbing the mind), phantasticant, psychotogen, oneirogen (producing dreams), entheogen (generating religious experience), phanerothyme (making feelings visible), psychotomimetic, and schizotoxin (Grinspoon and Bakalar, 1979; Stafford, 1992). Psychedelic represents the nonmedical, recreational, and illicit use of these drugs, while hallucinogen refers to these compounds within a medical-legal context.
The "classical" hallucinogens belong to several chemical families: phenethylamines (e.g., mescaline), indolealklyamines (e.g., psilocybin and N,N-dimethyltryptamine [DMT]), and lysergamides (e.g., LSD and morning glory seeds) (Nichols et al., 1991). 3,4-Methylene-dioxymethamphetamine (MDMA) ("X," "XTC") is a methoxylated amphetamine (phenethylamine), and produces effects that overlap those of classical compounds (Lister et al., 1992). Low doses of the dissociative anesthetics, phencyclidine and ketamine (Siegel, 1978), and antimuscarinic agents (Ketchum et al., 1973) also share subjective properties with the hallucinogens. However, hallucinogens do not produce anesthesia at high doses, as do the former compounds, nor is there a clouding of consciousness at "psychedelic" doses, as with the latter.
A clinically useful manner of representing hallucinogens refers to their temporal properties: onset, peak effect, and duration of action. An "ultra-short-acting" drug's onset is less than 1 minute, peak effects occur within 5 minutes, and duration is 30 minutes or less. Intravenous DMT is an example (Strassman et al., 1994). A "short-acting" hallucinogen's onset is between 5 and 15 minutes, peak effects are within 15 to 60 minutes, and duration is 1 to 2 hours (e.g., intramuscular N,N-diethyltryptamine; Faillace et al., 1967). "Intermediate-acting" hallucinogens include the orally active tryptamine psilocybin (Rinkel et al., 1960). Onset is within 15 to 30 minutes, peak effects are at 1 to 3 hours, with duration up to 6 hours. "Long-acting" hallucinogens include oral LSD and mescaline (Hoch et al., 1952), with onset at 30 to 90 minutes, peak effects at 3 to 5 hours, and duration of 8 to 12 hours. "Ultra-long-acting" compounds include the poorly characterized African plant drug ibogaine (Fernandez, 1982). Duration of action may last 18 to 24 hours.

Prevalence of Use
Hallucinogen use in the United States remained relatively constant from the late 1960s to the late 1980s (Pope et al., 1990). However, data from the National Institute on Drug Abuse (NIDA) show an increase in any LSD use by high school seniors "within the last 12 months" from 4.8% to 5.6% from 1988 to 1992. While the magnitude of this rise is slight, it stands in contrast to the abuse of other drugs. For example, the proportion of seniors who had used any cocaine dropped from 7.9% to 3.1% during the same period (Johnston et al., 1993). Thus, the proportion of respondents who reported any use of LSD was almost twice as high as the proportion reporting any cocaine use by high school seniors in 1992. The 1990 NIDA statistics reveal that lifetime prevalence rates for hallucinogens were about the same as those for cocaine, and 7 to 8 times higher than for heroin. LSD ranked first in the categories of "most intense" and "longest" high among respondents. Between 13 and 17 million individuals in this country have used a hallucinogen at least once (NIDA, 1991).

Legal Status
Hallucinogens reside in Schedule I of the Controlled Substances Act of 1970, which is reserved for drugs with "high abuse potential," "lack of established safety even under medical supervision," and "no known use in medical treatment" (Anonymous, 1970). Compounds with "substantially similar" structure or function also are Schedule I drugs, as a result of the passage of the Controlled Substances Analog Bill of 1986 (Anonymous, 1986).
The use of mescaline-containing peyote by the Native American Church has been debated for nearly a century (La Barre, 1989). Native American Church members may possess and ingest peyote in several states, and non-Native Americans may use it in Church ceremonies in some. In response to increasing judicial restrictions on peyote use, the Religious Freedom Restoration Act became law in 1993 (Anonymous, 1993). Interpretation of this law with respect to hallucinogenic "sacraments" by traditional non-Western (Rivier and Lindgren, 1972) and other "neo-religious" groups will be of interest.

Basic Neuropharmacology
The nearly simultaneous discoveries of serotonin (5HT) and LSD undoubtedly have had an impact on the preeminent role of this neurotransmitter in explicating hallucinogens' effects and mechanisms of action. Noradrenergic (Horita and Hamilton, 1969), dopaminergic (Ahn and Makman, 1979), and cholinergic (Cervoni et al., 1963) systems have also been investigated, but have received less attention.
Gaddum and Hameed (1954) and Woolley and Shaw (1954) first suggested that LSD antagonized the effects of 5-HT in lower animals. Soon thereafter, Freedman (1961) showed that LSD decreased particulate binding of 5-HT in the axon, raising brain levels of 5-HT and lowering those of its metabolite 5-hydroxyindoleacetic acid. 5-HT mechanisms have been demonstrated for electrophysiological (Aghajanian et al., 1968), pharmacological (Conn and Sanders-Bush, 1986), and behavioral (Glennon et al., 1985) effects of hallucinogens.
The animal model of "hallucinogenesis" most used is drug discrimination, wherein animals are trained to distinguish between a hallucinogen, usually LSD, and saline. Animal responses to a test drug as if it were LSD suggest that the "interoceptive" or "discriminative" cue is similar to LSD's (Glennon et al., 1983). However, several nonhallucinogens are LSD-like in this model, such as quipazine (Cunningham and Appel, 1987) and lisuride (Nielson, 1985), while psilocybin is not (Koerner and Appel, 1983), which emphasizes the need for human studies.
Hallucinogens were important in stimulating the burgeoning field of 5-HT receptor subtypes (Peroutka and Snyder, 1979). Current data emphasize effects upon the 5-HTlA and 5-HT2A,C subtypes (Glennon et al., 1985; Spencer et al., 1987), alone or in combination (Arnt and Hyttel, 1989).
Tolerance (Freedman et al., 1958) and cross-tolerance (Appel and Freedman, 1968) to behavioral effects of hallucinogens is seen rapidly, and is accompanied by downregulation of 5-HT2 sites (McKenna et al., 1989).

Human Psychopharmacology
Measurement of Hallucinogen Effects in Humans
Initial human studies with hallucinogens relied upon careful clinical observation, using psychoanalytic (Savage, 1952) or behavioral (Cheek and Holstein, 1971) perspectives, in normal subjects (Snyder et al., 1967) and psychiatric patients (Hoch et al., 1952). In addition, hallucinogen effects on previously validated psychological scales, such as the MMPI (Belleville, 1956), assessed change scores within individuals and allowed comparisons between hallucinogen-induced syndromes in normal subjects with other well-characterized psychopathological states.
Three rating scales were developed specifically for LSD effects in the 1960s. "Normative" data for all three scales were generated from effects in unexperienced hallucinogen users who were not told what the effects of LSD might be, making the data difficult to interpret, particularly when an attempt is made to determine their reinforcing properties in those who use them recreationally.
The Abramson et al. (1955) scale emphasized somatic, cognitive, and perceptual effects of LSD, while the Linton-Langs scale (Linton and Langs, 1962) assessed effects predicated on a psychoanalytic theory of consciousness. The Addiction Research Center Inventory (Haertzen et al.,1963), the standard rating scale for assessing effects of drugs of abuse, used LSD as one of several mind-altering compounds. Its LSD scale is known as the dysphoria scale, reflecting its emphasis on unpleasant effects (Haertzen and Hickey, 1987).
We have developed a new instrument, the Hallucinogen Rating Scale (HRS), that differs from these previous scales. It was drafted by interviewing experienced hallucinogen users, and modified during pilot studies with DMT in an additional cohort of well-prepared, educated, well-functioning, experienced hallucinogen users (Strassman et al., 1994).
The HRS also differs from other rating scales in its emphasis on a "mental status examination" clustering of items. In the Abramson et al. scale, derivative factors, such as paranoid ideation and generalized inhibitory effects, are used. The Linton-Langs scale also uses this manner of grouping items: feeling less inhibited and suspiciousness are examples. In the Addiction Research Center Inventory, similarities or differences between a test drug and "reference" drugs are made, without determining the nature of these similarities or differences. In the HRS, items are grouped into six "clinical clusters": somaesthesia (somatic/interoceptive/visceral cues), affect, perception, cognition (thought content and processes), volition (willful ability to interact with one's mental and physical self and the environment), and intensity (a global measure of robustness of response). These clinical clusters provided better resolution of subtle dose effects for DMT than multiple biological measurements in initial dose-response studies. Principal components factor analysis, choosing six factors to correspond to the clinical clusters, also proved superior to biological variables in differentiating among DMT doses, but generated a less heuristically useful grouping of individual items (Strassman et al., 1994).

Route of Administration
Whether LSD and longer-acting compounds produce their effects directly, or require secondary, "downstream" mechanisms, has been debated, because of the delay in onset of effects of LSD even with intravenous administration (Aghajanian and Bing, 1964). However, Hoch (1956) described nearly instantaneous onset of LSD effects with intraspinal administration, and intravenous DMT effects also are immediate (Strassman et al., 1994). Thus, access of drug to relevant brain sites, lipid solubility, clearance, and other pharmacokinetic factors determine the time course of drug effects, rather than secondary processes. However, there may be systems downstream from 5-HT receptor agonism that require extremely short time domains for activation.

LSD and other classical compounds elicit behavioral tolerance (Isbell et al., 1956) and cross-tolerance (Abramson et al., 1960a) after several daily doses. The exception is DMT, for which no behavioral tolerance has been demonstrated (Gillin et al., 1976), and which elicits a fully hallucinogenic response in LSD-tolerant subjects (Rosenberg et al., 1964).

Human Hallucinogen-Neurotransmitter Interactions
Serotonin. Bromo-LSD, a potent 5-HT antagonist in lower animals (Cerletti and Doepfner, 1958), although psychoactive in humans at much higher doses than LSD (Isbell et al., 1959b), antagonized LSD effects in both normal subjects (Ginzel and Mayer-Gross, 1956) and psychiatric patients (Turner et al., 1959). Cyproheptadine, a 5-HT2A c antagonist (Hoyer and Schoeffter, 1991), prevented the subjective effects of DMT in two of three normal volunteers (Meltzer et al., 1982). 5-Hydroxytryptophan loading studies attempted to surmount the 5-HT antagonism of LSD in humans, but did not demonstrate clinically relevant effects (Pare and LaBrosse, 1963). Chronic monoamine oxidase inhibition reduced LSD's effects in humans (Resnick et al., 1964), perhaps relating to downregulation of 5-HT sites. MAO inhibition also reduced DMT effects (Sai-Halasz, 1963). This latter phenomenon may relate to inhibition of DMT metabolism (Sitaram et al., 1987). Reserpine, if administered at adequate dosage and duration, enhanced responses to LSD in humans (Isbell and Logan, 1957; Resnick et al., 1965), supporting a functional "upregulation" of relevant mechanisms.
Both meta-chlorophenylpiperazine (Kahn and Wetzler, 1991) and 6-chloro-2-(1-piperzinyl)pyrazine (MK-212) (Murphy et al., 1991) share pharmacological characteristics with the classical hallucinogens, and elicit "hallucinogenic" effects in patients with schizophrenia (Krystal et al., 1993) or alcoholism (Lee and Meltzer, 1991), but not in normal subjects (Murphy et al., 1991). Higher doses in normal subjects may produce more typical responses.
Dopamine. LSD has agonist effects at postsynaptic receptors (Burt et al., 1976), and DMT has dopamine-releasing properties (Haubrich and Wang, 1977). While chlorpromazine was suggested to be a "specific antidote" to LSD effects (Isbell and Logan, 1957), it may enhance LSD's effects if given during the acute intoxication (Abramson et al., 1960b; Schwartz, 1967). Similarly, haloperidol pretreatment enhanced the neuroendocrine and subjective effects of DMT in one subject (Meltzer et al., 1982). In addition, methamphetamine (a dopamine agonist) ameliorated acute LSD effects (Hoch, 1956). Thus, affinities of hallucinogens for dopamine receptors, relative to primarily dopaminergic or antidopaminergic compounds, may determine the end result of manipulating dopaminergic neurotransmission on responses to hallucinogens. Other. Little data exist regarding manipulating cholinergic (Isbell et al., 1959a) and adrenergic (Murphree, 1962) systems on hallucinogen effects in humans, and require further study.

