OPEN Foundation

Other subjects

The pharmacology of psilocybin

Abstract

Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamin e) is the major psychoactive alkaloid of some species of mushrooms distributed worldwide. These mushrooms represent a growing problem regarding hallucinogenic drug abuse. Despite its experimental medical use in the 1960s, only very few pharmacological data about psilocybin were known until recently. Because of its still growing capacity for abuse and the widely dispersed data this review presents all the available pharmacological data about psilocybin.

Passie, T., Seifert, J., Schneider, U., & Emrich, H. M. (2002). The pharmacology of psilocybin. Addiction Biology, 7(4), 357-364. http://dx.doi.org/10.1080/1355621021000005937

Link to full text

No Difference in Brain Activation During Cognitive Performance Between Ecstasy (3,4-Methylenedioxymethamphetamine) Users and Control Subjects: A [H215O]-Positron Emission Tomography Study

Abstract

The long-term use of the serotonin-releaser and uptake-inhibitor 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) has been associated with memory impairments and increased liability to depressive mood and anxiety attacks. It is unclear, however, whether these psychologic deviations are reflected in alterations of the underlying neurophysiologic substrate. The authors compared mood and regional cerebral blood flow (rCBF) profiles between regular polytoxic Ecstasy users and Ecstasy-naive controls. Brain activity as indexed by rCBF was measured during cognitive activation by an attentional task using positron emission tomography and [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”][H2(15)O]. Mood was assessed by means of the Hamilton Rating Scale for Depression (HAM-D) and the EWL Mood Rating Scale. Statistical parametric mapping revealed that brain activity did not differ between the two groups. Both groups also performed equally on the cognitive task requiring sustained attention. However, significantly higher levels of depressiveness as determined by the HAM-D and EWL scales were found in Ecstasy-using subjects. These data indicate that, despite differences in mood, polytoxic Ecstasy users do not differ from Ecstasy-naive controls in terms of local brain activity. Heightened depressiveness in the Ecstasy group was consistent with results from previous studies and could be related to serotonergic hypofunction resulting from repeated MDMA consumption. However, this study cannot exclude the possibility that the observed differences are preexisting rather than a result of Ecstasy use.

 

Gamma, A., Buck, A., Berthold, T., & Vollenweider, F. X. (2001). No difference in brain activation during cognitive performance between ecstasy (3, 4-methylenedioxymethamphetamine) users and control subjects: a [H215O]-positron emission tomography study. Journal of clinical psychopharmacology, 21(1), 66-71. http://dx.doi.org/10.1097/00004714-200102000-00012

 

[/fusion_builder_column][/fusion_builder_row][/fusion_builder_container]

Deconstructing Ecstasy: The Politics of MDMA Research

Abstract

What is Ecstasy? Defined by the New Webster’s Dictionary as a state of intense overpowering emotion, a condition of exultation or mental rapture induced by beauty, music, artistic creation, or the contemplation of the divine, ecstasy derives etymologically from the ancient Greek ekstasis, which means flight of the soul from tbe body. The anthropologist, Mircea Eliade, who explored the roots of religious experience in his book Shamanism: Archaic Techniques of Ecstasy, has described the function of this intense states of mind among aboriginal peoples. Select individuals are called to become shaman, a role specializing, in inducing ecstastic states of trance where the soul is believed to leave the body and ascend to the sky or descend to the underworld. The shaman is thus considered a ‘technician of the sacred’, having been initiated through a process of isolation, ritual solitude, suffering and the imminence of death. Such initiation into the function of ecstatic states of consciousness, always accompanied by comprehensive tutelage from tribal elders, allows the shaman to assume for his tribal group the vital role of intermediary, or conduit, between the profane world of everyday existence and the sacred domains of alternative reality (Eliade, 1951; Schultes and Hofmann 1992)

Grob, C. S. (2000). Deconstructing Ecstasy: The Politics of MDMA Research. Addiction Research & Theory, 8(6), 549-588. http://dx.doi.org/10.3109/16066350008998989
Link to full text

Role of Serotoninergic Neurons and 5-HT Receptors in the Action of Hallucinogens

Abstract

Brain serotonin receptors and serotoninergic pathways have received increasing attention as targets for a wide variety of therapeutic agents. Perhaps peculiar to this realm, however, are the so-called hallucinogenic drugs, which presently lack demonstrated therapeutic utility, and still remain, as they have for at least the past 50 years, pharmacological curiosities. Research into their mechanism of action is generally poorly funded, and we know relatively little about how they affect the brain, despite their continued popularity as recreational drugs among a significant proportion of the population.

Nichols, D. E. (2000). Role of serotoninergic neurons and 5-HT receptors in the action of hallucinogens. In Serotoninergic Neurons and 5-HT Receptors in the CNS (pp. 563-585). Springer Berlin Heidelberg. http://dx.doi.org/10.1007/978-3-642-60921-3_21

Link to full text

Serotonergic Agents That Activate 5HT2A Receptors Prevent NMDA Antagonist Neurotoxicity

Abstract

Phencyclidine, ketamine, and other agents that block NMDA glutamate receptors trigger a schizophrenia-like psychosis in humans and induce pathomorphological changes in cerebrocortical neurons in rat brain. Accumulating evidence suggests that a complex network disturbance involving multiple transmitter receptor systems is responsible for the neuronal injury, and it is proposed that a similar network disturbance is responsible for the psychotomimetic effects of NMDA antagonists, and might also be involved in the pathophysiology of schizophrenia. In the present study we present evidence that serotonergic agents possessing 5HT2A agonist activity prevent NMDA antagonist neurotoxicity in rat brain. It isproposed that 5HT2A agonists may also prevent the psychotomimetic effects of NMDA antagonists. Among the 5HT2A agonists examined and found to be neuroprotective are LSD and related hallucinogens. The apparent contradiction in proposing that these agents might have antipsychotic properties is resolved by evidence linking their hallucinogenic activity to agonist action at 5HT2C receptors, whereas antipsychotic activity would be attributable to agonist action at 5HT2A receptors.

Farber, N. B., Hanslick, J., Kirby, C., McWilliams, L., & Olney, J. W. (1998). Serotonergic Agents That Activate 5HT2A Receptors Prevent NMDA Antagonist Neurotoxicity. Neuropsychopharmacology, 18(1), 57-62. http://dx.doi.org/doi:10.1016/S0893-133X(97)00127-9

Link to full text

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
Link to full text

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.

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
Link to full text

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
Link to full text
 

7 May - Psychedelics, Nature & Mental Health with Sam Gandy

X