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PTSD and MDMA in the ‘picture’

December 6, 2021 / Anxiety disorders / PTSD, Articles, MDMA, Publications, Research / By

a5_ptsd_508With an upcoming fMRI study in the United Kingdom, an attempt is being made to outline the neurobiological mechanisms that are hypothesized to underlie the favorable outcome of MDMA-assisted psychotherapy in posttraumatic stress disorder (PTSD).

Earlier studies found that after just a few treatment sessions with MDMA in addition to psychotherapy, there was a significant short [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”][1] and long [2] term improvement of PTSD symptomatology in patients that were resistant to regular psycho- and/or pharmacotherapy [3]. Up to today, not much is known about the factors that contribute to the success of this form of treatment. Several researchers suggest that MDMA, o.a. by temporarily reducing fear and by easing interpersonal contact, facilitate the therapy on a psychological level [4], but about the neurobiological foundations remains to be speculated.

By using fMRI, dr. Ben Sessa and his research team at Cardiff University will try to image the manifestation of MDMA in PTSD patients. To capture the effects of the compound in isolation, the patients will not receive any psychotherapy during this study.

The research proposal is currently waiting for approval of the Committee of Ethics.

 
[1] Mithoefer, Wagner, Mithoefer, Jerome, & Doblin (2011)
[2] Mithoefer et al. (2012)
[3] A similar study from Oehen, Traber, Widmer, & Schnyder (2013) did not reach significance on the primary measurement (p = .066), a diagnostic tool to assess PTSD symptomatology, though at a subjective level the patients indicated to have some relief from their former complaints. Bouso et al. (2008) couldn’t draw any firm conclusions on their data of the first MDMA-assisted psychotherapy study in PTSD, due to a sudden unexpected cancellation of the study and the consequencing small study sample.
[4] Bouso, Doblin, Farré, Alcázar, & Gómez-Jarabo (2008), Mithoefer et al. (2011), Oehen et al. (2013)
 
References
Bouso, J. C., Doblin, R., Farré, M., Alcázar, M. A., & Gómez-Jarabo, G. (2008). MDMA-assisted psychotherapy using low doses in a small sample of women with chronic posttraumatic stress disorder. Journal of Psychoactive Drugs, 40(3), 225–36. doi:10.1080/02791072.2008.10400637
Mithoefer, M. C. M., Wagner, M. M. T., Mithoefer, A. A. T., Jerome, L., Martin, S. F., Yazar-Klosinski, B., … Doblin, R. (2012). Durability of improvement in posttraumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. Journal of Psychopharmacology (Oxford, England), 27, 28–39. doi:10.1177/0269881112456611
Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T., Jerome, L., & Doblin, R. (2011). The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Journal of psychopharmacology (Oxford, England) (Vol. 25, pp. 439–452). doi:10.1177/0269881110378371
Oehen, P., Traber, R., Widmer, V., & Schnyder, U. (2013). A randomized, controlled pilot study of MDMA (± 3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD). Journal of Psychopharmacology (Oxford, England), 27(1), 40–52. doi:10.1177/0269881112464827[/fusion_builder_column][/fusion_builder_row][/fusion_builder_container]

Psychedelic Research 2.0 – Part 1

December 6, 2021 / Articles, Background articles, Publications, Research / By

After a 20 year study-shutdown on psychedelics, a second wave of interest in the nature and applications of these compounds has engulfed the international research community and rendered a wealth of studies. To help you find your way in the forest of exciting information, this two-part series of articles provides an overview of contemporary (1990 – present) psychedelic research themes. Part 1 will focus on more fundamental research, while part 2 will focus on clinical research.

Part 1: Fundamental psychology

Before getting to the exciting part of this article where we will dive into studies that are done in the psychology field, let’s start with some definitions and explanations. According to the American Psychological Association (APA, 2014), psychology is:

“… the study of the mind and behavior. The discipline embraces all aspects of the human experience — from the functions of the brain to the actions of nations, from child development to care for the aged. In every conceivable setting from scientific research centers to mental healthcare services, “the understanding of behavior” is the enterprise of psychologists.”

For the sake of clearance, conciseness and convenience, the studies with a psychological character will be discussed in two separate articles with a distinction being made between fundamental and clinical research. This first part of the series of psychedelic research themes 2.0 will provide an overview of fundamental research. Fundamental research aims at exposing the general processes that underlie the phenomena of interest and does not necessarily have a direct application. Clinical research tends to be of a more practical nature, since it is primarily aimed at understanding a particular disease or maladjustment and searching for an adequate cure. Though these classes are treated as distinct in this series, please keep in mind that there is a considerable overlap and synergy between the two.

In the fundamental corner, roughly four psychedelic research themes that have been under the microscope for the past twenty years will be distinguished in this article. These concern matters related to cognition, creativity, personality and psychopharmacology.

Cognition

Cognition is a broad term and can be defined in several ways depending on the discipline in which it is used. In neuroscience, cognition is usually considered from the information processing view, explaining human behavior in terms of executive functions. Put simply: there is input (perceptual information), there is output (behavior), and there is something happening in the black box that is known as the brain (executive functions). Cognition usually refers to the total package of processes that is involved in this ongoing cycle of day to day functioning.

Psychedelics exert an acute influence on a variety of these functions, which have been extensively studied with behavioral tasks and neuroimaging techniques. Conclusions about the exact nature of this temporary alteration in cognition have been mixed and even contradictory, which might partially be due to the inconsistency of the study design and substance involved. Amongst others, acute changes in working memory, attention and perception have been described in the literature (for a comprehensive overview, see Passie, Halpern, Stichtenoth, Emrich, & Hintzen, 2008; Bouso, Fábregas, Antonijoan, Rodríguez-Fornells, & Riba, 2013). The fine-tuning of the knowledge that is currently available about the relation between psychedelics and cognitive skills goes hand in hand with increasing information about receptor binding sites, localization of function and brain connectivity.

More standardized study designs seem to be a necessity to learn more about the causes of the inconclusive evidence.

Creativity

From Nevole’s (1947, as cited in Winkler & Csémy, 2014) point of view “…the normal human way of perceiving and thinking, is just one possibility out of many potential possibilities”. He argues that ‘normal’ perception, thoughts and behavior of an individual are the result of socio-cultural learning. The integration of culturally established norms and values might have an evolutionary purpose, but may put constrain on cognitive processes such as creativity.