Hallucinogens and Schizophrenia
The association between ingestion of hallucinogens and onset of acute schizophrenic episodes is discussed below (see Adverse Effects). One of the initial indications for LSD in clinical research was for elicitation of a time-limited "psychotomimetic" syndrome. However, the degree of overlap has been vigorously debated (Hollister, 1962; Langs and Barr, 1968; Vardy and Kay, 1983; Young, 1974). The criticism that visual effects were relatively uncommon in functional psychoses has been tempered by the high incidence of these symptoms in later studies (Bracha et al., 1989). It appears that acutely ill, positive-symptom patients show more "psychedelic" symptoms than do chronic, undifferentiated, negative-symptom predominating patients, particularly in the prodromal state (Bowers and Freedman, 1966).
Hallucinogens also were administered to psychotic patients and comparisons were made between drug effects and preexisting symptoms (Cholden et al., 1955). These studies were limited by the highly anecdotal nature of ratings of "subjective" effects. Some studies reported that hallucinogens produced different symptoms than those patients were normally experiencing (Fink et al., 1966; Turner et al., 1959), while others reported an exacerbation of preexisting psychopathology (Hoch et al., 1952; MacDonald and Galvin, 1956). A relatively consistent finding was that "burned out," predominantly negative symptom-laden patients showed blunted responses to hallucinogens (Boszormenyi and Szara, 1958; Hoch et al., 1952). This latter finding supports lower levels of 5-HT2 sites in the cortex of schizophrenics (Mita et al., 1986). It also prompted a search for "endogenous schizotoxins," in which case "tolerance" to naturally occurring psychotomimetics would confer resistance to exogenously administered agents in patients.
The short-chained tryptamines, DMT and 5-methoxyDMT, were leading candidates for endogenous hallucinogens (Corbett et al., 1978; Franzen and Gross, 1965). Requisite enzymes for DMT biosynthesis were found in human blood (Wyatt et al., 1973), brain (Saavedra and Axelrod, 1972), and lung (Axelrod, 1962). Although correlations were seen between acute symptomatology and DMT excretion in patients (Murray et al., 1979), interest waned because peripheral DMT levels were not consistently different between normal and psychotic subjects (Gillin et al., 1976). However, peripheral levels do not accurately reflect either concentrations at discrete brain areas, nor differential sensitivity to comparable levels between normal subjects and patients with psychoses. Lack of tolerance to its psychological effects, given either twice daily for 5 days (Gillin et al., 1976) or every 30 minutes four times, strengthens its importance as a putative schizotoxin.

Psychotherapy Research
Relatively few studies used LSD as a "psychopharmacotherapeutic" agent in humans, i.e., daily dosing regimes. Daily LSD elicited robust antidepressant responses in depressives in an uncontrolled study, while tolerance to its psychedelic effects developed rapidly (Savage, 1952). These data are consistent with similar
effects of chronic LSD and antidepressants on 5-HT receptor function (Buckholtz et al., 1990; Stolz et al., 1983). Beneficial responses to daily dosing in some autistic children also were seen (Bender, 1966; Freedman et al., 1962; Simmons et al., 1966).
The first suggestion that LSD may hasten psychotherapy was made in the early 1950s (Busch and Johnson, 1950), and series of cases soon followed (Eisner and Cohen, 1958). LSD was believed useful in recovering early memories, enhancing associative processes, reducing repression, intensifying affective responses, and magnifying aspects of the transference (Chandler and Hartman,1960; Hollister et al., 1962; Snyder et al.,1968). These early protocols utilized relatively low doses (25 to 100 mcg) within the context of ongoing psychoanalytic psychotherapy. This was termed the psycholytic approach, and utilized multiple sessions over months or years. These studies were hampered by lack of adequate control groups and impartial raters, small sample size, and primarily anecdotal data. However, their emphasis on repeated sessions merits attention when assessing results from "psychedelic" research protocols. This latter approach, described below, may have limited efficacy by depending inordinately upon one or two highly charged sessions, without the benefit of "working through" available in the psycholytic model.
The psychedelic approach, favored by North American researchers, involved administration of a single, or at most a small number of, high dose (300 to 1500 mcg) LSD session(s) after a relatively short course of psychotherapy (Pahnke et al., 1970). This psychotherapy encouraged the patient to undergo a "psychedelic experience," which had many aspects of a religious epiphany. As many "spontaneously recovered" drug abusers report similar spiritual-mystical experiences (Ludwig, 1985), this approach was turned to substance abuse treatment (Hollister et al., 1969; Savage and McCabe, 1973). Uncontrolled, often anecdotal reports from psychedelic studies also demonstrated some promise in the treatment of sociopathy (Shagass and Bittle, 1967), prisoner recidivism (Leary and Metzner, 1967-68), and the pain and despair associated with terminal illness (Grof et al., 1973; Kast and Collins, 1964).
Substance abuse treatment studies were numerous, and while initial reports were enthusiastic (Kurland et al., 1967; MacLean et al., 1961; Smith, 1958), studies using control groups and longer follow-up demonstrated less impressive results (Cheek et al., 1966; Hollister et al., 1969; Johnson, 1969). However, a review of 31 studies involving 1100 alcoholics concluded that meaningful generalizations could not be reached because of the inconsistent designs and criteria for improvement (Abuzzahab and Anderson, 1971).
In summary, many of the initial studies suggesting enhancement of psychotherapy with hallucinogens were hampered by lack of methodological rigor. However, placebo/control treatments are problematic. For example, when 50 1lg of LSD were used as "active placebo" against 450,ug of LSD in an alcoholism treatment study using the psychedelic model, minimal differences in outcome among groups were discerned (Kurland et al., 1971). That many of the low-dose group also underwent a "peak experience" emphasizes the importance of assessing the interplay between pharmacology, psychotherapy, and subjective experience. Minimum requirements for future studies should include independent raters of effects and outcome, identical (nondrug) treatment in the control group, and adequate follow-up (at least 1 year) (O'Brien and Jones, 1994). The choice of inactive and/or active placebo must be given careful consideration. Finally, a hybrid of the psychedelic and psycholytic models, in which more frequent high-dose sessions are used, may provide additional flexibility and allow more psychotherapeutic work to take place than either model alone.

Adverse Effects
The profoundly altered mental status elicited by hallucinogens requires astute clinical management, including thorough screening and preparation of prospective patient or volunteer subjects, careful supervision of drug sessions, and consistent and responsive follow-up which may require psychotherapeutic intervention.
Early clinical investigators provided reassuring safety data. A survey of American clinical research documented in normal volunteers a rate of attempted suicide of 0/1,000, completed suicide of 0/1,000, and "psychotic reactions over 48 hours" of.8/1,000. Corresponding figures in patients were 1.2/1,000,.4/1,000, and 1.8/1,000 (Cohen, 1960). These data were derived from over 5,000 subjects who had received LSD or mescaline more than 25,000 times, single individuals taking between 1 and 80 doses, using LSD doses from 25 to 1,500 mcg. A British survey reported comparable results (Malleson, 1971).
Once hallucinogens escaped from the laboratory, however, emergency rooms and clinics were quickly impacted by adverse effects in unprepared, unsupervised, and psychiatrically ill individuals taking hallucinogens, especially LSD (Frosch, 1969; Ungerleider et al., 1968). LSD was nearly always of uncertain quality and dose, and combinations of LSD and other drugs and alcohol were usual (Frosch et al., 1965).
These adverse consequences may be classified temporally as acute, subacute, and chronic (Strassman, 1984).

Acute adverse effects include: a) brief panic reactions to effects of the drug, which generally responded to verbal reassurance and protection of the patient, and only in severe instances, to medication (Taylor et al., 1970); and b) psychotic reactions, disorganized states that lasted longer than 24 hours and required more intensive management and often hospitalization. These psychotic reactions usually were superimposed on preexisting psychotic disorders in polydrug-abusing patients (Blumenfield and Glickman, 1967; Hekimian and Gershon, 1968; Hensala et al., 1967; Vardy and Kay, 1983). They typically responded to treatments appropriate to the non-drug-induced syndromes they resembled (Strassman, 1984).
Toxicology laboratories now can measure sub-nanogram/milliliter concentrations of LSD in body fluids (Nelson and Foltz, 1992), aiding diagnosis of acute adverse reactions.

Subacute effects requiring clinical intervention are flashbacks, which refer to unbidden re-experiencing of certain aspects of hallucinogen-induced effects, often visual, but partaking of all psychic functions (Wesson and Smith, 1976). They occur after an intervening period of normalcy after a drug experience (Horowitz, 1969). Not all flashbacks are felt to be adverse, and many members of the psychedelic subculture find brief "free trips" pleasurable (Wesson and Smith, 1976). The incidence is reported to vary between 15% and 77% of individuals who have had at least one LSD experience (Strassman, 1984).
In our DMT studies with experienced hallucinogen users, we have seen an incidence of 5% to 10% in volunteers with at least one high-dose DMT session. These sessions, it should be noted, are almost uniformly regarded as "higher than I have ever been," and thus may be considered traumatic. Meditation, smoking marijuana, and falling to or waking from sleep are the most common precipitants. Several volunteers willfully attempt to re-experience aspects of the DMT state by these means.
The etiology of flashbacks is not known, but organic, psychological, and social hypotheses have been proposed (Alarcon et al., 1982). Their presence in post-traumatic stress disorder and elicitation by lactate infusion (Rainey et al., 1987) suggest a complex interaction of anxiety and stress with memory processes (McGee, 1984). Flashbacks are usually self-limited, if psychoactive drugs, especially hallucinogens and marijuana, are avoided. Persistent or particularly disturbing symptoms (Abraham, 1983) require a neurological evaluation.

Chronic adverse effects may be divided into functional and organic. Functional syndromes rarely may be quite debilitating and treatment resistant, resembling an ego-syntonic, negative symptom-laden schizophrenic disorder (Glass and Bowers, 1970).
More difficult to diagnosis confidently as directly related to LSD use are changes in lifestyle and interpersonal behaviors associated with hallucinogen use (Blacker et al., 1968). The confluence of drugs and preexisting personality styles is suggested in McGlothlin and Arnold's (1971) 10-year follow-up of psychotherapy patients and normal volunteers who participated in sanctioned LSD studies. This study suggested a catalytic effect of LSD use in individuals predisposed to unconventional aesthetic and philosophic ideas (McGlothlin and Arnold, 1971).
LSD-induced organic central deficits have been difficult to document with certainty, because of no premorbid data and an inability to control for other substances of abuse (Acord and Barker, 1973). Statistically, but not clinically, significant decrements were reported in several studies. Lower Halsteads' Category and Reitan's Trail Making A test scores were reported in hallucinogen users compared with control subjects; however, both of these tests were within normal ranges in drug users (Culver and King, 1974; McGlothlin et al., 1969). Nonspecific EEG changes also were described (Blacker et al., 1968).
Chronic visual disturbances, posthallucinogen perceptual disorder, akin to chronic flashbacks, may partake of functional and organic bases. The validity of this diagnosis is uncertain because of lack of premorbid data and inability to control for other drugs of abuse. Its responsiveness to benzodiazepines (Abraham, 1983) support an anxiety/functional rather than organic disorder (McGee, 1984).

Mutagenicity / Teratogenicity
Initial reports of chromosomal (Cohen et al., 1967) and reproductive (Jacobson and Berlin, 1972) disorders in LSD users were not replicated in later studies (Dishotsky et al., 1971; Muneer, 1978). Until more controlled data are forthcoming, however, woman who are pregnant or not using reliable contraception are not suitable candidates for hallucinogen research protocols.

Conclusions and Recommendations
Hallucinogens are powerful drugs, with the potential to elicit or exacerbate psychiatric symptoms. Particularly aversive or overwhelming acute effects may traumatize or sensitize the individual, setting up the potential for flashbacks akin to those seen in post-traumatic stress disorder. The use of experienced hallucinogen users may reduce the traumatic nature of high-dose hallucinogen sessions, and is recommended for psychopharmacological research. Additionally, truly informed consent is possible only in experienced users. Studies comparing responses in normal subjects with those in psychiatric patients (see below) should use the lowest doses that will generate requisite data.
Psychotherapy protocols require a careful assessment of risk to benefit ratios balancing morbidity or mortality of an untreatable psychiatric condition with the likelihood of psychological sequelae of hallucinogen exposure. The risk associated with psychotherapy research protocols may be lessened by using the lowest possible dose of drug. If high-dose administration is necessary, it may be prudent to gradually build up to this dose over several sessions.

Current Research
In the United States, we have been administering DMT since late 1990 (Strassman, 1991) in psychopharmacologic studies utilizing experienced hallucinogen users (Strassman and Qualls, 1994; Strassman et al., 1994). The University of Miami has begun phase I studies of ibogaine in preparation for substance abuse treatment research. Similar phase I studies have begun at UCLA with MDMA, also in anticipation of therapeutic applications. Psychopharmacological studies using subanesthetic, psychotomimetic doses of ketamine in normal volunteers and patients with schizophrenia are ongoing at Yale University (Krystal et al., 1994). A substance abuse treatment amendment to the University of Maryland's inactive LSD protocol has been approved, and may begin within a year.
In Europe, group and individual psychodynamic psychotherapy with LSD or MDMA has been taking place in Switzerland since 1985, but no research data have been generated. The University of Zurich is studying the effects of psilocybin and ketamine on positron emission tomography and neuropsychological responses in normal volunteers (Vollenweider, 1994). In Germany, several sites are studying mescaline and MDE (the N-ethyl derivative of MDMA) effects in normal volunteers, studies in which multiple neurobiological variables are characterized (Hermle et al., 1992, 1993).

Areas for Future Research
As described previously, a wide range of temporal characteristics are available with the hallucinogens, and may be exploited for research with different goals. For example, psychotherapy protocols might be best served using short-acting drugs whose effects last between 1 and 2 hours, while neuroendocrine challenge studies would benefit from using ultra-short-acting drugs and keeping interactions with the environment to a minimum. Protocols requiring multiple within-individual assessments could use long-and ultra-long-acting drugs.

Measurement Variables
Recent DMT studies demonstrate the superiority of subjective (HRS) responses to biological ones with respect to subtle dose effects (Strassman et al., 1994). Thus, despite better characterization of mechanisms of action for neuroendocrine, cardiovascular, and other autonomic variables, sensitivity for effects of experimental manipulations is relatively low. This emphasizes the importance of introspection and subjective data in characterizing the effects of hallucinogens, especially using a within-subjects design.

