Hallucinogenic drugs in psychiatric research and treatment: perspectives and prospects

This review article (1995) looks back at the pre-renaissance studies on psychedelics.

Abstract

“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.”

Author: Rick J. Strassman

Summary

©1995 Williams & Wilkins

Clinical research with hallucinogens has resumed after a generation’s hiatus. Current studies emphasize systematic psychopharmacology, in addition to psychotherapy protocols, and will help define unique mind-brain interfaces and provide mechanistic hypotheses and treatment options for psychiatric disorders.

Mescaline, from the peyote cactus, has been used in clinical research protocols from the 1890s to the present, and LSD-25 was discovered in 1943 by Albert Hofmann. Hallucinogens elicit a multifaceted clinical syndrome, affecting many of the functions that characterize the human mind. Understanding these drugs’ properties may enhance understanding of important mind-brain relationships, and may provide novel insights and treatments into endogenous psychoses.

Nomenclature

Many terms have been used to describe the effects of these drugs, including psychedelic, psychodysleptic, phantasticant, psychotogen, oneirogen, entheogen, phanerothyme, psychotomimetic, and schizotoxin.

The “classical” hallucinogens are phenethylamines, indolealklyamines, and lysergamides. They share subjective properties with the dissociative anesthetics, phencyclidine and ketamine, and antimuscarinic agents, but do not produce anesthesia at high doses.

A clinically useful manner of representing hallucinogens refers to their temporal properties: onset, peak effect, and duration of action. Intravenous DMT is an example of an ultra-short-acting hallucinogen; psilocybin is an example of an intermediate-acting hallucinogen; and ibogaine is an example of an ultra-long-acting hallucinogen.

Prevalence of Use

Hallucinogen use in the United States remained relatively constant from the late 1960s to the late 1980s, but increased from 4.8% to 5.6% among high school seniors from 1988 to 1992. LSD ranked first in the categories of “most intense” and “longest” high among respondents.

Legal Status

Hallucinogens are drugs with high abuse potential, no known use in medical treatment, and no established safety even under medical supervision. The Religious Freedom Restoration Act was passed in response to increasing judicial restrictions on peyote use.

Basic Neuropharmacology

LSD antagonizes the effects of serotonin (5HT) in lower animals, and noradrenergic, dopaminergic, and cholinergic systems have also been investigated, but received less attention.

LSD increases brain levels of 5-HT and lowers those of its metabolite 5-hydroxyindoleacetic acid. This effect is mediated by the 5-HTlA and 5-HT2A,C subtypes, alone or in combination.

Human Psychopharmacology Measurement of Hallucinogen Effects in Humans

Initial human studies with hallucinogens relied upon careful clinical observation, using psychoanalytic or behavioral perspectives, in normal subjects and psychiatric patients. These studies used validated psychological scales, but were performed on unexperienced hallucinogen users.

The Hallucinogen Rating Scale (HRS) was developed by interviewing experienced hallucinogen users, and differs from previous scales in that it assesses effects predicated on a psychoanalytic theory of consciousness.

The HRS was modified during pilot studies with DMT in an additional cohort of well-prepared, educated, well-functioning, experienced hallucinogen users to include six clinical clusters that provided better resolution of subtle dose effects than multiple biological measurements in initial dose-response studies.

Route of Administration

LSD and longer-acting compounds may produce their effects directly, or via secondary, “downstream” mechanisms. However, the time course of drug effects is determined by pharmacokinetic factors, rather than secondary processes.

Tolerance

LSD and other classical compounds elicit behavioral tolerance and cross-tolerance after several daily doses, except for DMT.

Human Hallucinogen-Neurotransmitter Interactions

Serotonin. Bromo-LSD, cycloheptadine, 5-hydroxytryptophan, monoamine oxidase inhibition, reserpine, and DMT antagonize the effects of LSD in humans, suggesting that the effects of LSD are due to the upregulation of relevant mechanisms.

Meta-chlorophenylpiperazine and 6-chloro-2-(1-piperzinyl)pyrazine are hallucinogens that produce hallucinogenic effects in patients with schizophrenia or alcoholism, but not in normal subjects.

LSD and DMT have dopamine-releasing properties, and chlorpromazine may enhance LSD’s effects if given during the acute intoxication. Haloperidol pretreatment enhanced DMT’s neuroendocrine and subjective effects in one subject.

Hallucinogens and Schizophrenia

The degree of overlap between LSD and functional psychoses has been vigorously debated, but it appears that acutely ill, positive-symptom patients show more “psychedelic” symptoms than chronic, undifferentiated, negative-symptom predominating patients.

Hallucinogens were administered to psychotic patients and comparisons were made between drug effects and preexisting symptoms. A relatively consistent finding was that “burned out,” predominantly negative symptom-laden patients showed blunted responses to hallucinogens.

The short-chained tryptamines, DMT and 5-methoxyDMT, were leading candidates for endogenous hallucinogens, but their peripheral levels did not accurately reflect concentrations at discrete brain areas, nor differential sensitivity to comparable levels between normal subjects and patients with psychoses.

Psychotherapy Research

Few studies have used LSD as a psychopharmacotherapeutic agent in humans, but daily dosing regimes elicited robust antidepressant responses in depressives and tolerance to its psychedelic effects developed rapidly.