In psychological literature, creativity is usually defined in terms of divergent thinking: the ability to generate multiple answers to a set problem (Guilford, 1966). Because the psychedelic experience is characterized by an alteration in perception, changes in emotion and expansion of thought and identity (Sessa, 2008), it is not unthinkable that they could provide an aid to ‘think out of the box’.

During the ’50’s and 60’s, the exploration of creative problem solving under the influence of psychedelic agents was a popular research topic. An interesting article was published by Harman, McKim, Mogar, Fadiman, and Stolaroff (1966) in which the results of an experimental study with LSD were described in a group of men which occupation required creative problem-solving ability. The study consists of objective measures of the effects of LSD on problem solving ability, and subjective ratings of the ability to approach a pre-specified, work-related problem. The latter being one of the strengths of the study, since it permits the participant to consider options in a meaningful context. Some of the mutually agreed on subjective effects of the psychedelic compound seem to correspond to ideas about facilitative conditions under which creativity arises, such as low inhibition and anxiety, the capacity to structure problems in a larger context and high fluency and flexibility of ideation. This article may be considered classic in the psychedelic/creativity domain.

Surprisingly, contemporary research on this exciting topic is scarce, perhaps due to the lack of understanding of the concept of creativity itself, or the methodological challenge to measure it. Results from recent studies that were done with ayahuasca (Frecska, Móré, Vargha, & Luna, 2012) and cannabis (Jones, Blagrove, & Parrott, 2009) suggest the ability of users of psychedelics to produce more original ideas than non-users. It has to be noted here that these are not measures that were taken under the acute intoxication of the substances, but as a comparison between groups that were sober at the time of measurement.

There is a strong need for more studies with intelligent experimental designs in order to understand the source of creativity. The field doesn’t seem to have made full use of the modern imaging techniques, such as electro-encephalography (EEG), functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) to explore the interaction of acute psychoactive chemistry and creative thinking. Opportunities are waiting here…

Personality

In exploring the interaction between psychedelics and personality, most research follows the nature/nurture discussion of stable versus unstable personality traits. According to Cloninger, Svrakic, & Przybeck (1993) personality can be thought of as a dynamic process between two types of traits. Temperament refers to the more stable, genetically determined set of traits, whereas character can be considered the fine-tuning of personality due to socio-cultural factors.

Evidence in the psychedelic research field suggests that differences exist between users and non-users in both personality domains (Bouso et al., 2012; Grob et al., 1996; Móró, Simon, Bárd, & Rácz, 2011), but this doesn’t answer the question of causality: Are people with a certain set of personality traits more likely to start experimenting with psychedelics, or is there a possibility that these substances can account for shaping personality?

Two recent studies found evidence that certain dimensions of personality which are regarded as stable traits were altered after exposure to ayahuasca (Barbosa, Cazorla, Giglio, & Strassman, 2009) and psilocybin (MacLean, Johnson, & Griffiths, 2011). In the ayahuasca study, differences in the personality aspects reward dependence and harm avoidance were found after repeated exposure to the beverage. A single session of psilocybin seemed to be sufficient to cause a change in the openness to experience dimension.

The results are tentative, but promising: for persons dealing with personality disorders psychedelics might be considered valuable tools. More research on this topic would certainly be encouraged.

Psychopharmacology

Psychopharmacology can be defined as “the study of drugs that affect the brain” (Stahl, 2008). This definition exposes that the psychopharmacologist engages himself in matters related to ‘drugs’, the ‘brain’ and their interaction.

Before diving into contemporary research within this field, it is worth mentioning two pieces of work that are written by Alexander Shulgin (1925 – 2014) – one of the most influential scientists in this field – and his wife Ann Shulgin; PIKHAL, A Chemical Love Story (1991) and TIKHAL, The Continuation (1997). Besides a fictionalized autobiography of these key figures of psychedelic research and a detailed description of over 200 compounds, the books also contain lively and informative subjective research reports from the group of friends in which the substances were ‘tested’. Together, the books cover a wide array of research issues, biochemical information, personal experience and spiritual considerations related to psychedelics.

Back to the 21st century then, in which questions like ‘How do psychedelics manifest itself in the human brain?’ and ‘How does this interaction alter perception and behavior?’ keep persisting. Recent studies have been done to examine the neurobiological mechanisms of ketamine (Hahn et al., 2014), salvia (Johnson, MacLean, Reissig, Prisinzano, & Griffiths, 2011), psilocybin (Muthukumaraswamy et al., 2013) and ayahuasca (dos Santos et al., 2011; Riba et al., 2003; Riba, McIlhenny, Valle, Bouso, & Barker, 2012). Data from substance-by-substance research has led to more holistic neuroscientific theories such as the entropic brain hypothesis, in which a division between two types of consciousness (primary and secondary) is proposed as a way to explain phenomena that can’t be accounted for by a neuroscienfitic perspective on its own (Carhart-Harris et al., 2014).

As substance-by-substance research can provide a stepping stone for theories about human behavior, so can fundamental research complement the understanding of clinical expression. The extensive research that has been done on the role and functioning of the amygdala for example, supports and complements explanations about the effectiveness of antidepressant drugs that are used in the treatment of anxiety and mood related complaints (Crupi, Marino & Cuzzocrea, 2011).

Want to know what this has to do with psychedelics? That, and more will be discussed in the second part of this series: Clinical Research.