Human hallucinogen psychopharmacology requires further study, for both clinical and heuristic purposes. Research should assess the role of non-5-HT neurotransmitters, particularly dopamine. Risperidone, with potent 5-HT2 and D2 antagonism, is more potent than ritanserin, a pure 5-HT2A,( agent, in antagonizing animal responses to LSD (Meert et al., 1989). The importance of combined 5-HT/DA antagonism corresponds to efficacy in schizophrenia treatment with "atypical" antipsychotic medications (Meltzer, 1989), and suggests that antagonists to hallucinogens' behavioral effects in humans may be efficacious in schizophrenia.
Pretreatment blockade studies, based upon relevant animal and human data, will suggest interruption strategies for acute adverse reactions in the emergency setting. Blockade strategies (Kosten and Kosten, 1991) also could be utilized to prevent subjective effects in those prone to chronic abuse of hallucinogens in a manner similar to naltrexone.
Although most classical hallucinogens' qualitative psychopharmacological properties are believed identical (Isbell, 1959), little data exist for within-subject studies using multiple drugs. Many congeners of classical compounds have been administered safely to humans (Isbell et al., 1959b). Assessment of salient similarities and differences will suggest structure-activity relationships for design of drugs with desirable functional profiles for clinical research purposes (Nichols, 1987).
Responses to hallucinogens in psychiatric populations with presumed abnormalities in neurotransmitter systems relevant to hallucinogen action may be tested, if appropriate safeguards are in place. Such studies would generate unique human data relating disturbed subjective experience in psychiatric patients to pharmacological manipulations, generating both therapeutically and mechanistically valuable data.
Studies exploiting recently developed hallucinogen-induced animal models of information-processing defects in schizophrenia (Braff and Geyer, 1990) could be applied to normal volunteers' responses to these drugs, further comparing the two syndromes. In addition, the HRS could be applied to more carefully characterized schizophrenic patients at various stages of the disorder, allowing novel comparisons between functional and drug-induced psychoses.
Advances in in vivo brain-imaging techniques may better characterize hallucinogen effects and mechanisms of action. These include topographic pharmacoelectroencephalography, positron emission tomography (assessing metabolic effects of psychoactive doses, and distribution of low doses of labeled compounds), and magnetic resonance imaging (spectroscopy and functional imaging).

Economic constraints create increasing pressure for cost-effective medical psychotherapy (Krupnick and Pincus, 1992). Sophisticated psychotherapy protocols with proven efficacy (Frank et al., 1990) provide a strong foundation upon which hallucinogen-assisted psychotherapy research may be re-examined. Courses of therapy utilizing adjunctive, high-dose, hallucinogen-assisted sessions should be considered in a model combining the psychedelic and psycholytic models. This would be a logical extension of earlier work that suggested robust short-term improvement, but less impressive maintenance of therapeutic effects, in high-dose models.
The growing numbers of terminally ill cancer and acquired immune deficiency syndrome patients who require palliative, quality-of-life treatment suggest additional areas for future psychotherapy research that would build upon older, uncontrolled studies indicating beneficial responses. The reported elements of increased pain control, improved family relationships, and greater acceptance of illness and impending death, if verified by controlled studies, would provide additional clinical support for these patients. The use of "flooding" to treat post-traumatic stress disorder in both combat veterans (Grigsby, 1987) and others (Saigh, 1989) may also provide a unique interfacing of hallucinogenic drug effects with an established treatment modality for a particularly pernicious and common disorder. Hallucinogen-enhanced imagery and associations, and associated affective responses to these, could be used to enhance the efficacy of this treatment.

Set and Setting
Although complex and potentially controversial, set and setting issues require further study. Set refers to the personality, state, and expectations of the subject, and setting to the environment in which the session takes place. Setting partakes of the physical surroundings, e.g., inpatient, high-technology research unit or comfortable outpatient consultation suite; nuances of the investigator/therapist presentation, including clothing, appearance, odor, and other physical characteristics; being belted to the bed (Smart et al., 1966) or able to move about freely; and eyes open or blindfolded (Denber, 1958). In addition, it involves the "set" of the research team members, including the nature of countertransference and empathy (Day, 1957), type and amount of training in psychotherapy and working with regressed/psychotic individuals, and the theoretical model and expectations of the research, psychotomimetic, psychedelic, or otherwise.
Finally, research team members' experience with hallucinogens may affect the nature of the results of research/treatment protocols. Swiss and German health authorities require that the principal investigators first take study drugs at doses to be used in their protocols, both for safety issues and to provide more adequate informed consent.3 In the United States, self-experimentation by research teams initially was encouraged (Cerletti and Rothlin, 1955; Johnson, 1969; Szara, 1957). However, in response to highly publicized cases of self-experimentation and extraresearch drug taking with volunteers (Leary, 1968), this practice was discontinued. Future research must carefully account for these setting variables in assessing outcome measures, and the European practice of "going first" should be considered.

Training Issues
The small number of protocols using hallucinogens allows for very close contact between investigators and regulatory agencies overseeing this work. However, renewed examination of these compounds may generate a large number of requests to use them in clinical studies. State of the art methodologies are no guarantee against disasters resulting from imprudent administration of hallucinogens to humans.
Transference and countertransference issues are rarely discussed in psychopharmacology research, and increasingly less so in psychotherapy research. However, the regressed, suggestible, and unusual behavior of subjects under the influence of hallucinogens is easily observable. Interpersonal exchanges that would be readily overlooked in a normal state of awareness may assume extreme and confusing meaning. The clinical investigator not only may become the object of infantile wishes and fears, but may, in the subject's mind, actually look, smell, feel, and sound identical to highly emotionally charged people in his or her life. In addition, the clinical researcher may have multiple, conflicting, and more-or-less conscious motivations for administering incapacitating drugs to humans. These may include narcissistic, grandiose or sadistic, and voyeuristic impulses. Callous, offhand, or teasing remarks made for these and other, less malignant, but similarly unexamined, motivations can dramatically alter the course of a volunteer's hallucinogenic drug experience, from a psychedelic to psychotomimetic. Sexual relations between clinician and subject, during or after a hallucinogenic drug session, the most disastrous acting-out of both parties' drug-altered sensibilities, do occur.
Regulatory agencies determine professional qualifications and adequacy of facilities for conducting this research. However, I believe that specialized training, and perhaps certification, is necessary for clinical investigators performing human hallucinogen research. Such training/certification and ongoing periodic supervision would reduce the likelihood of subtle or flagrant misuse of these compounds by unknowing or unscrupulous clinical investigators. Specific proposals regarding the nature of this training and supervision is beyond the scope of this article. This suggestion is meant to stimulate further debate and discussion at institutional and governmental levels.

The renewal of human hallucinogen research is encouraging. However, it must be tempered with an appreciation that the controversial nature of these drugs caused a suspension of nearly a generation's worth of research in the field (Dahlberg et al., 1968). Ongoing studies are taking a painstaking, systematic approach, and are avoiding claims that cannot be substantiated by data. Careful attention to selection, screening, preparation, supervision, and follow-up of subjects undergoing hallucinogenic drug sessions is absolutely necessary. In addition, the training, characteristics, and research setting of clinical investigators desiring to work with these compounds must be addressed directly.
These precautions will provide a safety net to minimize many of the mistakes and false leads that plagued the first round of human studies. If appropriate circumspection is practiced, the re-examination of the role of hallucinogens in clinical research and treatment will be substantial.

