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Increased Activation of Indirect Semantic Associations under Psilocybin

Abstract

The spread of activation in semantic networks can be measured using semantic and indirect semantic priming effects in lexical decision tasks (Spitzer et al 1993a and b). For example, in thought-disordered schizophrenic patients, activation spreads faster and farther than in non-thought-disordered patients and normal subjects, which results in an increased direct and indirect semantic priming effect (see below). This has been interpreted as the result of a decreased signal-to-noise ratio in cortical neural networks that process semantic information. Such a decreased signal-to-noise ratio has been related to a decreased dopaminergic modulation (Servan-Schreiber et al. 1990; Cohen and Servan- Schreiber 1992, 1993), which we recently were able to confirm directly in a study on the effects of L-dopa on semantic and indirect semantic priming (Kischka et al 1995).

As dopamine was found to have a focusing effect on the activity in semantic networks, i.e., it increases the signal-to-noise ratio and reduces the spread of activation (measured as reduced indirect semantic priming), we set out to investigate the effect of the hallucinogenic agent psilocybin on this task. Since psilocybin is known to act on the serotonin (5-HT) system and has effects of “broadening” conscious experiences, we hypothesized that it might exert a defocusing effect on semantic networks (i.e., decrease the signal-to-noise ratio), which should lead to an increased indirect semantic priming effect.

To test this hypothesis directly, we conducted a double-blind, placebo-controlled study on the effects of psilocybin on semantic and indirect semantic priming as part of a larger project that was designed to assess the behavioral effects and pharmacokinetic properties of this hallucinogenic agent (the results will be reported elsewhere; cf. Holzmann 1995).

Spitzer, M., Thimm, M., Hermle, L., Holzmann, P., Kovar, K., Heirnann, H., … Schneider, F. (1996). Increased Activation of Indirect Semantic Associations under Psilocybin. Biological Psychiatry, 39(12),  1055–1057. http://dx.doi.org/10.1016/0006-3223(95)00418-1
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The psychopharmacology of hallucinogens.

Abstract

Hallucinogenic drugs have been inhaled, ingested, worshipped, and reviled since prehistory. With the purification and synthesis of bontanical preparations and the ensuing discovery of chemically unique agents, hope was raised regarding their therapeutic potential, but this hope has been clouded by an epidemic of abuse and an inventory of adverse effects. This review examines aspects of that controversy, including the history of hallucinogens, epidemiology of current hallucinogen abuse, the association of LSD use with prolonged psychoses and hallucinogen persisting perception disorder, and the efforts to demonstrate the drug’s therapeutic efficacy. Human subject ramifications in hallucinogen experimentation are discussed. Future lines of research are suggested in human, animal, and tissue culture paradigms.

Abraham, H. D., Aldridge, A. M., & Gogia, P. (1996). The psychopharmacology of hallucinogens. Neuropsychopharmacology, 14(4), 285-298. https://dx.doi.org/10.1016/0893-133X(95)00136-2
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Receptor binding profile suggests multiple mechanisms of action are responsible for ibogaine's putative anti-addictive activity

Abstract

The indole alkaloid ibogaine (NIH 10567, Endabuse) is currently being examined for its potential utility in the treatment of cocaine and opioid addiction. However, a clearly defined molecular mechanism of action for ibogaine’s putative anti-addictive properties has not been delineated. Radioligand binding assays targeting over 50 distinct neurotransmitter receptors, ion channels, and select second messenger systems were employed to establish a broad in vitro pharmacological profile for ibogaine. These studies revealed that ibogaine interacted with a wide variety of receptors at concentrations of 1-100 microM. These included the mu, delta, kappa, opiate, 5HT2, 5HT3, and muscarinic1 and 2 receptors, and the dopamine, norepinephrine, and serotonin uptake sites. In addition, ibogaine interacted with N-methyl-D-aspartic acid (NMDA) associated ion and sodium ion channels as determined by the inhibition of [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][3H]MK-801 and [3H]bactrachotoxin A 20-alpha-benzoate binding (BTX-B), respectively. This broad spectrum of activity may in part be responsible for ibogaine’s putative anti-addictive activity.

Sweetnam, P. M., Lancaster, J., Snowman, A., Collins, J. L., Perschke, S., Bauer, C., & Ferkany, J. (1995). Receptor binding profile suggests multiple mechanisms of action are responsible for ibogaine’s putative anti-addictive activity. Psychopharmacology, 118(4), 369-376.
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Placeboing with Psychedelics

Letter to the editor

When we consider the so-called “placebo effect,” we should realize that it is not something mysterious that merely happens on its own. It is something we do with our minds that effects our bodies. To be more accurate: we placebo. To placebo is a verb. Our minds plus our bodies do this, and like any other human activity we can speak of placeboing. When looked at this way, we can ask: How do we placebo? and Can we learn placeboing more skillfully?