 
References
American Psychology Association. About APA and about psychology. How does the APA define “psychology”? Consulted on July 14, 2014 via http://www.apa.org/support/about/apa/psychology.aspx#answer
Barbosa, P. C., Cazorla, I. M., Giglio, J. S., & Strassman, R. (2009). A six-month prospective evaluation of personality traits, psychiatric symptoms and quality of life in ayahuasca-naive subjects. J Psychoactive Drugs, 41, 205–212. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19999673
Bouso, J. C., Fábregas, J. M., Antonijoan, R. M., Rodríguez-Fornells, A., & Riba, J. (2013). Acute effects of ayahuasca on neuropsychological performance: differences in executive function between experienced and occasional users. Psychopharmacology, 230(3), 415–24. doi:10.1007/s00213-013-3167-9
Bouso, J. C., González, D., Fondevila, S., Cutchet, M., Fernández, X., Ribeiro Barbosa, P. C., … Riba, J. (2012). Personality, psychopathology, life attitudes and neuropsychological performance among ritual users of ayahuasca: A longitudinal study. PLoS ONE, 7. doi:10.1371/journal.pone.0042421
Calder, a J., Lawrence, a D., & Young, a W. (2001). Neuropsychology of fear and loathing. Nature Reviews. Neuroscience, 2(5), 352–63. doi:10.1038/35072584
Carhart-Harris, R. L., Leech, R., Hellyer, P. J., Shanahan, M., Feilding, A., Tagliazucchi, E., … Nutt, D. (2014). The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs. Frontiers in Human Neuroscience, 8(February), 20. doi:10.3389/fnhum.2014.00020
Cloninger, C. R., Svrakic, D. M., & Przybeck, T. R. (1993). A psychobiological model of temperament and character. Archives of General Psychiatry, 50, 975–990. doi:10.1001/archpsyc.1993.01820240059008
Cupri, R., Marino, A., Cuzzocrea, S. (2011). New therapeutic strategy for mood disorders. Current Medicinal Chemistry, 18, 4284-4298. doi: 10.2174/092986711797200417
Dos Santos, R. G., Valle, M., Bouso, J. C., Nomdedéu, J. F., Rodríguez-Espinosa, J., McIlhenny, E. H., … Riba, J. (2011). Autonomic, Neuroendocrine, and Immunological Effects of Ayahuasca. Journal of Clinical Psychopharmacology. doi:10.1097/JCP.0b013e31823607f6
Frecska, E., Móré, C. E., Vargha, A., & Luna, L. E. (2012). Enhancement of Creative Expression and Entoptic Phenomena as After-Effects of Repeated Ayahuasca Ceremonies. Journal of Psychoactive Drugs. doi:10.1080/02791072.2012.703099
Grob, C. S., McKenna, D. J., Callaway, J. C., Brito, G. S., Neves, E. S., G., O., … Boone, K. B. (1996). Human pharmacology of hoasca, a plant hallucinogen used in ritual context in Brazil. The Journal of Nervous and Mental Disease, 184(2), 86–94.
Hahn, A., Höflich, A. S., Winkler, D., Sladky, R., Baldinger, P., Vanicek, T., … Lanzenberger, R. (2014). Acute ketamine infusion alters functional connectivity between dorsal attention and default mode networks, 11(9), 2014.
Harman, W. W., McKim, R. H., Mogar, R. E., Fadiman, J., & Stolaroff, M. J. (1966). Psychedelic Agents in Creative Problem-Solving. A pilot study. Psychological Reports, 19(2), 211–227.
Johnson, M. W., MacLean, K. a, Reissig, C. J., Prisinzano, T. E., & Griffiths, R. R. (2011). Human psychopharmacology and dose-effects of salvinorin A, a kappa opioid agonist hallucinogen present in the plant Salvia divinorum. Drug and Alcohol Dependence, 115(1-2), 150–5. doi:10.1016/j.drugalcdep.2010.11.005
Jones, K. a., Blagrove, M., & Parrott, a. C. (2009). Cannabis and Ecstasy/MDMA: Empirical Measures of Creativity in Recreational Users. Journal of Psychoactive Drugs, 41(4), 323–329. doi:10.1080/02791072.2009.10399769
MacLean, K. A., Johnson, M. W., & Griffiths, R. R. (2011). Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness. Journal of Psychopharmacology. doi:10.1177/0269881111420188
Móró, L., Simon, K., Bárd, I., & Rácz, J. (2011). Voice of the Psychonauts: Coping, Life Purpose, and Spirituality in Psychedelic Drug Users. Journal of Psychoactive Drugs. doi:10.1080/02791072.2011.605661
Muthukumaraswamy, S. D., Carhart-Harris, R. L., Moran, R. J., Brookes, M. J., Williams, T. M., Errtizoe, D., … Nutt, D. J. (2013). Broadband cortical desynchronization underlies the human psychedelic state. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience, 33(38), 15171–83. doi:10.1523/JNEUROSCI.2063-13.2013
Passie, T., Halpern, J. H., Stichtenoth, D. O., Emrich, H. M., & Hintzen, A. (2008). The pharmacology of lysergic acid diethylamide: a review. CNS Neuroscience & Therapeutics, 14(4), 295–314. doi:10.1111/j.1755-5949.2008.00059.x
Phelps, E. A., & LeDoux, J. E. (2005). Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron, 48(2), 175–87. doi:10.1016/j.neuron.2005.09.025
Riba, J., McIlhenny, E. H., Valle, M., Bouso, J. C., & Barker, S. a. (2012). Metabolism and disposition of N,N-dimethyltryptamine and harmala alkaloids after oral administration of ayahuasca. Drug Testing and Analysis, 4, 610–6. doi:10.1002/dta.1344
Riba, J., Valle, M., Urbano, G., Yritia, M., Morte, A., & Barbanoj, M. J. (2003). Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics. The Journal of pharmacology and experimental therapeutics (Vol. 306, pp. 73–83). doi:10.1124/jpet.103.049882.Britain
Sessa, B. (2008). Is it time to revisit the role of psychedelic drugs in enhancing human creativity? Journal of Psychopharmacology (Oxford, England), 22(8), 821–7. doi:10.1177/0269881108091597
Winkler, P., & Csémy, L. (2014). Self-Experimentations with Psychedelics Among Mental Health Professionals: LSD in the Former Czechoslovakia. Journal of Psychoactive Drugs, 46(1), 11–19. doi:10.1080/02791072.2013.873158

The Therapeutic Potentials of Salvinorin A

February 7, 2022 / Articles, Background articles, Research, Salvia / Salvinorin A / By

Salvia divinorum is a sprawling perennial herb found in the Sierra Mazatec region of Mexico. It has a history of use as a divinatory psychedelic, and has been widely available since the mid 1990s primarily as a smoked herb. Jean Basset Johnson was the first to document its use in 1939. R. Gordon Wasson, better known for his ‘discovery’ of the psilocybin mushroom, continued to document the Salvia divinorum herb and eventually confirmed its psychoactivity on himself in ‘A new Mexican psychotropic drug from the mint family’ published in Botanical Museum Leaflets (1962). Salvia divinorum remained an obscure psychedelic until the mid 1990s when Daniel Siebert, a then still unknown independent researcher, began self experimentation and documented its effects extensively. The Salvia divinorum experience is rather elusive, that is to say its effects seem to vary even more tremendously then other psychedelics, both between people and across sessions.