Abraharn HD (1983) Visual phenomenology of the LSD flashback. Arch Gen Psychiatry 40:884-889.
Abramson HA, Jarvik ME, Kaufman MR, Kornetsky C, Levine A, Wagner M (1955) Lysergic acid diethylamide (LSD-25): 1. Physiological and perceptual responses. J Psychol 39:3-60.
Abramson HA, Rolo A, Sklarofksy B, Stache J (1960a) Production of cross-tolerance to psychosis-producing doses of Iysergic acid diethylamide and psilocybin. J Psychol 49:151-154.
Abramson HA, Rolo A, Stache J (1960b) Lysergic acid diethylamide (LSD-25) antagonists: Chlorpromazine. J Neuropsychiatry 1:307-310.
Abuzzahab FS Sr, Anderson BJ (1971) A review of LSD treatment in alcoholism. Int Pharmacopsychiatry 6:223-235.
Acord LD, Barker DD (1973) Hallucinogenic drugs and cerebral deficit. J Nerv Ment Dis 156:281-283.
Aghajanian GK, Bing OHL (1964) Persistence of Iysergic acid diethylamide in the plasma of human subjects. Clin Pharmacol Ther 5:611-614.
Aghajanian GK, Foote WE, Sheard MH (1968) Lysergic acid diethylamide: Sensitive neuronal units in the midbrain raphe. Science 161:706 708.
Ahn H, Makman M (1979) Interaction of LSD and other hallucinogens with dopamine-sensitive adenylate cyclase in pnmate brain. Brain Res 162:77 88.
Alarcon RD, Dickinson WA, Dohn HH (1982) Flashback phenomena: Clinical and diagnostic dilemmas. J Nerv Ment Dis 170:217-233.
Anonymous (1970) Controlled Substances Act, Public L No. 91-153, 21 USC 801 et seq.
Anonymous (1986) Controlled Substances Analog Enforcement Act of 1986, Public L No. 99-570, 21 USC 813.
Anonymous (1993) Religious Freedom Restoration Act of 1993, Public L No. 103-141, 42 USC 2000bb.
Appel JB, Freedman DX (1968) Tolerance and cross-tolerance among psychotomimetic drugs. Psychopharmacology 13:267-274.
Arnt J, Hyttel J (1989) Facilitation of 8-OHDPAT-induced forepaw treading of rats by the 5-HT2 agonist DOI. Eur J Pharmacol 161:45-51.
Axelrod J (1962) The enzymatic N-methylation of serotonin and other amines. J Pharmacol Exp Ther 138:28-33.
Belleville R (1956) MMPI score changes induced by Iysergic acid diethylamide. J Clin Psychol 12:279-282.
Bender L (1966) D-Lysergic acid in the treatment of the biological features of childhood schizophrenia. Dis Nerv Sys 22 (Suppl):43-46.
Blacker KH, Jones R, Stone G, Pfefferbaum D (1968) Chronic users of LSD: The "acidheads." Am J Psychiatry 125:341-351.
Blumenfield M, Glickman L (1967) Ten months expenence with LSD users admitted to county psychiatric receiving hospital. NY State JMed 67:1849-1853.
Boszormenyi Z, Szara SI (1958) Dimethyltryptamine experiments with psychotics. J Ment Sci 104:445 453.
Bowers M Jr, Freedman DX (1966) "Psychedelic" experiences in acute psychoses. Arch Gen Psychiatry 15:240-248.
Bracha HS, Wolkowitz OM, Lohr JB, Karson CN, Bigelow LB (1989) High prevalence of visual hallucinations in research subjects with chronic schizophrenia. Am J Psychiatry 146:526 528.
Braff DL, Geyer MA (1990) Sensorimotor gating and schizophrenia. Human and animal model studies. Arch Gen Psychiatry 47: 181-188.
Buckholtz NS, Zhou D, Freedman DX, Potter W (1990) Lysergic acid diethylamide (LSD) administration selectively downregulates serotonino receptors in rat brain. Neuropsychopharmacology 3: 137-148.
Burt DR, Creese I, Snyder SH (1976) Properties of l lH]haloperidol and [¢H]dopamine binding associated with dopamine receptors in calf brain membranes. Mol Pharmacol 12:800-812.
Busch AK, Johnson WC (1950) L.S.D. 25 as an aid in psychotherapy. Dis Nerv Sys 11:241-243.
Cerletti A, Doepfner W (1958) Comparative study on the serotonin antagonism of amide derivatives of Iysergic acid and of ergot alkaloids. JPharmacol Ezp Ther 122:124-136.
Cerletti A, Rothlin E (1955) Role of 5-hydroxytryptamine in mental diseases and its antagonism by Iysergic acid derivatives. Nature 176:785 786.
Cervoni P, Bertino JR, Geiger LE (1963) Medullary vagal effects of d-lysergic acid diethylamide in the decerebrate cat. Nature 199:700-701.
Chandler AL, Hartman MA (1960) Lysergic acid diethylamide (LSD25) as a facilitating agent in psychotherapy. Arch Gen Psychiatry 2:286 299.
Cheek FE, Holstein CM (1971) Lysergic acid diethylamide tartrate (LSD-25) dosage levels, group differences, and social interaction. J Nerv Ment Dis 153:133-147.
Cheek FE, Osmond H, Sarett M, Albahary RS (1966) Observations regarding the use of LSD-25 in the treatment of alcoholism. JPsychopharmacol 1:56 74.
Cholden LS, Kurland AA, Savage C (1955) Clinical reachons and tolerance to LSD in chronic schizophrenia. J Nerv Ment Dis 122:211-221.
Cohen MM, Marinello MJ, Back N (1967) Chromosomal damage in human leukocytes induced by Iysergic acid diethylamide. Science 155:1417-1419.
Cohen S (1960) Lysergic acid diethylamide: Side effects and complications. J Nerv Ment Dis 130:30 40.
Conn PJ, Sanders-Bush E (1986) Regulation of serotonin-stimulated phosphoinositide hydrolysis: Relation to the 5-HT2 site. J Neurosci 6:3669-3675.
Corbett L, Christian ST, Monn RD, Benington F, Smythies JR (1978) Hallucinogenic N-methylated indolealkylamines in the cerebrospinal fluid of psychiatric and control populations. Br J Psychiatry 132: 139-144.
Culver CM, King FW (1974) Neuropsychological assessment of undergraduate marijuana and LSD users. Arch Gen Psychiatry 31:707-711.
Cunningham KA, Appel JB (1987) Neuropharmacological reassessment of the discriminative stimulus properties of d-lysergic acid diethylamide (LSD). Psychopharmacology 91:67-73.
Dahlberg CC, Mechaneck R, Feldstein S (1968) LSD research: The impact of lay publicity. Am J Psychiatry 125:685-689.
Day J (1957) The role and reaction of the psychiatrist in LSD therapy. J Nerv Ment Dis 125:437 438.
Denber HCB (1958) Studies on mescaline Vlll: Psychodynamic observations. Am JPsychiatry 115:239-244.
Dishotsky Nl, Loughman WD, Mogar RE, Lipscomb WR (1971) LSD and genetic damage. Science 172:431 440.
Dobkin de Rios M (1984) Hallucinogens: Cross-cultural perspectives. Albuquerque NM: University of New Mexico Press.
Eisner BG, Cohen S (1958) Psychotherapy with Iysergic acid diethylamide. J Nerv Ment Dis 127:528 539.
Faillace LA, Vourlekis A, Szara Sl (1967) Clinical evaluation of some hallucinogenic tryptamine derivatives. J Nerv Ment Dis 145:306 313.
Fernandez JW (1982) Bwiti. An ethnography of the religious imagination in Africa. Princeton, NJ: Princeton University Press.
Fink M, Simeon J, Haque W, Itil T (1966) Prolonged adverse reactions to LSD in psychotic subjects. Arch Gen Psychiatry 15:450 454.
Frank E, Kupfer DJ, Perel JM, Cornes C, Jarrett DB, Mallenger AG, Thase ME, McEachran AB, Grochocinski VJ (1990) Three-year outcomes for maintenance therapies in recurrent depression. Arch Gen Psychiatry 47:1093-1099.
Franzen F, Gross H (1965) Tryptamine, N,N-dimethyltryptamine, N,Ndimethyl-5-hydroxytryptamine and 5-methoxytryptamine in human blood and urine. Nature 206:1052.
Freedman AM, Ebin EV, Wilson EA (1962) Autistic schizophrenic children. An experiment in the use of D-lysergic acid diethylamide (LSD-25). Arch Gen Psychiatry 6:203-213.
Freedman DX (1961) Effects of LSD-25 on brain serotonin. JPharmacol Exp Ther 134:160-166.
Freedman DX, Aghajanian GK, Ornitz EM, Rosner BS (1958) Patterns of tolerance to Iysergic acid diethylamide and mescaline in rats. Science 127:1173 1174.
Frosch WA (1969) Patterns of response to self administration of LSD. In RE Meyer (Ed), Adverse reactions to hallucinogenec drugs. Rockville, MD: US Department of Health, Education, and Welfare.
Frosch WA Robbins E, Stern M (1965) Untoward reactions to Iysergic acid diethylamide (LSD) resulting in hospitalization. N Engl J Med 273:1235-1239.
Gaddum JH, Hameed KA (1954) Drugs which antagonize 5-hydroxytryptamine. Br J Pharmacol 9:240-248.
Gillin JC, Kaplan J, Stillman R, Wyatt RJ (1976) The psychedelic model of schizophrenia: The case of N,N-dimethyltryptamine. Am JPsychiatry 133:203-208.
Ginzel KH, Mayer-Gross W (1956) Prevention of psychological effects of d-lysergic acid diethylamide (LSD 25) by its 2-brom derivative (BOL 148). Nature 178:210.
Glass G, Bowers MB Jr (1970) Chronic psychoses associated with long-term psychotomimetic drug abuse. Arch Gen Psychiatry 23:97-103.
Glennon RA, Rosecrans JA, Young R (1983) Drug-induced discrimination: A description of the paradigm and a review of its specific application to the study of hallucinogenic agents. Med Res Rev 3:289-340.
Glennon RA, Titeler M, McKenney J (1985) Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic drugs. Life Sci 35:2505-2511.
Grigsby JP (1987) The use of imagery in the treatment of posttraumatic stress disorder. J Nerv Ment Dis 175:55-59.
Grinspoon L, BakalarJB (1979) Psychedelie drugs reconsidered. New York: Basic Books.
Grof S, Goodman LE, Richards WA, Kurland AA (1973) LSD-assisted psychotherapy in patients with terminal cancer. Int Pharmacopsychiatry 8:129-144.
Haertzen CA, Hickey JE (1987) Addiction Research Center Inventory (ARCI): Measurement of euphoria and other drug effects. In JA Bozarth (Ed), Methods of assessing the reinforcing properties of abused drugs. New York: Springer-Verlag.
Haertzen CA, Hill HE, Belleville RE (1963) Development of the Addiction Research Center Inventory (ARCI): Selection of items that are sensitive to the effects of various drugs. Psychopharmacology 4:155-166.
Haubrich DR, Wang PFL (1977) N,N-Dimethyltryptamine lowers rat brain acetylcholine and dopamine. Brain Res 131:158-161.
Hekimian LJ, Gershon S (1968) Characteristics of drug abusers admitted to a psychiatnc hospital. JAMA 205:115-130.
Hensala JD, Epstein LJ, Blacker KH (1967) LSD and psychiatnc inpatients. Arch Gen Psychiatry 16:554-559.
Hermle L, Funfgeld M, Oepen G, Botsch H, Borchardt D, Gouzoulis E, Fehrenbach RA, Spitzer M (1992) Mescaline-induced psychopathological, neuropsychological, and neurometabolic effects in normal subjects: Experimental psychosis as a tool for psychiatnc research. Biol Psychiatry 32:976-991.
Hermle L, Spitzer M, Borchardt D, Kovar Karl-A, Gouzoulis E (1993) Psychological effects of MDE in normal subjects. Neuropsychopharmacology 8:171-176.
Hoch PH (1956) Studies in routes of administration and counteracting drugs. In L Cholden (Ed), Lysergic acid diethylamide and mescaline in experimental psychiatry. New York: Grune & Stratton.
Hoch PH, Cattell JP, Pennes HH (1952) Effects of mescaline and Iysergic acid diethylamide (d-LSD-25). Am J Psychiatry 108:579-584.
Hollister LE (1962) Drug-induced psychoses and schizophrenic reactions: A critical comparison. Ann NYAcad Sci 96:80-92.
Hollister LE, Degan RO, Schultz SD (1962) An experimental approach to facilitation of psychotherapy by psychotomimetic drugs. JMent Sci 108:99-100.
Hollister LE, Shelton J, Krieger G (1969) A controlled companson of Iysergic acid diethylamide (LSD) and dextroamphetamine in alcoholics. Am JPsychiatry 125:1352-1357.
Honta A, Hamilton AE (1969) Lysergic acid diethylamide: Dissociation of its behavioral and hyperthermic actions by DL-o-methyl-ptyrosine. Science 164:78-79.
Horowitz MJ (1969) Flashbacks: Recurrent intrusive images after the use of LSD. Am J Psychiatry 126:565-569.
Hoyer D, Schoeffter P (1991) 5-HT receptors: Subtypes and second messengers.JReceptRes 11:197-214.
Isbell H (1959) Comparison of the reactions induced by psilocybin and LSD-25 in man. Psychopharmacology 1:29-38.
Isbell H, Belleville RE, Fraser HF, Wikler A, Logan CR (1956) Studies on Iysergic acid diethylamide (LSD-25). 1. Effects in former morphine addicts and development of tolerance during chronic intoxication. Arch Neurol Psychiatry 76:468 478.
Isbell H, Logan CR (1957) Studies on the diethylamide of Iysergic acid (LSD-25).11. The effects of chlorpromazine, azacyclonol, and reserpine on the intensity of the LSD reaction. Arch Neurol Psychiatry 77:350-358.
Isbell H, Logan CR, Miner EJ (1959a) Studies on Iysergic acid diethylamide (LSD-25). III. Attempts to attenuate the LSD-reaction in man by pretreatment with neurohumoral blocking agents. Arch Neurol Psychiatry 81:20 27.
Isbell H, Miner EJ, Logan CR (1959b) Relationships of psychotomimetic to anti-serotonin potencies of congeners of Iysergic acid diethylamide (LSD-25). Psychopharmacology 1:20 28.
Jacobson CB, Berlin CM (1972) Possible reproductive detriment in LSD users. JAMA 222:1367-1373.
Johnson FG (1969) LSD in the treatment of alcoholism. Am JPsychiatry 126:481-487.
Johnston LD, O'Malley PM, Bachman JG (1993) National Survey Results on Drugs Use from Monitoring the Future Study, 19751992, Vol I. Secondary school students. Rockville, MD: National Institute on Drug Abuse.
Kahn R, Wetzler S (1991) m-Chlorophenylpiperazine as a probe of serotonin function. Biot Psychiatry 30:1139-1166.
Kast EC, Collins VJ (1964) Lysergic acid diethylamide as an analgesic agent. Anesth Analg 43:285 291.
Ketchum JS, Sidell FR, Crowell EB Jr, Aghajanian GK, Hayes AH Jr (1973) Atropine, scopolamine, and ditran: Comparative pharmacology and antagonists in man. Psychopharmacology 28:121-145.
Koerner J, Appel JB (1983) Psilocybin as a discriminative stimulus: Lack of specificity in an animal behavioral model for "hallucinogens." Psychopharmacology 76:130-135.
Kosten TA, Kosten TR (1991) Pharmacological blocking agents for treating substance abuse. J Nerv Ment Dis 179:583 592.
Krupnick JL, Pincus HA (1992) The cost-effectiveness of psychotherapy: A plan for research. Am J Psychiatry 149:1295 1305.
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199-214.
Krystal JH, Seibyl JP, Price LH, Woods SW, Heninger GR, Aghajanian GK, Charney DS (1993) mChlorophenylpiperazine effects in neuroleptic-free schizophrenic patients. Evidence implicating serotonergic systems in the positive symptoms of schizophrenia. Arch Gen Psychiatry 50:624-635.
Kurland M, Savage C, Pahnke WN, Grof S, Olsson JE (1971) LSD in the treatment of alcoholics. Pharmatopsychiat Neuro-Psychopharmalcol 4:83-94.
Kurland AA, Unger S, Shaffer JW, Savage C (1967) Psychedelic therapy using LSD in the treatment of the alcoholic patient: A preliminary report. Am JPsychiatry 123:1202-1209.
La Barre W (1989) The peyote cult (5th ed). Norman, OK: University of Oklahoma Press.
Langs RJ, Barr HL (1968) Lysergic acid diethylamide (LSD-25) and schizophrenic reactions. A comparative study. J Nerv Ment Dis 147:163-172.
Leary T (1968) High priest. New York: World Publishing.
Leary T, Metzner R (1967-1968) Use of psychedelic drugs in pnsoner rehabilitation. Br J Sociol 2:27-51.
Lee MA, Meltzer HY (1991) Neuroendocrine responses to serotonergic agents in alcoholics. Biol Psychiatry 30:1017-1030.
Linton HB, Langs RJ (1962) Subjective reactions to Iysergic acid diethylamide (LSD-25). Arch Gen Psychiatry 6:352-368.
Lister MB, Grob CS, Bravo GL, Walsh RN (1992) Phenomenology and sequelae of 3,4-methylenedioxymethamphetamine use. J Nerv Ment Dis 180:345-356.
Ludwig AM (1985) Cognitive processes associated with a "spontaneous" recovery from alcoholism. J Stud Alcohol 46:53-58.
MacDonald JM, Galvin JAV (1956) Experimental psychotic states. Am J Psychiatry 112:970-976.
MacLean JR, MacDonald DC, Byrne UP, Hubbard AM (1961) The use of LSD-25 in the treatment of alcoholism and other psychiatric problems. Q J Stud Alcohol 22:34 45.
Malleson N (1971) Acute adverse reactions to LSD in clinical and experimental use in the United Kingdom. Br J Psychiatry 118:229-230.
McGee R (1984) Flashbacks and memory phenomena. J Nerv Ment Dis 172:273-278.
McGlothlin WH, Arnold DO (1971) LSD revisited (a ten-year followup of medical LSD use). Arch Gen Psychiatry 24:35 49.
McGlothlin WH, Arnold DO, Freedman DX (1969) Organicity measures following repeated LSD ingestion. Arch Gen Psychiatry 21:704-709.
McKenna DJ, Nazarali AJ, Himeno A, Saavedra JM (1989) Chronic treatment with (+)DOI, a psychotomimetic 5-HT2 agonist, downregulates 5-HT2 receptors in rat brain. Neuropsychopharmacology 2:81-87.
Meert TF, de Haes P, Janssen PAJ (1989) Risperidone (R 64 766), a potent and complete LSD antagonist in drug discrimination by rats. Psychopharmacology 97:206 212.
Meltzer HY (1989) Clinical studies on the mechanism of action of clozapine: The dopamine-serotonin hypothesis of schizophrenia. Psychopharmacol ogy 99: S 18-S27.
Meltzer HY, Wiita B, Tncou BJ, Simonovic M, Fang VS, Manov G (1982) Effects of serotonin precursors and serotonin agonists on plasma hormone levels. In BT Ho, JC Schoolar, E Usdin (Eds), Serotonin in biological psychiatry. New York: Raven.
Mita T, Hanada S, Nishino N, Kuno T, Nakai H, Yamadori T, Mizoi Y, Tanaka C (1986) Decreased serotonin S2 and increased dopamine D2 receptors in chronic schizophrenics. Biol Psychiatry 21:1407-1414.
Mitchell SW (1896) The effects of Anhalonium lewinf i (the mescal button). Br Med J 2:1625 1628.
Muneer RS (1978) Effects of LSD on human chromosomes. Mutat Res 51:403 410.
Murphree HB (1962) Quantitative studies in humans on the antagonism of Iysergic acid diethylamide by chlorpromazine and phenoxybenzamine. Clin Pharmacol Ther 3:314 320.
Murphy DL, Lesch Klaus-P, Aulakh CS, Pigott TA (1991) Serotoninselective arylpiperazines with neuroendocrine, behavioral, temperature, and cardiovascular effects in humans. Pharmacol Rev 43:527-552.
Murray RM, Oon MCH, Rodnight R, Birley JLT, Smith A (1979) Increased exeretion of dimethyltryptamine and certain features of psychosis. A possible association. Arch Gen Psychiatry 36:644-649.
National Institute on Drug Abuse (1991) National household survey on drug abuse. Populations estimates 1990. Rockville, MD: U.S. Department of Health and Human Services.
Nelson CC, Foltz RL (1992) Chromatographic and mass spectrometnc methods for determination of Iysergic acid diethylamide (LSD) and metabolites in body fluids. J Chromatogr Biomed Appl 580:97-109.
Nichols DE (1987) Discovery of novel psychoactive drugs: Has it ended? J Psychoactive Daug 19:33 37.
Nichols DE, Oberlender RA, McKenna DJ (1991) Stereochemical aspects of hallucinogenesis. In R Watson (Ed), Biochemistry and physiology of substance abuse. Boca Raton, FL: CRC Press.
Nielson EB (1985) Discriminative stimulus properties of Iysergic acid diethylamide in the monkey. J Pharmacol Exp Ther 234:244-249.
O'Brien CP, Jones RT (1994) Methodological issues in the evaluation of LSD or other hallucinogens as an adjunct in psychotherapy. In A Pletscher (Ed), Fifty years of LSD: State of the art and perspectives of hallucinogens. London: Parthenon.
Pahnke WN, Kurland AA, Unger S, Savage C, Grof S (1970) The experirmental use of psychedelic (LSD) psychotherapy. JAMA 212:1856 1863.
Pare CMB, LaBrosse EH (1963) A further study of alleviation of the psychological effects of LSD in man by pretreatment with 5-hydroxytryptophan. J Psychiat Res 1:271-277.
Peroutka SJ, Snyder SH (1979) Multiple serotonin receptors: Differential binding of [ lH]5-hydroxytryptamine, [lH]lysergic acid diethylamide and [ lH]spiroperidol. Mol Pharmacol 16:687-690.
Pope HJr, Ionescu-Pioggia M, Aizley H, Varma D (1990) Drug use and life style among college undergraduates in 1989: A comparison with 1969 and 1978. Arn J Psychiatry 147:998 1001.
Rainey JM Jr, Aleem A, Ortiz A, Yeragani V, Pohl R, Berchou R (1987) A laboratory procedure for the induction of flashbacks. Am J Psychiatry 144:1317-1319.
Resnick O, Krus DM, Raskin M (1964) LSD-25 action in normal subjects treated with a monoamine oxidase inhibitor. Life Sci 3: 1207-1214.
Resnick O, Krus DM, Raskin M (1965) Accentuation of the psychological effects of LSD-25 in normal subjects treated with reserpine. Life Sci 4:1433 1437.
Rinkel M, Atwell CR, DiMascio A, Brown J (1960) Experimental psychiatry. V. Psilocybine, a new psychotogenic drug. N Engl J Med 262:295-297.
Rivier L, Lindgren Jan-E (1972) "Ayahuasca," the South American hallucinogenic drink: An ethnobotanical and chemical investigation. Econ Bot 26:101-129.
Rosenberg DE, Isbell H, Miner EJ, Logan CR (1964) The effect of N,N-dimethyltryptamine in human subjects tolerant to Iysergic acid diethylamide. Psychopharmacology 5:217-227.
Saavedra JM, Axelrod J (1972) Psychotomimetic N-methylated tryptamines: Formation in brain in vivo and in vitro. Science 175: 1365-1366.
Saigh PA (1989) The use of an in vitro flooding package in the treatment of traumatized adolescents. J Dev Behav Pediatr 10:17-21.
Sai-Halasz A (1963) The effect of MAO inhibition on the experimental psychosis induced by dimethyltryptamine. Psychopharmacology 4:385-388.
Savage C (1952) Lysergic acid diethylamide (LSD-25). A clinical-psychological study. Am J Psychiatry 108:896 900.
Savage C, McCabe OL (1973) Residential psychedelic (LSD) therapy for the narcotic addict. A controlled study. Arch Gen Psychiatry 28:808-814.
Schwartz CJ (1967) Paradoxical responses to chlorpromazine after LSD. Psychosomatics 8:210-211.
Shagass C, Bittle RM (1967) Therapeutic effects of LSD: A follow-up study. J Nerv Ment Dis 144:471-478.
Siegel RK (1978) Phencyclidine and ketamine intoxication: A study of four populations of recreational users. In RC Peterson, RC Stillman (Eds), Phencyclidine (PCP) abuse: An appraisal. NIDA Research Monograph Series 21. Rockville, MD: Department of Health, Education and Welfare.
Simmons JQ 111, Leiken SJ, Lovaas Ol, Schaeffer B, Perloff B (1966) Modification of autistic behavior with LSD-25. Am J Psychiatry 122:1201-1211.
Sitaram BR, Lockett L, Talomsin R, Blackman GL, McLeod WR (1987) In vivo metabolism of 5-methoxy-N,N-dimethyltryptamine and N,Ndimethyltryptamine in the rat. Biochem Pharmacol 36:1509-1512.
Smart RG, Storm T, Baker EFW, Solursh L (1966) A controlled study of Iysergide in the treatment of alcoholism. l. The effects on drinking behavior. Q J Stud Alcohol 27:469-482.
Smith C (1958) A new adjunct to the treatment of alcoholism: The hallucinogenic drugs. Q J Stud Alcohol 19:406 417.
Snyder SH, Faillace LA, Hollister L (1967) 2,5-Dimethoxy-4-methylamphetamine (STP): A new hallucinogenic drug. Science 158:669-670.
Snyder SH, Faillace LA, Weingartner H (1968) DOM (STP), a new hallucinogenic drug, and DOET: Effects in normal subjects. Am J Psychiatry 125:357 364.
Spencer D Jr, Glaser T, Traber J (1987) Serotonin receptor subtype mediation of the interoceptive discriminative stimuli induced by 5-methoxy-N,N-dimethyltryptamine. Psychopharmacology 93: 158-166.
Stafford P (1992) Psychedelics encyclopedia (3rd ed). Berkeley, CA: Ronin Press.
Stoll WA (1947) Lysergsaure-diathylamid, ein Phantasticum aus der Mutterkorngruppe. Schweiz Arch Neurol Psychiat 60:279-323.
Stolz J, Marsden C, Middlemiss D (1983) Effect of chronic antidepressant treatment and subsequent withdrawal on [3H]5-hydroxytryptamine and [3H]spiperone binding in rat frontal cortex and serotonin receptor mediated behavior. Psychopharmacology 80:150-155.
Strassman RJ (1984) Adverse reactions to psychedelic drugs. A review of the literature. J Nerv Ment Dis 172:577-595.
Strassman RJ (1991) Human hallucinogenic drug research in the United States: A present-day case history and review of the process. J Psychoactive Drug 23:29-38.
Strassman RJ, Qualls CR (1994) Dose-response study of N,N-dimethyltryptamine in humans: 1. Neuroendocrine, autonomic, and cardiovascular effects. Arch Gen Psychiatry 51:85-97.
Strassman RJ, Qualls CR, Uhlenhuth EH, Kellner R (1994) Doseresponse study of N,N-dimethyltryptamine in humans: 11. Subjective effects and preliminary results of a new rating scale. Arch Gen Psychiatry 51:98 108.
Szara SI (1957) The comparison of the psychotic effects of tryptamine derivatives with the effects of mescaline and LSD-25 in self-experiments. In W Garattini, V Ghetti (Eds), Psychotropic drugs. New York: Elsevier.
Taylor RL, Maurer JI, Tinklenberg JR (1970) Management of "bad trips" in an evolving drug scene. JAMA 213:422 425.
Turner WJ Jr, Almudevar M, Merlis S (1959) Chemotherapeutic tnals in psychosis: III. Addendum. 2-Brom-D-lysergic acid diethylamide (BOL). Am JPsychiatry 116:261-262.
Ungerleider JT, Fisher DD, Goldsmith SR, Fuller M, Forgy E (1968) A statistical survey of adverse reactions to LSD in Los Angeles County. Am J Psychiatry 125:352-357.
Vardy MM, Kay SF (1983) LSD psychosis or LSD-induced schizophrenia? A multimethod inquiry. Arch Gen Psychiatry 40:877-883.
Vollenweider FX (1994) Evidence of a cortical-subcortical dysbalance of sensory information processing during altered states of consciousness using PET and FDG. In A Pletscher (Ed) Fifty years of LSD: State of the art and perspectives of hallucinogens. London: Parthenon.
Wesson DR, Smith DE (1976) An analysis of psychedelic drug flashbacks. Am J Drug Alcohol Abuse 3:425 438.
Woolley DW, Shaw EN (1954) A biochemical and pharmacological suggestion about certain mental disorders. Science 119:587-588.
Wyatt RJ, Saavedra JM, Axelrod J (1973) A dimethyltryptamine-forming enzyme in human blood. Am J Psychiatry 130:754-760.
Young BG (1974) A phenomenological comparison of LSD and schizophrenic states. Br J Psychiatry 124:64-74.