A clue comes from studies of stress and emotions in the immune system. It is widely known that negative emotions and stressful life events weaken the immune system, while positive emotions and life events strengthen it. Since positive life events strengthen our immune system, here is a clue to learning to placebo.

A common healing cluster of positive feelings and thoughts accompany many instances of spontaneous remission and spiritual healing. These include feelings of exceedingly positive mood, being cared for in the hands of a loving power, dropping stress, feelings of sacredness, feeling at home in the world, among others. Thoughts include a sense of temporarily transcending one’s identity, forgiving oneself and others, overwhelming gratitude, and increased sense of reality—this is the way things really are and ought to be.

If we can reproduce this cluster, we will be on the way to learning to placebo. Various mindbody techniques including meditation, imagery, contemplative prayer, yoga, the martial arts, breathing techniques, hypnosis, and chanting all suggest a yes answer to this question, and more research to follow these apparent leads may lead to learning how to use these mindbody methods to increase our placeboing skills by strengthening our immune systems.

Do examples of extreme positive emotional states produce extreme healing? The recent flurry of articles about current research into exploring the psychotherapeutic use of psychedelics for post traumatic stress disorder, death anxiety, and other disorders show that these substances are successful when they produce states of unitive consciousness (mystical experiences) and not successful when they do not.

Lost in this discussion is that fact that mystical experiences are the most powerful emotionally positive experiences humans can have, and if normal daily positive events boost the immune system somewhat, do these strongest positive experiences boost it a great deal?

Can this spontaneous cluster of healing thoughts and feelings be recreated in a medical setting? As a 2008 Johns Hopkins study of psilocybin induced mystical experiences showed, under the right conditions and with careful screening, preparation, and professional guidance, psychedelic sessions can produce mystical experiences and a similar cluster of emotions and experiences in normal, healthy, adult volunteers. In a 14-month following up, volunteers’ comments illustrated this healing cluster:

– The utter joy and freedom of letting go—without anxiety—without direction— beyond ego self.
– The understanding that in the eyes of God—all people—were equally important and equally loved by God.
– When I confronted my shadow and yelled “What do you want?” and it disappeared in a puff smoke.

Among the other outcomes were positive mood changes, improved sense of well-being and life satisfaction, positive attitudes about life and/or self, and altruistic social effects. About two-thirds of healthy adults rated as one of the five most important spiritual experiences of their lives, including about one-third who rated them as the single most important spiritual experience of their lives. However, the researchers did not measure possible effects on the immune system.

A question on placeboing: Do overwhelmingly powerful peak experiences stimulated by psychedelics as part of professionally guided sessions boost the immune system? A possible major advance in mindbody health awaits an answer.

Roberts, T. B. (1987). Is There a Placebo Ability? Advances: Journal of the Institute for the Advancement of Health, 4(1), 5.

Differences Between the Mechanism of Action of MDMA, MBDB, and the Classic Hallucinogens. Identification of a New Therapeutic Class: Entactogens

Nichols, D. E. (1986). Differences between the mechanism of action of MDMA, MBDB, and the classic hallucinogens. Identification of a new therapeutic class: entactogens. Journal of psychoactive drugs, 18(4), 305-313. http://dx.doi.org/10.1080/02791072.1986.10472362
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Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and beta-carboline constituents of ayahuasca

Abstract

Ayahuasca is a hallucinogenic beverage derived by boiling the bark of the Malpighiaceous liana Banisteriopsis caapi together with the leaves of various admixture plants, viz. Psychotria viridis, Psychotria carthagenensis, or Diplopterys cabrerana. B. caapi contains harmine, harmaline, and tetrahydroharmine while the admixtures contain N,N-dimethyltryptamine (DMT). DMT, a potent hallucinogen, is inactive orally due to degradation by visceral monoamine oxidase (MAO). The β-carbolines, however, are highly active reversible inhibitors of MAO and may protect the DMT from deamination by MAO and render it orally active. This mechanism has been proposed to underlie the oral activity of ayahuasca but has not been experimentally confirmed. In the present study the constituents of the admixture plants and the alkaloids of eight ayahuasca samples from Peru were qualitatively and quantitatively analyzed using two-dimensional thin-layer chromatography (TLC), high pressure liquid chromatography (HPLC) and gas chromatography/mass spectrometry (GC/MS).

Several B. caapi cultivars were quantitatively compared for variations in alkaloid content. Three admixture plants used rarely in the manufacture of ayahuasca were also screened for alkaloids. A selected sample of β-carbolines were screened for activity as MAO inhibitors using an in vitro assay system, and structure/activity relationships were compared. Inhibition observed with single compounds was compared with the activity of selected samples of ayahuasca which were screened in the system and also with the activity of mixtures of β-carbolines. The levels of DMT and β-carbolines found in the ayahuasca samples examined in the present study were an order of magnitude greater than the levels reported in a previous study. Ayahuasca was found to be an extremely effective inhibitor of MAO in vitro and the degree of inhibition was directly correlated with the concentration of MAO-inhibiting β-carbolines. Inhibition experiments using mixtures of β-carbolines indicated that their effects in combination are additive, rather than synergistic or antagonistic. Implications of the results in understanding the pharmacology of ayahuasca are discussed.