The molecule, or more specifically; ‘neoclerodane diterpenoid’ (not to be confused with ‘alkaloid’, which always contains a nitrogen atom), behind the dramatic effects of Salvia divinorum is the extremely potent Salvinorin A. “Essentially inactive if taken orally”, says Valdés in ‘Salvia divinorum and the unique diterpene hallucinogen, Salvinorin A’ (1994), “the compound is effective in doses of 200 to 500 mcg when smoked”. This makes Salvinorin A the first documented diterpene hallucinogen and the most potent naturally occurring hallucinogen thus far isolated”. “Salvinorin A”, says Siebert in ‘Salvia divinorum and Salvinorin A: new pharmacological findings’ (1994), “produces effects which are subjectively identical to those experienced when the whole herb is ingested. Salvinorin A is effectively deactivated by the gastrointestinal system, so alternative routes of absorption must be used to maintain its activity”.

This compound is interesting for many reasons, but recently it has come to the attention of researchers because it acts as a kappa opioid receptor agonist (Roth, 2002). It is the first known compound acting on this receptor that is not an alkaloid. The κ-opioid receptor is a protein and is one of four related receptors that bind opium-like compounds in the brain and are responsible for mediating the effects of these compounds. These effects include altering the perception of pain, motor control, and mood. Wang et al. (2013) demonstrated that “administration of Salvinorin A after hypoxia/ischemia preserves cerebral autoregulation via the κ-opioid receptor pathway”, ultimately presenting a novel opportunity for the prevention of prenatal cerebral hypoxia/ischemia. Fichna et al. (2012) investigated the effect of Salvinorin A (administered intraperitoneally once a day) on acute pain, oedema and formalin-induced persistent pain in mice. The researchers concluded that Salvinorin A exerts analgesic actions and also shows moderate anti-inflammatory effects.

More recently Salvinorin A was used to research the relationship between the claustrum (a sheet of neurons which is attached to the neocortex in the center of the brain) and consciousness. Stiefel et al. (2014) suggests that “the consciousness-altering effects of S. divinorum/salvinorin A are due to a κ-opioid receptor mediated inhibition of primarily the claustrum and, additionally, the deep layers of the cortex, mainly in prefrontal areas”. This finding leads them to believe that Salvinorin A might be new evidence in favour of the ‘Crick and Koch theory’ (1990) which claims that the claustrum is the “conductor of consciousness”, not unlike the philosopher René Descartes claimed for the pineal gland.

Dr. Karl Hanes, researcher at the ‘Cognitive-Behavioural Treatment Centre’ in Melbourne Australia, reported on a treatment-resistant depressed patient (Ms. G) under his care and the management of her symptoms of depression through Salvia (2001). “During a review consultation some seven months after discontinuing cognitive-behavioural therapy”, says Hanes, “Ms. G claimed to have found relief from her symptoms of depression with use of the herb Salvia divinorum. A HAM-D score of 2 confirmed remission of her symptoms of depression at this time. Ms. G claims that she discovered its antidepressant effects accidentally after smoking the herb and had later developed a method of oral consumption which she claimed maintained its antidepressant effects even after she abstained from using it for up to a week”. Preliminary research (animal models) asserts Ms. G’s case and shows that Salvinorin A might become a therapeutic agent in the treatment of depression.

Carlezon et al. (2006) found that Salvinorin A “decreased extracellular concentrations of dopamine within the nucleus accumbens, a critical component of brain reward circuitry, without affecting extracellular concentrations of serotonin (5-HT)”. Butelman et al. (2004) showed that “the naturally occurring hallucinogen Salvinorin A produces discriminative stimulus effects similar to those of a high efficacy κ-agonist in non-human primates” (rhesus monkeys). Much research is done in the field of addiction and focuses primarily on Salvinorin A’s supposed anti-addictive effects. Activating the kappa-opioid receptors (KORs or KOPrs) produces anti-addictive effects by regulating dopamine levels in the brain (Kivel et al., 2014). The κ-opioid receptor may provide a natural addiction control mechanism, and therefore, drugs that act as agonists and increase activation of this receptor may have therapeutic potential in the treatment of addiction. “Activation of KORs”, says Tomasiewicz (2008), “reduces the reward-related effects of cocaine. Inasmuch as cocaine-induced behavioral stimulation in rodents may model key aspects of enhanced mood in humans, these findings raise the possibility that KOR agonists might ameliorate symptoms of conditions characterized by increased motivation and hyperfunction of brain reward systems, such as mania and stimulant intoxication”. These are obviously very exciting effects. “The development of KOPr-selective agents with improved drug-like characteristics” says Carlezon (2009), “would facilitate preclinical and clinical studies designed to evaluate the possibility that KOPrs are a feasible target for new medications”.

“Unfortunately”, says Kivel (2014), “classic kappa-opioid agonists have undesired side effects such as sedation, aversion, and depression, which restrict their clinical use”. Acute activation of kappa opioid receptors produces ‘anti-cocaine’ like effects, but because of considerate adverse effects their clinical use has remained limited (Simonson, 2014). Salvinorin seems to sidestep this problem. “Salvinorin A and its semi-synthetic analogs”, says Simonson (2014), “have been shown to have potent KOPr agonist activity and may induce a unique response with similar anti-cocaine addiction effects as the classic KOPr agonists but with a different side effect profile”. Salvinorin A retains the anti-addictive properties of traditional kappa-opioid receptor agonists with remarkable reduction of side effects.

However, there are still many obstacles to be overcome. For instance, a major problem is Salvinorin A’s rapid metabolism in the human body. Because of the short length of activation, Salvinorin as such will probably not be a good candidate for clinical development. In an effort to re-engineer Salvinorin’s pharmacokinetics, researchers have sought to produce kappa-opioid receptor agonists based on the structure of Salvinorin A that do have the desired length of activity. “While work in this field is still in progress”, says Kivel (2014), “several analogs with improved pharmacokinetic profiles have been shown to have anti-addictive effects”. These new analogs will eventually provide the characteristics sought after by clinical researchers for treatment.

Given the reemergence of interest into psychedelics and their potential as therapeutic agents it is hardly surprising that Salvia divinorum would attract attention. Salvia manifests a powerful psychedelic experience which is grounded in a unique neurochemical process which seems to have anti-addictive potential. It is surely a substance worth exploring within the psychiatric and psychopharmacological disciplines in the future.