Ibogaine in the treatment of chemical dependence disorders: clinical perspectives

Ibogaine in the treatment of chemical dependence disorders: clinical perspectives
H. S. Lotsof

The primary purpose of this paper is to provide general information to the clinician who will be using the Lotsof Proceduresm (Goutarel, 1993) developed by NDA International, Inc. in which Ibogaine is administered to treat chemical dependence disorders. This is a preliminary report. The patient base upon which my conclusions have been made totals thirty-five treatment episodes. All clinical observations conducted after 1963 have been made on patients treated outside of the United States.

Ibogaine is not a substitute for narcotics or stimulants, is not addicting and is given in a single administration modality (SAM). It is a chemical dependence interrupter. Retreatment may occasionally be needed until the people being treated with Ibogaine are able to extinguish certain conditioned responses related to drugs they abuse. Early data suggests that for many patients, a period of approximately two years of intermittent treatments may be required to attain the goal of long-term abstinence from narcotics and stimulants. The majority of patients treated with Ibogaine remain free from chemical dependence for a period of three to six months after a single dose. Approximately ten percent of patients remain free of chemical dependence for two or more years from a single Ibogaine treatment. An equal percentage return to drug use within two weeks after treatment. Multiple administrations of Ibogaine over a period of time are generally more effective in extending periods of abstinence. It is noteworthy that twenty-nine of the thirty-five patients successfully treated with Ibogaine had numerous unsuccessful experiences with other treatment modalities.

A Brief History
Ibogaine is a naturally occurring alkaloid found in Tabernanthe iboga and other plant species of Central West Africa. It was first reported to be effective in interrupting opiate narcotic dependence disorders in U.S. patent 4,499,096 (Lotsof, 1985), cocaine dependence disorders, U.S. patent 4,587,243 (Lotsof, 1986) and poly-drug dependence disorders, U.S. patent 5,152,994 (Lotsof, 1992). The initial studies demonstrating Ibogaine's effects on cocaine and heroin dependence were conducted in a series of focus group experiments by H. S. Lotsof in 1962 and 1963. Additional data on the clinical aspects of Ibogaine in the treatment of chemical dependence were reported by Kaplan (1993), Sisko (1993), Sanchez-Ramos & Mash (1994), and Sheppard (1994).
Prior to Ibogaine's evaluation for the interruption of various chemical dependencies, the use of Ibogaine was reported in psychotherapy by Naranjo (1969, 1973) and at the First International Ibogaine Conference held in Paris (Zeff, 1987). The use of Ibogaine-containing plants has been reported for cen-turies in West Africa in both religious practice and in traditional medicine (Fernandez, 1982; Gollnhofer & Sillans 1983, 1985). An overview of the history of Ibogaine research and use was published by Goutarel et al. (1993).

Claims of efficacy in treating dependence to opiates, cocaine, and alcohol in human subjects were supported in preclinical studies by researchers in the United States, the Netherlands and Canada. Dzoljic et al. (1988) were the first researchers to publish Ibogaine's ability to attenuate narcotic withdrawal. Stanley D. Glick et al. (1992) at Albany Medical College published original research and a review of the field concerning the attenuation of narcotic withdrawal. Maisonneuve et al. (1991) determined the pharmacological interactions between Ibogaine and morphine, and Glick et al. (1992) reported Ibogaine's ability to reduce or interrupt morphine self-administration in the rat. Woods et al. (1990) found that Ibogaine did not act as an opiate, and Aceto et al. (1991) established that Ibogaine did not precipitate withdrawal signs or cause dependence.