The first suggestion that LSD may hasten psychotherapy was made in the early 1950s. Several studies were conducted, but the results were limited by lack of adequate control groups and impartial raters, small sample size, and primarily anecdotal data.

The psychedelic approach, favored by North American researchers, involved administration of a single high dose LSD session after a relatively short course of psychotherapy. This approach demonstrated some promise in the treatment of sociopathy, prisoner recidivism, and the pain and despair associated with terminal illness.

Many studies suggesting enhancement of psychotherapy with hallucinogens were hampered by lack of methodological rigor. However, placebo/control treatments are problematic, and a hybrid of the psychedelic and psycholytic models may provide additional flexibility and allow more psychotherapeutic work to take place.

Adverse Effects

Early clinical investigators reported reassuring safety data, with attempted suicide, completed suicide, and psychotic reactions over 48 hours rates of 0/1,000, 1.2/1,000, and 1.8/1,000, respectively, in normal volunteers and patients.

Once hallucinogens escaped from the laboratory, emergency rooms and clinics were quickly impacted by adverse effects in unprepared, unsupervised, and psychiatrically ill individuals taking hallucinogens, especially LSD.

Acute

Acute adverse effects of LSD include panic reactions and psychotic reactions, which usually are superimposed on preexisting psychotic disorders in polydrug-abusing patients. These reactions typically respond to treatments appropriate to the non-drug-induced syndromes they resemble.

Subacute effects requiring clinical intervention are flashbacks, which are unbidden re-experiencings of certain aspects of hallucinogen-induced effects. Some individuals find brief “free trips” pleasurable, and many people willfully attempt to re-experience aspects of the DMT state by these means.

Flashbacks are a common symptom of post-traumatic stress disorder and can be triggered by lactate infusion. They are usually self-limited and require no medical treatment.

LSD use may be debilitating and treatment resistant, resembling an ego-syntonic, negative symptom-laden schizophrenic disorder, and may also cause changes in lifestyle and interpersonal behaviors. LSD use may also be associated with organic central deficits, but this is difficult to document with certainty.

Chronic visual disturbances, posthallucinogen perceptual disorder, may be an anxiety/functional rather than organic disorder.

Mutagenicity / Teratogenicity

Initial reports of chromosomal and reproductive disorders in LSD users were not replicated in later studies.

Conclusions and Recommendations

Hallucinogens are powerful drugs, with the potential to elicit or exacerbate psychiatric symptoms. Experienced hallucinogen users may reduce the traumatic nature of high-dose hallucinogen sessions, and truly informed consent is possible only in experienced users.

Current Research

In the United States, DMT has been used in psychopharmacologic studies since late 1990, and ibogaine and MDMA have been used in phase I studies since 1994. Ketamine studies have also been conducted, and a substance abuse treatment amendment to the University of Maryland’s protocol has been approved.

Areas for Future Research

Hallucinogens can be used for research with different goals, such as psychotherapy, neuroendocrine challenge studies, and multiple within-individual assessments.

Measurement Variables

Recent studies of DMT demonstrate the superiority of subjective responses to biological ones with respect to subtle dose effects.

Psychopharmacology

Human hallucinogen psychopharmacology requires further study, particularly the role of non-5-HT neurotransmitters, particularly dopamine. Risperidone, a 5-HT2A and D2 antagonism agent, is more potent than ritanserin, a pure 5-HT2A,( agent, in antagonizing animal responses to LSD.

Although many congeners of classical hallucinogens have been administered safely to humans, little data exists for within-subject studies using multiple drugs.

Hallucinogen-induced animal models of information-processing defects in schizophrenia could be applied to normal volunteers’ responses to hallucinogens, allowing novel comparisons between functional and drug-induced psychoses.

Psychotherapy

Economic constraints create increasing pressure for cost-effective medical psychotherapy. Hallucinogen-assisted psychotherapy may be a logical extension of earlier work that suggested robust short-term improvement, but less impressive maintenance of therapeutic effects.

Future psychotherapy research may focus on the use of hallucinogen-enhanced imagery and associations to treat terminally ill cancer and acquired immune deficiency syndrome patients, as well as post-traumatic stress disorder in combat veterans.

Set and Setting

Although complex and potentially controversial, set and setting issues require further study. These issues include the personality, state, and expectations of the subject, as well as the physical surroundings, nuances of the investigator/therapist presentation, and the theoretical model and expectations of the research.

Training Issues

Hallucinogens are used in a small number of protocols, but new examinations may generate many requests to use them in clinical studies.

Transference and countertransference issues are rarely discussed in psychopharmacology research, but the regressed, suggestible, and unusual behavior of subjects under the influence of hallucinogens is easily observable. Sexual relations between clinician and subject may occur during or after a hallucinogenic drug session. Regulatory agencies determine professional qualifications and adequacy of facilities for conducting human hallucinogen research. Specialized training and periodic supervision are necessary to prevent misuse of these compounds.

Conclusion

The renewal of human hallucinogen research is encouraging, but careful selection, screening, preparation, supervision, and follow-up of subjects is necessary. In addition, the training, characteristics, and research setting of clinical investigators must be addressed directly.