 
References
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Roth, B. L., Baner, K., Westkaemper, R., Siebert, D., Rice, K. C., Steinberg, S., … & Rothman, R. B. (2002). Salvinorin A: a potent naturally occurring nonnitrogenous κ opioid selective agonist. Proceedings of the National Academy of Sciences, 99(18), 11934-11939.
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Tomasiewicz, H. C., Todtenkopf, M. S., Chartoff, E. H., Cohen, B. M., & Carlezon Jr, W. A. (2008). The kappa-opioid agonist U69, 593 blocks cocaine-induced enhancement of brain stimulation reward. Biological psychiatry, 64(11), 982-988.
Valdés, L. J. (1994). Salvia divinorum and the unique diterpene hallucinogen, Salvinorin (divinorin) A. Journal of psychoactive drugs, 26(3), 277-283.
Wang Z., Ma N., Riley J., Armstead WM., Liu R (2013). Autoregulation Preservation by Salvinorin A After Brain Hypoxia/Ischemia and Reperfusion in Piglet Model. Trans Periop & Pain Med. doi:10.4000/2330-4871.1000001
Wasson, R. G. (1962). A new Mexican psychotropic drug from the mint family. Botanical Museum Leaflets, Harvard University, 77-84.

Psilocybin and Mood Regulation

December 6, 2021 / Articles, Mushrooms / Psilocybin, Publications, Research / By

With their recent publication, Kraehenmann et al. (2014) have increased our understanding of the mechanism that is thought to underlie the potential effectiveness of psychedelic–assisted psychotherapy in relieving mood and anxiety related symptomology. Their results elaborate on earlier findings that the administration of psychedelics [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”][1] in addition with psychotherapy reduces anxiety symptoms on a relatively short term (Gasser et al., 2014; Moreno, Wiegand, Taitano, & Delgado, 2006), with one study even showing a reduction of anxiety and an increase of positive mood six months after only a single dose of psilocybin (Grob et al., 2011).

These clinical observations are now complemented by the finding that psilocybin attenuates amygdala [2] reactivity in response to emotionally loaded pictures in healthy volunteers, and that these changes are associated with a positive mood change. The authors suggest that psilocybin might have the potential to normalize neurobiological systems that are dysregulated in individuals with a depressed mood state. In addition to the psychometric evidence and clinical observations that psilocybin-assisted psychotherapy improves mood within a clinical population, the results of the current study provide a possible neurobiological explanation for these effects. The questions that arise from this study relate to the degree to which these results can be generalized to a clinical population, and if and to what extent the acute changes in amygdala reactivity by themselves may account for long term changes in the processing of emotions.

According to the Trimbos Institute (2014) [3] there is a current prevalence of 4 – 10 % of people suffering from depression in Western society. Because of its high prevalence and devastating individual and societal consequences, depression is considered a major public health problem (Spijker, van Straten, Bockting, Meeuwissen, & van Balkom, 2013). The regular treatment options include psychotherapy, pharmacotherapy or a combination of the two, of which the latter is thought to establish the most favorable outcome. One of the added values of the study of Kraehenmann (2014) is the finding that psilocybin – with its pharmacological effect on amygdala reactivity – shares a neurobiological mechanism of action with selective serotonin reuptake inhibitors (SSRI’s), which are prescription drugs that are commonly deployed in the treatment of depression and other mood related disorders. What then, might be the necessity of exploring these psychedelic compounds as alternatives for customary treatment options?

The treatment of mood disorders with SSRI’s has several disadvantages, with probably the most prominent criticism being the modest response (47%) and remission rates (between 28 – 33%; Trivedi et al., 2006). Other disadvantages include a delayed therapeutic action (Stahl, 1998), withdrawal difficulties (Schatzberg, 1997), and the daily pharmacological treatment routine. Results from the psychedelic-assisted treatment sessions imply a prolonged uplift of mood after the pharmacological intervention, which is only implemented occasionally. These results are far too preliminary to abandon the extensively reviewed prescription drugs in the treatment of mood disorders and switch to less scientifically studied compounds that share some of the same neurobiological features, but it might be valuable to elucidate upon their therapeutical potential. What is it that psychologically distinguishes one type of drug with antidepressant properties from the other, and who are the people that might benefit from making this distinction? With one out of ten people suffering from depressive symptoms [4], the need for this kind of knowledge may not be underestimated.

 
[1] Red. classical psychedelics, which are isolated from a broader categorization of psychedelics by their pharmacological manifestation as serotonin 5-HT2A receptor agonists
[2] The amygdala is a structure in the limbic system that plays a major role in the processing of emotions and is therefore a key target for psychopharmacological interventions to treat mood and anxiety disorders (Phelps & LeDoux, 2005)
[3] The Trimbos Institute is a Dutch organization that serves as an information centre for matters related to mental health
[4] In Western societies (Trimbos Institute, 2014)
 
References
Gasser, P., Holstein, D., Michel, Y., Doblin, R., Yazar-Klosinski, B., Passie, T., & Brenneisen, R. (2014). Safety and Efficacy of Lysergic Acid Diethylamide-Assisted Psychotherapy for Anxiety Associated With Life-threatening Diseases. The Journal of Nervous and Mental Disease, 00(00), 1. doi:10.1097/NMD.0000000000000113
Grob, C. S., Danforth, A. L., Chopra, G. S., Hagerty, M., McKay, C. R., Halberstadt, A. L., & Greer, G. R. (2011). Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Archives of General Psychiatry, 68(1), 71–8. doi:10.1001/archgenpsychiatry.2010.116
Kraehenmann, R., Preller, K. H., Scheidegger, M., Pokorny, T., Bosch, O. G., Seifritz, E., & Vollenweider, F. X. (2014). Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with Enhanced Positive Mood in Healthy Volunteers. Biological Psychiatry, 1–9. doi:10.1016/j.biopsych.2014.04.010
Moreno, F. A., Wiegand, C. B., Taitano, E. K., & Delgado, P. L. (2006). Safety, Tolerability, and Efficacy of Psilocybin in 9 Patients With Obsessive-Compulsive Disorder. The Journal of Clinical Psychiatry, 67(11), 1735–1740. doi:10.4088/JCP.v67n1110
Moreno, F. A., Wiegand, C. B., Taitano, E. K., & Delgado, P. L. (2006). Safety, Tolerability, and Efficacy of Psilocybin in 9 Patients With Obsessive-Compulsive Disorder. The Journal of Clinical Psychiatry, 67(11), 1735–1740. doi:10.4088/JCP.v67n1110
Spijker, J., van Straten, A., Bockting, C. L. H., Meeuwissen, J. a C., & van Balkom, A. J. L. M. (2013). Psychotherapy, antidepressants, and their combination for chronic major depressive disorder: a systematic review. Canadian Journal of Psychiatry. Revue Canadienne de Psychiatrie, 58(7), 386–92. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/23870720
Stahl, S. M. (1998). Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic effects and side effects. Journal of Affective Disorders, 51(3), 215–35. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10333979
Trimbos Instituut (2014). Feiten en cijfers depressie. Reviewed on July 12, 2014 at http://www.trimbos.nl/onderwerpen/psychische-gezondheid/depressie/feiten-en-cijfers
Trivedi, M. H., Rush, a J., Wisniewski, S. R., Nierenberg, A. a, Warden, D., Ritz, L., … Fava, M. (2006). Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. The American Journal of Psychiatry, 163(1), 28–40. doi:10.1176/appi.ajp.163.1.28[/fusion_builder_column][/fusion_builder_row][/fusion_builder_container]