Cappendijk and Dzoljic (1993) published Ibogaine's effect in reducing cocaine self-administration in the rat. Broderick et al. (1992) first published Ibogaine's ability to reverse cocaine-induced dopamine increases and later reported on Ibogaine's reduction of cocaine-induced motor activity and other effects (1994). Broderick et al.'s research supported the findings of Sershen et al. (1992), that Ibogaine reduced cocaine-induced motor stimulation in the mouse. Sershen (1993) also demonstrated that Ibogaine reduced the consumption of cocaine in mice. Glick (1992) and Cappendijk (1993) discovered in the animal model that multiple administrations of Ibogaine over time were more effective than a single dose in interrupting or attenuating the self-administration of morphine and cocaine, supporting Lotsof's findings in human subjects (1985).

Popik et al. (1994) determined Ibogaine to be a competitive inhibitor of MK-801 binding to the NMDA receptor complex. MK-801 has been shown to attenuate tolerance to opiates (Trujillo & Akil 1991) and alcohol (Khanna et al. 1993). MK-801 has also shown to blockade reverse tolerance of stimulants (Karler et al. 1989). Ibogaine's effects on dopamine and the dopamine system (dopamine is a substance hypothesized to be responsible for reinforcing pleasurable effects of drugs of abuse) were found by Maisonneuve et al. (1991), Broderick et al. (1992) and Sershen et al. (1992). Ibogaine binding to the kappa opiate receptor was reported by Deecher et al. (1992). Thus we begin to see a broad spectrum of mechanisms by which Ibogaine may moderate use of substances as diverse as opiate narcotics, stimulants and alcohol.

Clinical Practice
The effects of Ibogaine treatment are viewed in three categories: acute, intermediate and long-term. The acute and intermediate effects have sometimes been referred to as the effects and aftereffects. The two major effects of Ibogaine are the ability to interrupt narcotic and stimulant withdrawal, and the attenuation or elimination of the craving to continue to seek and use opiates, stimulants and alcohol (Lotsof 1985, 1986, 1989). Knowledge concerning the use of Ibogaine in treating alcohol dependence is limited to: 1) a single alcohol-only dependent patient, 2) the atten-uation and, in some cases, cessation of alcohol use in persons treated for poly-drug dependence disorders. Ibogaine's ability to treat nicotine dependence (Lotsof, 1991) has been observed in poly-drug dependent subjects treated primarily for opiate and/or cocaine use. There are some general considerations in reviewing the use of Ibogaine. The primary obligations of the treatment team are four-fold: 1) to earn the trust of the patient, 2) to maintain the comfort of the patient, 3) to assist the patient in interrupting their chemical dependence and 4) to supply the psychosocial support network needed by the majority of patients to enable them to develop a sense of personal accomplishment and the ability to function as productive members of society. This is a process the Dutch treatment community refers to as normalization. In the Lotsof Proceduressm, for which a manual is now being prepared, the sense of conflict seen in most treatment modalities between the doctor and patient over the immediate cessation of drug use does not exist. The patients have been allowed, if narcotic-dependent, to continue their use of narcotics until a certain time prior to treatment with Ibogaine. There is no conflict over opiate use before treatment, as our position has been that Ibogaine will either work to interrupt chemical dependence or it will not. Patients dependent on stimulants are not maintained on stimulants and this has not created a problem for the patients or the medical staff. Prior to our conducting Ibogaine treatments in hospitals, addicted patients were allowed to use their personal supply of narcotics until the evening before treatment. However, during hospital-administered Ibogaine sessions, the narcotic-dependent patient is maintained on medications prescribed by the principal investigator during the three to five day intake process preceding their treatment with Ibogaine. Even under these circumstances, patient distrust of the medical establishment and extreme fear of going into withdrawal has resulted in the smuggling of narcotics into hospital environments. In order to protect the patient from possible overdose due to narcotics, stimulants or other drugs, a thorough physical examination is performed on all patients upon their admission to hospital environments. The examination and a search of the patient's possessions prior to treatment with Ibogaine serve two important functions. The first, is to limit the possibility of accidental overdose from hidden drugs. The second is to provide a complete understanding of the patient's physical health, since many of the people seeking treatment for chemical dependence have masked various and often numerous medical problems for years or even decades by self-medicating with illicit drugs.

Acute Effects Regimen
The acute effects of Ibogaine are dramatic. The initial reaction is usually noted within forty-five minutes after the oral administration. Full effects are generally evident within two to two and a half hours. The earliest subjective indication by patients of Ibogaine's effects is the report of a pervasive oscillating sound. The patient tends to lie down and, if asked to stand or walk, shows signs of ataxia.
The protocol for the Lotsof Procedures(sm) stipulates that the patient remain in bed with as little movement as possible from the time of Ibogaine administration. This is because nausea associated with Ibogaine use has proven to be motion-related and/or, in later stages (those longer than four hours after administration), possibly to be a psychosomatic reaction to previously repressed traumatic experiences. In addition to keeping the patient as still as possible, we use a non- phenothiazine anti-nauseant, since phenothiazines may interfere with the psychoactive properties of Ibogaine. If the patient vomits in less than two and a half hours after the administration of Ibogaine, an examination of the regurgitated material should be made to determine how much Ibogaine may have already been absorbed by the patient. A rectal infusion of Ibogaine to supplement the lost portion of the dose may be provided if it is not possible for this dose to be administered orally. The rectal administration should occur only if the patient has previously consented to this mode of dosing.

One of Ibogaine's principal effects during its first phase of action is to produce a state which emulates dreaming, except that the subject is fully awake and has the ability to respond to the treatment staff's questions. In most cases, people under the influence of a therapeutic dose of Ibogaine do not wish to speak. They prefer instead to pay close attention to the visual presentation of memories or phenomena that they are experiencing. These phenomena have been noted to have both Freudian and Jungian connotations.
The presentation of visual material is rapid. Some patients have described it as a movie run at high speed. Others describe it as a slide show, each slide containing a motion picture of a specific event or circumstance in the viewer's life. In either case, the presentation of visual material is so compressed and fast moving that distracting the patient for even a moment may interfere with the process of abreaction. Therefore, during the primary phase of Ibogaine treatment, the intrusion of the medical staff should be kept to a minimum.

Autonomic Responses
During the first through the fifth hour there is a moderate rise in blood pressure of ten to fifteen percent and, in some cases, an associated decline in the pulse rate. The most significant autonomic changes occur between one and a half and two and a half hours after administration of therapeutic doses of Ibogaine. In many cases pulse rates are elevated due to pre-administration anxiety.
On two occasions, persons with transient hypertension were treated. In one of those instances the patient's blood pressure dropped to normal levels during the primary and secondary stages of treatment. The second hypertensive exhibited little change at a 23mg/kg therapeutic dose, but showed significant changes on two occasions when provided with only a 1.6mg/kg test dose. The two 1.6mg/kg doses were supplied due to our concern over the patient's hypertension. He had been previously treated with an 18 mg/kg dose by Dutch Addict Self-Help (DASH) with no apparent negative results. This alleviated some of our concern for the patient's safety. Variation in individual patient reactions should be anticipated.

Female Patient Safety
One 24-year-old female patient treated with Ibogaine for chemical dependence died from undiagnosed causes in the Netherlands. Although her autopsy did not determine the cause of death, it reported Ibogaine levels of 0.75 mg/liter in blood. This level has not been seen to be toxic in animal research or in our prior human experience. Subsequent to this death and to the previously reported death of a Swiss woman who received Ibogaine during a psychotherapy session in Europe (totally unrelated to NDA's research program), the FDA excluded women from the present clinical trials taking place at the University of Miami. However, the FDA decision is contrary to the gender guidelines of the National Institutes of Health. The guidelines with regard to women call for the inclusion of women at the earliest stages of clinical trials, as this would provide the greatest determination of drug safety for women. Thirty percent of NDA International's patients have been women who have shown no negative effects from taking Ibogaine either during or after treatment. However, considering all of the circumstances, the Procedure should be administered only in a hospital or clinic with the patient under continuous staff observation and electronic monitoring.
An ongoing international research program is developing evidence to determine a hypothesis for the cause of death of the woman in the Netherlands. We are additionally seeking Swiss government cooperation concerning the death of the Swiss woman. The results of this research may facilitate either an exclusion criteria or an antidote allowing Ibogaine safely to treat chemical dependence in women.

Cognitive Evaluation
During the second phase of Ibogaine's action in the Lotsof Procedures, the patient experiences the intellectual evaluation of his or her previous life experiences and decisions. This occurs after the visualization phase, which generally ends abruptly in three to five hours. However, individual reactions and variations are the norm and not the exception within the parameters of the Procedure.
When various decisions were made by the patient in the past, those decisions appeared to be the only options available at the time. However, due to Ibogaine's ability to catalyse the reevaluation of one's life, actions and behavior, it is possible for patients to understand that alternatives to their original decisions were available. This knowledge appears to allow the patient to modify their current behavior and cease their drug dependence.

Behavioral Immobility
During the periods of visualization, and extending into the stage of cognitive evaluation, patients will demonstrate a state of behavioral immobility (Depoortere, 1987). Brain wave patterns associated with dreaming and sleep, but distinct from those states, are represented by rhythmic slow activity of 4-6 Hz. These EEG patterns are associated with a state characterized by a lack of movement. Some early observers of the Lotsof Proceduressm (Kaplan, personal communication, 1990) initially believed that the condition represented paralysis, but when patients were asked to stand and move around, the patients were able to do so, albeit with difficulty.

Attenuation of Narcotic Withdrawl
One of the major acute effects experienced with Ibogaine treatment is the attenuation or elimination of narcotic withdrawal in opiate- dependent patients. This is extremely important to the narcotic-dependent patients who live in fear of going into withdrawal.
The treatment team's experience in the field is of the utmost importance in dealing with this aspect of the Procedure. Withdrawal symptoms are a combination of physical and, in many cases, psychosomatic manifestations that are anxiety-driven. Therefore, it is imperative for the medical and paramedical staff to have experience in identifying and distinguishing between these varieties of symptoms. Provided below are examples of psychosomatic withdrawal manifestations demonstrated by two of the patients treated outside the United States.

Example One

On one occasion I was called into the room by a colleague about twenty hours after Ibogaine had been administered to a twenty-five year old male heroin-dependent patient. The patient had been using approximately 1/4 gram of heroin a day, but had increased his daily intake to two grams while in the Netherlands.

I was informed that the patient was complaining of muscle spasms. I asked the patient if this was true, and he responded in the affirmative. I asked if I might see these spasms. The patient agreed, showing me the calf of his leg. He was exhibiting what appeared to be involuntary movements. I checked his pupils and observed that they were not dilated, nor was he exhibiting any other form or manifestation of withdrawal. When I turned to my colleague for discussion I noticed the patient's spasms had ceased. Upon reexamination of his calf, the spasms returned. I turned away once again, but continued to watch him and the spasms ceased again. I informed the patient that I believed the spasms to be psychosomatic in origin. I placed a pillow under the patient's calf to give it support and covered the patient with a blanket. The spasms did not occur again.

Example Two

On another occasion I received a call from a person involved with Dutch Addict Self-Help (DASH) groups who had been observing a number of treatments. She informed me that a Yugoslavian woman in her mid to late twenties had been complaining of narcotic withdrawal during Ibogaine treatment. However, the DASH observer did not believe this to be the case, as there were no observable signs of withdrawal.

When I arrived, the patient was sitting on a couch. I checked her pupils and observed they were not dilated, and asked her if she was in withdrawal. The patient said she was. "How are you in withdrawal? What are its manifestations?" I asked.
"I'm sick," she said.
I asked her if her eyes were tearing.
"Yes," she said, but her eyes were not tearing.
"Is your nose running?"
"Yes," she said, but her nose was dry.
"Do you have goose bumps?" I asked.
"Yes," she said, but I pointed out to her that she did not have goose bumps, and finally I said, "Do you have diarrhea?"
"Yes," she said, but I had no way to determine the validity of her statement.

The patient requested that I provide her with funds to return home. I told her I did not think it wise for her to leave at this time, but would give her carfare in the morning. The following day the DASH observer told me that the patient had left about four hours after I did, informing the observer as she left that she had not been sick, but had only said she was. This example should further demonstrate the im-portance of hospital administered treatments with a full medical staff of psychiatrists, neurologists, internists, therapists, nurses, peer counselors and patient advocates capable of evaluating and responding to any aspect of the patient's condition at all times.

The complaint of experiencing narcotic withdrawal after leaving the treatment environment has been reported in three cases. We have provided additional treatments six months to a year after the initial treatment to patients who were re-addicted and stated they had experienced some form of withdrawal within a week of their first Ibogaine treatment. Our working group decided to keep patients making such complaints under observation for periods equal to the number of post treatment days during which the patients stated they previously experienced withdrawal symptoms.

Our findings have been that, under the above conditions of monitoring, the reported withdrawal signs are usually symptoms of anxiety or anxiety related conditions that the patients characterized as withdrawal. These symptoms included nausea, diarrhea or increases in blood pressure in one hypertensive patient.

There have been two incidents which did not appear anxiety related, in which diarrhea occurred five to seven days after treatment in patients who had previously used one gram of heroin a day. These episodes were easily controlled with a single administration of an appropriate medication and did not occur again.