McKenna, D. J., Towers, G. N., & Abbott, F. (1984). Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and β-carboline constituents of ayahuasca. Journal of ethnopharmacology, 10(2), 195-223. 10.1016/0378-8741(84)90003-5
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LSD-assisted psychotherapy in patients with terminal cancer

Abstract

The paper describes the results of a clinical study exploring the potential of a complex psychotherapeutic program utilizing psychedelic compounds to alleviate the emotional and physical suffering of cancer patients. A total of 60 cancer patients participated in this experimental study. In 44 of these patients, LSD (200-500 ug per os) was administered as an adjunct to psychotherapy; in 19 patients, a new psychedelic compound, dipropyltryptamine (DPT) was administered (60-105 mg i.m.). Three of these patients received both LSD and DPT administered on different sessions.

The therapeutic results were assessed by means of a rating scale reflecting the degree of the patients’ depression, psychological isolation, anxiety, difficulty in management, fear of death, and pain. The ratings were done by attending physicians, nurses, family members, LSD therapists and cotherapists, and independent raters. In addition, the amount of narcotics required in the management of the patient was measured before and after the psychedelic sessions.

Systematic rating was carried out in a group of 31 cancer patients treated by LSD. The comparison of the means of individual ratings from pre- to posttreatment showed significant improvement in all the measured parameters for most of the raters. There was a definite reduction of the narcotic medication; it did not, however, reach the level of statistical significance. The pre- to post-treatment comparison of the global indexes used as gross indicators of the degree of emotional and physical distress, indicated that approximately 29 % of the patients showed dramatic improvement, and another 41.9 % moderate improvement, with 22.6 % essentially unchanged. In 6.4 % of the patients, global indexes showed a decrement in the post therapy ratings.

Grof, S., Goodman, L. E., Richards, W. A., & Kurland, A. A. (1972). LSD-assisted psychotherapy in patients with terminal cancer. International pharmacopsychiatry, 8(3), 129-144.
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LSD-Assisted Psychotherapy in Patients with Terminal Cancer

Abstract

The paper describes the results of a clinical study exploring the potential of a complex psychotherapeutic program utilizing psychedilic compounds to alleviate the emotional and physical suffering of cancer patients. A total of 60 cancer patients participated in this experimental study. In 44 of these patients, LSD (200-500 μg per os) was administered as an adjunct to psychotherapy; in 19 patients, a new psychedelic compound, dipropyltryptamine (DPT) was administered (60-105 mg i.m.). Three of these patients received both LSD and DPT administered on different sessions. The therapeutic results were assessed by means of a rating scale reflecting the degree of the patients’ depression, psychological isolation, anxiety, difficulty in management, fear of death, and pain. The ratings were done by attending physicians, nurses, family members, LSD therapists and cotherapists, and independent raters. In addition, the amount of narcotics required in the management of the patient was measured before and after the psychedelic sessions. Systematic rating was carried out in a group of 31 cancer patients treated by LSD. The comparison of the means of individual ratings from pre to posttreatment showed significant improvement in all the measured parameters for most of the raters. There was a definite reduction of the narcotic medication; it did not, however, reach the level of statistical significance. The pre to posttreatment comparison of the global indexes used as gross indicators of the degree of emotional and physical distress, indicated that approximately 29% of the patients showed dramatic improvement, and another 41.9% moderate improvement, with 22.6% essentially unchanged. In 6.4% of the patients, global indexes showed a decrement in the posttherapy ratings.
Grof, S., Goodman, L. E., Richards, W. A., & Kurland, A. A. (1973). LSD-assisted psychotherapy in patients with terminal cancer. International pharmacopsychiatry8, 129-144., 10.1159/000467984
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DPT as an adjunct in psychotherapy of alcoholics.

Abstract

The usefulness of dipropyltryptamine (DPT) as an adjunct to psychedelic therapy was explored in a pilot study carried out on 51 alcoholic patients from the Alcoholic Rehabilitation Unit at Spring Grove State Hospital. The evaluation of the results was based on the comparison of pre- and posttreatment results of a battery of psychological tests and of pretreatment and follow-up ratings of an independent team of social workers. The psychological tests involved the Minnesota multiphasic personality inventory (MMPI), Personal orientation inventory (POI), Raven progressive matrices, Psychiatric evaluation profile (PEP), and Benton visual retention test. The social history questionnaire used by the social workers for assessment of the patients’ adjustment consisted of 0-10-point scales measuring residential, occupational and interpersonal adjustment, abstinence, and global adjustment.
Grof, S., Soskin, R. A., Richards, W. A., & Kurland, A. A. (1973). DPT as an adjunct in psychotherapy of alcoholics. International pharmacopsychiatry8, 104-115., 10.1159/000467979
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