In Memoriam Alexander ‘Sasha’ Shulgin

February 7, 2022 / Articles, MDMA / By

With great sadness, the OPEN foundation would like to acknowledge the death of maverick chemist Alexander “Sasha” Shulgin, who passed away on June 2nd. Dubbed “the godfather of Ecstasy,” Shulgin was credited with introducing MDMA to psychologists in the late 70’s, years before the drug hit the global dance scene.

However MDMA was only one of hundreds of chemicals Shulgin synthesized during his lengthy career. After earning his biochemistry degree from UC Berkeley in 1954, he worked briefly as research director at BioRad Laboratories before becoming a senior research chemist at Dow Chemical Company, where he synthesized the first biodegradable insecticide, Zectran.

Because Shulgin made Dow a sizeable profit, he was granted the freedom to create and patent new drugs. He chose psychedelics. In the late 1950s, Shulgin experimented with mescaline, which he wrote revealed “that our entire universe is contained in the mind and spirit.” But his interest in pharmacology was sparked years earlier. While in the Navy as a teenager, he got a shot of morphine for an injury, making him wonder how drugs altered consciousness. This passion for understanding the human mind and how to unlock its potential—chemically, of course—would mark his career.

In 1966, Shulgin left Dow Chemical to freelance as a consultant and for the following decades worked from his backyard lab in Berkeley, California. In 1976, he heard about MDMA, which was first synthesized at Merck in 1912 as an unimportant precursor in a new synthesis for haemostatic substances and subsequently shelved. He went on to synthesize it, and discovered it was a powerful empathogen, “with emotional and sensual overtones.” He then introduced it to a therapist friend and word spread quickly both inside and outside the therapeutic community. Without MDMA, the dance music scene of the last 30 years would have looked entirely different.

Shulgin was a fixture in the psychedelic subculture that believed in better living through chemistry. He contributed a rational, scientific perspective to the field, coupled with enthusiasm for thorough self-experimentation.

When interviewed about the abuse potential of MDMA, which became a scheduled drug in 1985, Shulgin was quoted as saying it was “as real as the abuse potential of anything that gives pleasure and satisfaction. This applies to MDMA as much as it does to skydiving, mountain climbing and skiing.”

Shulgin died of several health complications after years of poor health, and had recently been diagnosed with terminal liver cancer. He was 88. His wife, Ann Shulgin, with whom he shared thousands of psychedelic experiences, survives him.

Autism and LSD-25 – Freeing the Most Imprisoned Minds?

February 7, 2022 / Articles, Background articles, LSD, Research / By

In the early sixties, a number of controversial clinical investigations were published involving the administration of LSD-25 (lysergic acid diethylamide) to young children said to suffer from severe forms of autism, or childhood-onset schizophrenia (COS), which were then regarded as closely related [1]. The reason for conducting the studies with young children was the supposed similarity between autism and COS. Prompted by the apparent results of studies conducted with LSD-25 and adult mute catatonic patients by Cholden, Kurland, and Savage (1955), hypotheses were constructed to research a possible therapeutic utility. “The goal in these therapeutic efforts”, said Bender in an article published in Recent Advances in Biological Psychiatry (1962), “has been to modify the secondary symptomatology associated with retarded, regressed, and disturbed behavior of the children”. The larger part of the children treated with LSD in these studies were between six and ten years old and completely unresponsive to all other forms of treatment. That the children couldn’t be treated by other means served, in part, for the justification for using a powerful psychoactive substance in child experiments. Surely this decision would have been criticized by the ethical commission today.

A pharmacological intervention by means of LSD was said to “nudge the lagging maturation” (Bender, 1962) into a (somewhat) normal developmental pattern. How exactly the administration of LSD would accomplish the “freeing of the most imprisoned minds” was still unknown (Mogar & Aldrich, 1969). LSD was supposed to achieve success through “breaking through the autistic defense” (Bender, 1963), and in this way be exceptionally helpful in “areas which are closely related to the process of psychotherapy” (Simmons et al., 1966). Some believed LSD was especially useful at helping patients to “unblock” repressed subconscious material through other psychotherapeutic methods (Cohen, 1959). Therapists took LSD to establish a connection with the experience of schizophrenia. “During the ‘model psychosis’ phase of LSD research when the psychedelic state was considered a chemically-induced schizophrenia”, says pioneer LSD researcher Stanislav Grof (1980), “LSD sessions were recommended as reversible journeys into the experiential world of psychotics which had a unique didactic significance”.

Some researchers, like Freedman et al. (1963), studied LSD for its supposed psychotomimetic (psychotogenic) properties, meaning that the drug mimics the symptoms of psychosis, including delusions and/or delirium, as opposed to merely hallucinations (Sewell et al., 2009). An exacerbation of ‘typical’ symptoms meant an opportunity for studying the (child)schizophrenic condition. Other researchers (Bender et al., 1963; Rolo, et al., 1965) considered the neurological mechanism behind the effect of LSD, which in that time was still highly obscure, as more important than its role as facilitator of the therapeutic process. For instance, LSD attracted theoretical interest as a serotonin inhibitor and an autonomic nervous system stimulant. Bender et al. (1963) concluded that “LSD-25 given daily in oral doses of 100 mcg [2] to pre-puberty autistic schizophrenic children appears to be an effective autonomic and central nervous system stimulant”, and that these changes “appear to be chronic with continuous administration of the drug”. Continuous administration consisted of daily administration over prolonged periods of time, varying from days to several weeks . The most persistent effects of LSD-25 therapy that were published included improved speech behavior, increased emotional responsiveness, positive mood (laughter) and a decrease of compulsions.