Aftereffects : Interruption of Craving
The acute interruption of craving to seek and use drugs of abuse is unique to the Lotsof Proceduressm as a treatment modality for chemical dependence disorders. This effect is generally not noticed by the patient until the principal actions of Ibogaine (visualization, cognitive evaluation, behavioral immobility and significant residual stimulation) are no longer evident and the patient has had the opportunity to sleep. The initial recognition of lack of craving is usually noticed forty-eight to seventy- two hours after Ibogaine administration. In a minority of treatments, recovery and the absence of craving may be evident to the person being treated in as little as twenty-four hours. The medical staff, on the other hand, usually notes the absence of craving in the patient in forty-five minutes to one and a half hours after Ibogaine administration. Our experience gained in recent years through the treatment of twenty persons outside the United States has shown that the majority of patients may need a series of treatments before the conditioned responses (craving) to a long history of chemical dependence can be extinguished. However, for three of these patients, a single treatment interrupted chemical dependence for a minimum of two years. The advantage of Ibogaine is that it allows patients time periods free of craving during which the psychiatrist, social worker, therapist, paraclinician and the patient often bond into a cohesive working group to ac-complish a state of long-term non-dependence by the patient to the drug(s) of abuse for which the patient is under treatment.

Psychosocial Support
All aspects of treatment for chemical dependence disorders common to other treatment modalities are common to the use of Ibogaine. The patient's characteristics in terms of psychopathology and behavior, societal accomplishments, as well as the skills of the treatment team are significant to treatment outcome.
In rare cases, when the patient already has the occupational, educational, and professional skills needed to succeed in society, the task may be somewhat easier. In cases where the patient does not have those societal skills, or lacks medical care for disorders other than chemical dependence, care and training must be provided through psychosocial support structures.

Trauma suffered by the patient during childhood appears to play an important part in the drive for love and the fear of abandonment that are common to many of the patients we have treated (Bastiaans, 1991). All psychosocial support paradigms should be available for the patient after the completion of an Ibogaine treatment. Their use should be contingent upon the evaluation of the patient's needs and progress. One of the primary differences that social workers, counselors or therapists offering psychosocial support notice in post-Ibogaine treated patients as compared to untreated subjects, is the rapidity with which the support can and must be provided to aid the patient in accomplishing goals and making decisions. Ibogaine presents a symptom-free window of opportunity, of which the patient and therapist must take advantage. One patient put it this way: Ibogaine and 12-Step (groups) both help you to get in touch with your soul. Ibogaine is like rocket fuel for that process. (Village Beat, 1990) This means moving quickly and dramatically to assist the patient to establish goals while the patient has the ability and desire to do so.

Ibogaine generally produces a receptive psychological state in the patient. This produces a relationship between the patient and the therapist which is mutually rewarding and beneficial, but requires the person providing psychosocial support to work both harder and faster than is the norm for other treatment modalities. Prior to the use of Ibogaine in the treatment of chemical dependence, it may have taken the therapist three to twenty-four months (Judd, personal communication, 1993) using traditional methods to assist the patient in reaching a state of well-being free of drug craving (Kaplan et al., 1993). This advantage that Ibogaine treatment provides enables the psychosocial support staff to assist patients in making decisions which facilitate their normalization and integration into society as self-fulfilled and productive human beings. Many of the accepted parameters of distance between the therapist and the patient are not effective in Ibogaine treatment. Patients require closer and more intensive guidance, and are generally more open to it. They require faster intervention to learn societal skills and to overcome and objectively understand various traumas experienced during their lives. Therefore, Ibogaine is not a treatment modality for clinicians whose pre- ference is to simply administer a pill or tablet and then distance themselves from their patients.

Reduction of the Need for Sleep
In all cases, Ibogaine temporally reduces the patient's need for sleep to as few as three or four hours a night. This effect may last a month or more, gradually returning to normal. Two theories have been put forth concerning the cause of this effect. One theory suggests the reduction in the need for sleep is due to the long-lasting bioavailability of Ibogaine or one of its metabolites. This is in keeping with the parmacokinetic studies conducted at the University of Miami (Mash, 1995). The second theory suggests the cause is due to the decrease in the psychological requirements for sleep associated with the necessity to dream. Evidence supporting this theory is that Ibogaine promotes an intense emulation of dreaming that lasts for many hours during its acute stage of activity. The reduction in the need for sleep is viewed by the majority of patients as a discomfort, since they have used drugs and sleep as an escape mechanism. These patients may require some mild form of sedation during the first days after treatment with Ibogaine. Normal precautions should be taken in providing sedatives to persons with a history of chemical dependence. In a minority of cases, patients have used this newly available time to advantage in their busy work schedules.

Long-Term Effects
Long-term effects are those which may be noticed from one to twenty-four months after treatment, and in some cases even longer. The following three examples illustrate this point.
Example One

A heroin-dependent couple was treated. The woman of 26 was a relatively new addict of three months while her 27-year-old husband had a history of over ten years of heroin use. At the time of their treatment, a protocol of treating one patient at a time was followed. These were early treatments and the medical and paramedical support staff were familiarizing themselves with what might be expected during such treatments.

Portions of the treatments were observed by Dr. Carlo Contoreggi, Deputy Medical Director of the Addiction Research Center of the National Institute on Drug Abuse in Baltimore and Dr. Lester Grinspoon of the Harvard School of Medicine.

The husband was treated first, and his wife was completely cooperative and helpful during his treatment. The following day, when the wife was administered her dose of Ibogaine, her husband demanded that he be allowed to leave his room and remain in bed with her. He informed the medical and paramedical staff present that unless he got his way he would create a disturbance to interfere with his wife's treatment. Rather than deal with a belligerent and angry patient, we decided it would be less harmful to let him have his way. He continuously disturbed his wife during her treatment. This resulted in a policy of treating couples simultaneously in separate rooms.

He recovered before his wife, as she had been administered Ibogaine twenty-four hours after his treatment. He complained that he was getting bedsore, was no longer able to stay in bed and asked for permission to go for a bicycle ride. Upon his leaving, his wife broke down and cried in the arms of a female paraclinician, stating she did not know if she could remain with her husband, but she was afraid he would die if she left him.

This was a concept he continuously stressed to her during their treatment.

After treatment, he followed a pattern of controlling his wife's contacts with other persons, including the treatment team, which was denied access to either of them. We later learned that they both returned to heroin use. However, three months later, the wife determined that her husband was incapable of loving himself or her and this was not the life she wanted. She stopped using heroin, enrolled in nursing school, filed divorce proceedings against her husband, and is now specializing in psychiatric nursing.

While initially she did not recognize that her decision to stop heroin use was due to her Ibogaine treatment, as the months went by, she realized that her determination to change her life was catalyzed by her experience with Ibogaine.

Example Two

A cocaine/cocaine-base dependent patient was treated with the Lotsof Procedure and experienced an acute interruption of his drug use. During his Ibogaine treatment, he had a strong impression that if he continued drug use God would punish him. He remained drug-free for about thirty days, after which he increased his drug use over the next months. He was then retreated. The dose he received proved to be inadequate due to his vomiting of the oral dose, and to a bowel movement immediately after the rectal administration of Ibogaine, which he requested to compensate for the loss of his oral dose. His drug use continued, but far below his original pretreatment levels.

About six months after his retreatment, the first Ibogaine therapy group sponsored by the International Coalition for Addict Self-Help, directed by psychotherapist Barbara Judd, CSW, was established in New York. The patient attended these sessions until fifteen months after his original treatment, when he recognized that he had to move away from his drug-infested neighborhood. Thereupon he moved to Florida.

In Florida, he has remained drug-free, even though he has access to cocaine. He is employed in the construction industry by a business with strict non-drug use guidelines that is owned and run by former drug users.

Example Three

One of the most important concepts learned by persons treated with Ibogaine is that addiction can be reversed. Persons dependent on drugs such as opiates or cocaine are not able to recognize that chemical dependence is a reversible phenomenon.

This third example is of the only chemically-dependent person from the 1962-1963 study to receive a series of Ibogaine treatments at therapeutic levels. The individual remained free of addiction for approximately three and a half years as a result of his series of treatments.

During that period he moved to California, married, and worked in pharmaceutical sales. He later lost his job and, when offered a ride back to New York, accepted it and returned to a life of minor drug dealing and use that resulted in his arrest and imprisonment.

After his release, he worked for a while as a machinist, then slowly fell back into heroin use and addiction in 1969. Luckily, this was a period when methadone programs were expanding, and he was able to enter one of the better programs run by Beth Israel Hospital. At that time, the programs were well-staffed with doctors, nurses and adequate counselors, and the patient reached a point in his life when he recognized that the life of a heroin addict was not what he wanted. It was not just the heroin, but the scene itself, wherein a human life was without value, where sometimes a human being would be murdered for two cents worth of an innocuous powder in a glassine envelope. The patient was ready to quit heroin, but was a slave to the craving to use opiates for the anxiolytic relief they provided.

Over a period of more than two years, the patient stabilized himself on methadone. He tried heroin once, two weeks after starting methadone, was satisfied with the level of blockage that methadone offered, and never used heroin again.

During the next few years the methadone programs changed. Many of the competent counselors were unable to continue in their positions due to the stress and sense of frustration in their work, a condition common in the treatment community. The Federal government placed more and more restrictions on methadone patients' freedom of movement and, though methadone is anticipated to maintain the methadone client for a period of twenty-four hours, in many cases it does not. For this patient, withdrawal signs were setting in at eighteen hours and not twenty-four. The patient began a slow detoxification process from 100mg of methadone per day that took approximately eighteen months.

The final stage of detoxification was followed by the patient's entry into University-level training, for which he had obtained a scholarship to a prominent university. At the time of the detoxification, the philosophy among methadone patients was that you could not get off methadone. However, having previously had the Ibogaine experience, the patient stated that he knew addiction was reversible. That knowledge allowed him to successfully leave addiction behind.

Current Treatments : A Self Report
The following report is from the type of patient we had been seeking for years: a medical doctor who needed to be treated with Ibogaine. The subject was chemically dependent on 600mg of Demerol a day, and had attempted to stop his drug use a number of times, without any lasting success. Our particular interest in this subject was the hope that, as a medical doctor, he might provide us with some professional insight into the results of his treatment. He kept notes and prepared a report on the four different doses he received. His report is presented below in its entirety.
This subject proved to be more sensitive to Ibogaine than any other individual in our studies conducted outside the United States, and had a full-blown experience from a 10mg/kg dose. The patient participated in a research protocol which called for an intermediate dose of 10mg/kg of Ibogaine. This dose was administered as part of a pharmacokinetic study, and was not expected to have a therapeutic effect, but it did. As part of the protocol, he was also administered a known therapeutic dose of 20mg/kg.

1st day - 100 mg (test dose #1)

I've taken my Ibogaine dose and went to bed, and stayed laying down. I felt nothing, until the medical staff arrived to do the 1 hour tests. I was surprised because in my mental measurements, I thought I had taken Ibogaine about 20 minutes earlier. When I stood up, I felt a little drowsiness, and it was difficult to walk in a straight line. I was feeling photophobia and every little noise seemed to be much louder than in reality. The sounds were very disturbing to me.

During the two hour testing, symptoms were worse. It was very difficult to walk in a straight line, and the room seemed to beat, like a heart. I felt very tired, and the only thing I wanted was to rest in bed. Each head movement seemed to make things worse.

When I stood up for the 3 hour test I felt that the symptoms were disappearing. I was very hungry and ate. After eating, I was a little nauseated. For the following hours I felt nothing, except for sensation that my mind images were richer in details than before, like a 3-D movie. I ate with no nausea, slept very well, and awakened in very good condition.

2nd day - 25 mg (test dose #2)

After this dose of Ibogaine I felt nothing different from my normal state.

3rd Day - 10 mg/kg (experimental dose)

For the first two hours I felt a little different, like I had smoked marijuana. I was very calm and relaxed and all the tension of the beginning of the procedure was gone. The room seemed to be a little different and the colors around me sharper than normal. The lights and sounds were disturbing to me, like the first time. Suddenly, with my eyes closed I began to see images that appeared in screens, exactly like TV or cinema screens. These screens were appearing in small sizes and then they would get bigger as I focused my attention on them. Sometimes they appeared small and would then begin to grow, like I was walking in their direction, and sometimes they were going from left to right, in a continuous way. The images on the screens were moving in slow motion and were very sharp and well defined. I saw trees moving with the wind, a man with bells in his hands, various landscapes with mountains and the sunset. At this time I was a little nauseated, and when the doctors asked me to stand up for some tests, I vomited. From all of the hundreds of images I saw this day, I recognized only two: the first, an image of myself as a child, static like a photo. This image began to approach me and get bigger, but something in the room happened and I opened my eyes, losing the image. The second image I recognized was one of some horses dancing in a circus. It was a TV show that I had seen two days before. The time seemed to go very quickly, because after about four hours (in my mind), they told me I had taken Ibogaine nine hours earlier! It was very difficult for me to speak in English or in Spanish. I was only able to speak in my native language. At this time the images started to appear at a slower rate and for another two hours I saw only screens with no images on them. About 10-11 hours after the beginning of the experiment they disappeared. I ate very well and stayed awake all night long, falling asleep only about 7 AM, almost 24 hours after the medication had been administered. During the night I had some insights about my life and about the things I realized I was doing wrong. I stayed all the following day very tired, sleepy, but very happy and relaxed, in a way I never was before.

5th day - 20 mg/kg (therapeutic dose)

The first 3 hours were similar to the last time; photophobia and a bad sensation with little noises. After that the images began to appear, in a slower rate than the other time. There were less images, but I was recognizing all of them as part of my childhood. I saw myself playing in my father's farm, riding a motorcycle, playing with a cousin, feeding a fish and other things. I saw some recent images, like one of my father, laughing in the living room of my house. This happened about a year ago. I understood that I had a happy childhood, and there was no one to blame for my addiction, only myself. I felt their love coming from my parents and relatives. I was feeling the same time distortion that I felt the other day, and after many hours I suddenly had an insight. It was that my mind and the universe were the same thing, and that all the people in the universe and all things in the universe are the only one. I saw many mistakes I was doing in my life, so many attitudes I could not have, and this helped me to decide very strongly that I will never use Demerol again. Now I can see very clearly that I don't need Demerol to live my life. And I feel better if I don't use it. During the first 8 hours of taking the Ibogaine I vomited 4 or 5 times, always when I tried to move. I was able to sleep about 4 AM, and to eat only about 9 AM the following day. I awakened feeling weak, tired and drowsy. As the hours were going, I slept a lot and began to feel better and in the morning of the following day I was normal."

Differences in day-by-day life after the experience
"I returned to my normal life with absolutely no cravings, with better appetite than before, and highly self-confident. Now I can see differences in some aspects of my personality, things are changed. For example, I used to avoid driving at night, because it reminded me of a car accident I had years ago. Now I can drive anytime, day or night, without anxiety. I'm sure that this is caused by Ibogaine, because now I'm not the same very anxious person I was. I'm not as shy as I used to be, too. It's easier now to contradict people when I think they are wrong, and to make them know what I want and what I think. I used to accept all that other people said only to avoid a discussion, even when I was sure that my point of view was the correct one.
These are the main happenings in my Ibogaine experience and the main differences I can perceive in these few days."

Some Months Later
"The most important thing I learned with all that happened is that I can never underestimate the power of the addictive personality I have inside. I can never say I'm cured because if I do this, I will forget to protect myself from drug using thoughts. I must know I have a chronic disease that will be quiet in its place until I decide to give it a chance to grow. This decision, and that's the point, is a conscious decision. If I give in, the disease will be out of control in a few days. But, if I could be strong to take real and honest control of my Demerol using thoughts, I will be free forever.
A few days ago, because of professional needs, I had to keep two Demerol doses with me, in my house, all night long. To protect myself, I gave them to my wife. But, it was amazing to see how I was not anxious to use them but, to give them to the patients that needed them. I clearly felt that Demerol was a strange thing in my environment. I wasn't curious about the place my wife had put them, I wasn't feeling any craving. I was only looking forward to the moment I could give them to the patient and say: I've done it. And I did it, because of all of you from NDA. I don't want to be boring, but I have no words to say how grateful we, my family and I, are. I will remember you for a lifetime."

Needless to say, this patient provided particular advantages in terms of his treatment outcome. He had a career, was highly motivated, and did not require the significant psychosocial support needed by so many others who do not have his background.

We have only been able to track a significant minority of patients for follow-up observations, about twenty-five percent. In many cases we have maintained direct contact with the patients for only two months after treatment. In a single case, for five years. The difficulty concerning patient contact has been one of geographic distances, both national and international, as our patients have come from diverse cities and countries. This factor, as well as the normal problems in tracking a chemically depen-dent population, must be taken into consideration when evaluating the findings of this paper.
General conclusions based on study observations are that a single administrationof Ibogaine is an interrupter for chemical dependence disorders. A series of treatments given over a period of time will produce more significant results. It may allow some of the persons treated to free themselves completely, (or for a period of years) from dependence to, or the use of, opiates and stimulants, including cocaine and nicotine. Data on alcohol dependence treatment in human subjects is minimal.

A single treatment of Ibogaine has the ability to significantly attenuate opiate with-drawal in all patients. In ninety percent of cases treated, a single treatment can interrupt an individual's craving to continue drug use for periods of time ranging from as short as two days to as long as two and a half years. Concurrently, Ibogaine has demonstrated the ability to precipitate the release of repressed memories and to foster a process of abreaction. I believe these are important aspects of Ibogaine's ability to interrupt chemical dependence.

In order to obtain the greatest benefit for those treated with Ibogaine, a psychosocial support structure should be in place. Providers of the Procedure should be knowledgeable in the field of chemical dependence treatment, and patients should be shown kindness and respect. In many cases, such an approach will be the first attentions of this kind the patient may have experienced in decades.

Patients are deserving of kindness and respect, and such care is an important part of the healing process. Ultimately, physicians and support staff should be specifically trained in the Lotsof Proceduressm to fully understand the physical and psychological transformation of the patient, the advantages of the Procedure, and the providers' responsibilities in administering Ibogaine to treat chemical dependence disorders. Eventually, the understanding of Ibogaine's actions may yield important data about memory, learning, dreams and sleep, as well as chemical dependence, tolerance and abuse.

The author acknowledges the editorial assistance of Norma E. Alexander; Rick Doblin; William J. Gladstone; David Goldstein; Barbara E. Judd, CSW; Daniel Luciano MD; Natalie Chantel Luke; Piotr Popik, MD; Bruce H. Sakow; Bob Sisko; Sylvia Thyssen; Boaz Wachtel and Rommell Washington.
The author thanks: N. Adriaans; N. Alexander; Z. Amit, Ph.D; J. Bastiaans, MD; P.A. Broderick, PhD; C. Contoreggi, MD; M.R. Dzoljic, MD; E. Della Sera, MD; G. Frenken; W.J. Gladstone; S.D. Glick, MD; O. Gollnhofer, PhD; R. Goutarel, MD (deceased); C. Grudzinskas, PhD; B.E. Judd, CSW; J.S. Kahan, Esq; C.D. Kaplan, PhD; D. Luciano, MD; D.C. Mash, PhD; G.J. Prud'Homme, Esq; L. Rolla, PhD; B.H. Sakow; J. Sanchez-Ramos, MD; B. Sisko; H. Sershen, PhD; Frank Vocci, PhD, B. Wachtel; R. Washington; Curtis Wright, MD and all of the volunteer patients for their courage, their science and the cooperation they have provided.

1. Aceto MD, Biological Evaluation of Compounds for Their Physical Dependence Potential and Abuse Liability, NIDA Research Monograph 119:506, 520-523, 1991, in Jacobson, AE.
2. Bastiaans J, The Psychiatric and Psychosomatic dimensions of Trauma, unpublished paper, 1991.

3. Broderick PS, Phelan FT & Berger SP, Ibogaine Alters Cocaine-Induced Biogenic and Psychostimulant Dysfunction, but Not [3H] GBR-12935 Binding to the Dopamine Transporter Protein, Problems of Drug Dependence 1991: Proceeding of the 53rd Annual Scientific Meeting, CPDD, NIDA Research Monograph 119:285, 1992.

4. Broderick PS, Phelan FT, Eng F & Wechsler T, Ibogaine Modulates Cocaine Responses Which are Altered Due to Environmental Habituation: In Vivo Microvoltammetric and Behavioral Studies, Pharmacology Biochemistry and Behavior, vol. 49, no. 3, 711-728, 1994.

5. Cappendijk SLT & Dzoljic MR, Inhibitory Effects of Ibogaine on Cocaine Self-Administration in Rats, European Journal of Pharmacology, 241:261-265, 1993.

6. Deecher, DC, Teitler M, Soderlund DM, Bornmann WG, Kuehne ME & Glick SD, Mechanisms of Action of Ibogaine and Harmaline Congeners Based on Radioligand Binding Studies, Brain Research., 571:242-247, 1992.

7. Depoortere H, Neocortical Rhythmic Slow Activity During Wakefulness and Paradoxical Sleep in Rats, Neuropharmacology, 18:160-168, 1987.

8. Dzoljic ED, Kaplan CD & Dzoljic MR, Effects of Ibogaine on Naloxone Precipitated Withdrawal Syndrome in Chronic Morphine Dependent Rats, Archive of International Pharmacodynamics, 294:64-70, 1988.

9. Fernandez JW, Bwiti: An Ethnography of Religious Imagination in Africa, Princeton University Press, 1982. 10. Glick, SD, Rossman K, Rao NC, Maisonneuve IM and Carlson JN, Effects of Ibogaine on Acute Signs of Morphine Withdrawal in Rats: Independence From Tremor, Neuropharmacology, 31(5):497-500, 1992

11. Glick SD, Rossman K, Steindorf S, Maisonneuve IM and Carlson JN, Effects and Aftereffects of Ibogaine on Morphine Self-Administration in Rats, European Journal of Pharmacology, 195:341-345. 1992.

12. Gollnhofer O & Sillans R, L'Iboga Psychotrope Africain (Iboga, An African Psychotropic Agent), Psychotropes, 1(1):11-27, 1983.

13. Gollnhofer O & Sillans R, Usages Rituels de l'iboga au Gabon (Ritual Uses of Iboga in Gabon), Psychotropes, 2(3):95-108, 1985.

14a. Goutarel R, Gollnhofer O & Sillans R, Pharmacodynamics And Therapeutic Applications of Iboga and Ibogaine, Psychedelic Monographs & Essays, 6:71-111, 1993.

14b. Goutarel R, Gollnhofer O & Sillans R, L'Iboga et l'ibogaine contre la dependence aux stupefiants. Pharmacodynamie et applications psychotherapeutiques, Psychotropes, vol. VIII, # 3, 1993.

15. Kaplan CD, Ketzer E, de Jong J, de Vries M, Reaching a State of Wellness: Multistage Explorations in Social Neuroscience, Social Neuroscience Bulletin 6(1), winter, 1993.

16. Karler R, Calder LD, Chaudhry IA, Turkanis SA, Blockade of ÒReverse ToleranceÓ to Cocaine and Amphetamine by MK-801, Life Sciences 45:599-606, 1989.

17. Khanna JM, Kalant H, Shah G, Chau A, Effect of D-cycloserine on Rapid Tolerance to Ethanol, Pharmacology Biochemistry & Behavior 45(4):983-986, 1993.

18. Lotsof HS, U.S. patent 4,499,096; Rapid Method for Inter-rupting the Narcotic Addiction Syndrome, 1985.

19. Lotsof HS, U.S. patent 4,587,243; Rapid Method for Inter-rupting the Cocaine and Amphetamine Abuse Syndrome, 1986.

20. Lotsof HS, U.S. patent 4,857,523; Rapid Method for Attenu-ating The Alcohol Dependency Syndrome, 1989.

21. Lotsof HS, U.S. Patent 5,026,697, Rapid Method for Interrupting or Attenuating The Nicotine / Tobacco Dependency Syndrome, 1991.

22. Lotsof, H.S., U.S. patent 5,124,994; Rapid Method for Interrupting or Attenuating Poly-drug Dependency Syndromes, 1992.

23. Maisonneuve IM, Keller RW Jr. and Glick SD, Interactions Between Ibogaine, A Potential Anti-Addictive Agent and Morphine: An In Vivo Microdialysis Study, European Journal of Pharmacology, 199:35-42, 1991.

24. Mash DC, Douyon R, Hearn WL, Sambol NC & Sanchez-Ramos J, A Preliminary Report on the Safety and Pharmacokinetics of Ibogaine, Biological Psychiatry, 1995 In Press.

25. Naranjo C, Psychotherapeutic Possibilities of New Fantasy Enhancing Drugs, Clinical Toxicology, 2(2):209. 1969.

26. Naranjo C, The Healing Journey, 174-228, Pantheon Books, Div. Random House, NY, 1973.

27. Popik P, Layer RT & Skolnick P, The Putative anti-addictive Drug Ibogaine is a Competitive inhibitor of [3H]MK-801 Binding to the NMDA Receptor Complex, Psychopharmacology, 114:672-674, 1994.

28. Sanchez-Ramos J & Mash DC; Ibogaine Research Update: Phase I Human Study, MAPS, IV(4):11 Spring 1994.

29. Sershen H, Hashim A, Harsing L, & Lajtha A, Ibogaine Antagonizes Cocaine-Induced Locomotor Activity in Mice, Life Sciences, 50:1079-1086, 1992.

30. Sershen H, Hashim A, & Lajtha A, Ibogaine Reduces Preferences for Cocaine Consumption in C57BL/6 By Mice, Pharmacology, Biochemistry and Behavior, 47 (1):13-19, 1994.

31. Sheppard SG, A Preliminary Investigation of Ibogaine: Case Reports and Recommendations for Further Study, J. Substance Abuse Treatment, 11(4):379-385, 1994.

32. Sisko B, Ibogaine and Substance Abusers: Follow-up on Four Case Histories, MAPS, IV(2):15-23, Summer 1993.

33. Trujillo KA & Akil H, Inhibition of Morphine Tolerance and Dependence by NMDA Receptor Antagonist MK-801, Science, 2512:85-87, 1991.

34. Village Beat, NYC, May 1990.

35. Woods HW, Medzihardsky F, Smith CB, Winger GD and Prince CP, 1989 Annual Report, Evaluation of New Compounds for Opioid Activity, NIDA Research Monograph 95:563, 655-656, 1990.

36. Zeff L, First International Ibogaine Conference, Paris, January 1987 (video tape).