But alas, however interesting and attractive these results seemed to be — the evidence didn’t stick. Today studies into the relationship of LSD and autism aren’t being conducted and the results that were produced are regarded as highly controversial, if not completely repudiated. This was in part because, in retrospect, the studies were greatly flawed. The researchers seemed to have brushed over the conceptual controversy too quickly by choosing “not to deal with the controversial issues concerning the definitions and etiological factors of either childhood schizophrenia (1) or the autistic reaction pattern (2)” (Bender et al., 1962). The debate about the correct place of (childhood) autism within the DSM (Diagnostic and Statistical Manual of Mental Disorders) remains problematic to this day (DSM-V), but autism has long been divorced from the umbrella of schizophrenia. Although both disorders share clinical features, clinical psychologists and psychiatrists regard autism to be a separate diagnostic ‘entity’ from schizophrenia. Because LSD was used as a drug for “intensifying pre-existing symptomology” of schizophrenia (Bender et al., 1962), a conceptual detachment from autism would have disturbed the foundation of the results.

Even if the researchers had chosen to ‘deal with the controversy’, in hindsight, sampling would have still ended up being very problematic. The children treated were demographically varied and covered a broad age range. Conflicting significance is given to the relationship between age and drug response, but Bender noted that “in contrast to pre- adolescents, younger children manifest consistently different reactions” (1962). In contrast, Fisher and Castile concluded that “older children were better candidates for psychedelic therapy because verbal communication was possible and also because they tended to be less withdrawn, more schizophrenic than autistic, and displayed more blatant symptomology” (Mogar & Aldrich, 1969). In addition to age, also the symptoms of treated children were heterogeneous and weren’t corrected for severity. There was no randomization, and most studies suffered from fluctuating frequency of administration and dosage. Lastly, the set and setting of the experiments varied strongly.

Although the studies conducted in the sixties had major flaws from an experimental point of view and therefore didn’t hold up to scientific scrutiny, Mogar and Aldrich argue in an article published in Behavioral Neuropsychiatry (1969) that the results considered as a whole do point to a utility of administering LSD to autistic children. “The significance of seemingly contradictory results”, say Mogar and Aldrich, “has often been obscured by the persistent search for static, ‘drug-specific’ reactions to LSD”. This is an interesting point; despite that the results don’t indicate significance in an experimental sense, there may still be a therapeutic utility. Mogar and Aldrich report that the greatest therapeutic benefit was related to “(a) the degree of active therapist involvement with the patient; (b) an opportunity to experience meaningful objects and interpersonal activities; and (c) congenial settings that were reasonably free of artificiality, experimental or medical restrictions, and mechanically administered procedures” (1969). In practice clinical therapy is usually far removed from theory. It could be that testing LSD, itself being a highly unpredictable drug, in combination with the therapy dynamic is too hard to substantiate. Mogar and Aldrich conclude that “the administration of LSD is inextricably embedded in a larger psychosocial process which should be optimized in accordance with particular treatment goals”.

Considering the recent growth of interest into this area of research, these older and rather obscure studies deserve to be excavated from the psychedelic research literature. Researchers at LA BioMed (Los Angeles Biomedical Research Institute) are now constructing a study which is said to test the already established anecdotal therapeutic relationship between MDMA (3,4-methylenedioxy-N-methylamphetamine) and autism in adults. The study is the latest in an expanding program of research into the therapeutic use of MDMA funded by the nonprofit Multidisciplinary Association for Psychedelic Studies (MAPS). “This new study will give us a chance”, says Charles Grob head researcher at LA BioMed (2014), “to determine the actual effects of differing dosages of medication that we know for certain is pure MDMA on adults on the autism spectrum. If the results of this research warrant further investigation, data from this study will be used to design additional clinical trials”. Now that the limitations for research into the psychedelic experience and its therapeutic effects are being removed and LSD is once again an object of study, these previously published results could serve for the production of new hypotheses.

 
[1] See (Abramson, 1960; Bender, et al., 1962; Bender, et al., 1963; Fisher & Castile, 1963; Freedman, et al., 1962; Rolo, et al., 1965; Simmons, et al., 1966).
[2] A common psychedelic dosage of LSD ranges from 100 to 200 mcg, a strong dose being 200 to 600 mcg.
 
References
Abramson, H.A. (Ed.) (1960). The Use of LSD in Psychotherapy. New York: Josiah Macy Foundation.
Bender, L., Faretra, G., & Cobrinik, L. (1963). LSD and UM-L treatment of hospitalized disturbed children. Recent Advances in Biological Psychiatry, 5, 84-92.
Bender, L., Goldschmidt, L., & Sankar, S.D.V. (1962). Treatment of autistic schizophrenic children with LSD-25 and UML-491. Recent Advances in Biological Psychiatry, 4, 170-177.
Cholden, L., Kurland, A., & Savage, C. (1955). Clinical reactions and tolerance to LSD in chronic schizophrenia. Journal of Nervous and Mental Disease, 122, 211-216.
Cohen, S., & Eisner, B. G. (1959). Use of lysergic acid diethylamide in a psychotherapeutic setting. AMA Archives of Neurology & Psychiatry, 81(5), 615-619.
Freedman, A.M., Ebin, E.V., & Wilson, E.A. (1962). Autistic schizophrenic children: An experiment in the use of d-lysergic acid diethylamide (LSD-25). Archives of General Psychiatry, 6, 203-213.
Gettys, T. (2014). MDMA Helps Reduce Social Anxiety for Autistic Adults, and Researchers Want to Find Out How. MAPS. Retrieved at: http://www.maps.org/media/view/mdma_helps_reduce_social_anxiety_for_autistic_adults_and_researchers_w/
Grof, S. (1980). LSD Psychotherapy. California: Hunter House Publishers.
Mogar, E. R., & Aldrich, W. R. (1969). The Use of Psychedelic Agents with Autistic Schizophrenic Children. Behavioral Neuropsychiatry, 1(8), 44-50.
Rolo, A., Krinsky. L.W., Abramson, H.A., & Goldfarb, L. (1965). Preliminary method for study of LSD with children. International Journal of Neuropsychiatry, 1, 552-555.
Sewell, R. A., Ranganathan, M., & D’Souza, D. C. (2009). Cannabinoids and psychosis. International Review of Psychiatry, 21(2), 152-162.
Simmons, J.Q., Leiken, SoJ., Lovaas, Q.I., Schaffer, B., & Perloff, B. (1966). Modification of autistic behavior with LSD-25. The American Journal of Psychiatry, 122, 1201-1211.

Survey: Ayahuasca Consumption in Europe

December 6, 2021 / Articles, Ayahuasca, Publications, Research / By

survey_508

Researchers are calling for participants to complete an anonymous online questionnaire about their ayahuasca consumption. This information will be presented at the upcoming World Ayahuasca Conference in September 2014.

The researchers are looking for people living in Europe who have already used ayahuasca, including those who no longer partake. The aim of the questionnaire is to create a comprehensive profile of European ayahuasca users and better understand their motivation for drinking ayahuasca, as well as how it may have benefited them.

To take the survey, click here. The survey takes 15 minutes and is completely anonymous.

Ketamine Reconsidered

February 7, 2022 / Articles, Background articles, Ketamine, Research / By

Ketamine is causing a lot of ‘buzz’ inside neuropsychiatry at the moment. Duman and Aghajanian called the substance in Science (2012) “the biggest breakthrough in depression research in a half century”. The APA (American Psychiatric Association) is dedicating a surprisingly large amount of time discussing the new implications concerning ketamine in the 167th ‘annual meeting’ this year (2014). Abrams says in The Atlantic (2012) that the effects of ketamine suggest that depression isn’t caused by a chemical imbalance in the brain, as is believed by most neuropsychologist, but by damage to brain cells caused by chronic stress. Ketamine is said to stimulate the process of synaptogenesis (the formation of synapses in the brain), which repairs the damage caused by stress (Zarate 2006, Duman 2012). These findings could eventually become the base for a “synaptogenic hypothesis” of depression (Duman, 2012).

Ketamine is used very diversely in scientific studies [1], which shows well how contingent the ideas surrounding a substance can be. In 1962, eight years before the American president Nixon signed the Controlled Substances Act and shut the door for research of the effects of substances like LSD, psilocybin and mescaline, ketamine was synthesised in the Parke Davis Lab in Detroit. Ketamine is considered an arylcyclohexylamine in chemistry, the same category that phencyclidine (PCP) belongs to. Ketamine, then still CI581, was initially explained as a fast-acting anesthetic for general use. It was used in the instance of severe damage to the skin caused by radiation or burns. Children were given ketamine when they had bad reactions to other tranquilizing substances or when a more superficial anesthesia was called for. Ketamine’s effects were popular in animal medicine as well. In 1970 ketamine started playing a significant role in the Vietnam war. Upon return, many veterans told stories about odd mental experiences which they had during operations for their injuries. It’s only when ketamine started to be used recreationaly [2] that the dissociative effect, the literal separation of mind and body, came to the forefront.

In 1973, near the end of the Vietnam war, the Iranian psychiatrist E. Khorramzadeh published an article on the use of ketamine during psychotherapy in Psychosomatic Journal. In South-America, this led to the emergence of several therapies which used ketamine as a means for psychoanalytical regression. John C. Lilly published his phenomenological magnus opus The Scientist in 1978, which made his own experiments as well as that of others in the field available for philosophical scrutiny. Lilly came to the conclusion that ketamine opens the door for ‘metaprogramming’ [3], a process which he describes as the conscious manipulation of the synapses to cause changes in behavior and personality patterns. In that same year Journeys into the Bright World by Marcia Moore and her husband Howard Alltounian appeared, which explored the possibility of using ketamine in Jungian psychotherapy. Krupitsky brought ketamine together with addiction therapy in 1985. Krupitsky, head of the research laboratory for addiction and psychopharmacology in St. Petersburg, developed a ‘psychedelic therapy’ which, to his own surprise, resulted in complete abstinence of at least a year in 66% of his alcohol addicted patients (1995). In collaboration with Strassman, famous for his monumental study into DMT and the book The Spirit Molecule (2000) which followed it, Krupitsky published the results of a study into ketamine and heroin addiction. Although ketamine did not show lasting effects of abstinence, which the researchers sought, there was a noticeable improvement in the withdrawal process. They accredited these results to a positive transformation of the self-concept as well as in emotional, moral and spiritual attitudes.

Karl Jansen, eminent ketamine researcher and proponent of further psychotherapeutic integration of the experiences induced by ketamine, adds an important layer to the work of Krupitsky. He proposes that the experience which ketamine offers is therapeutic in itself. Jansen draws a comparison between ketamine and the state of consciousness that people experience ‘near death’. According to Jansen this experience, like with ketamine, has effects on personality; it increases altruistic behavior, decreases the fear of death and makes people less materialistic (2001).

Modern neuroscientist go a step further than Krupitsky; that ketamine is itself effectively therapeutic, according to them has got little to do with the psychedelic experience. The experience as therapeutic process is replaced with a neurochemical mechanism. The characteristics of the experience or the impressions which people extract out of it don’t account for the therapeutic effect, according to these neuroscientists the therapeutic effect is caused by an intervention outside of consciousness. The qualities which are desired in the eyes of psychonauts [4] are annoying side-effects which they have to get rid of to be able to use ketamine as an antidepressant. According to researchers of other psychedelic substances ketamine’s growing success is a good opportunity to get attention for their results. However, it remains to be seen if this doesn’t devalue research into the psychedelic experience.

The effects that ketamine appears to have on the mental condition of individuals with a depression diagnosis were introduced by researchers like John Krystal and Karl Jansen, but until Zarate et al. (2006) there weren’t any robust double-blind placebo controlled studies conducted. Zarate et al. found a strong and fast antidepressant effect with a single dose of ketamine. Unfortunately the amount of time that the effects lasted still varied too much, from two days to two weeks. They concluded that ketamine, at the present moment, should at least play a role in acute suicidal episodes. It’s still unknown if or how the antidepressant effect can be lengthened. Baumeister et al. conducted a meta-analysis, published in Therapeutic Advances in Psychopharmacology (2014), in which they present evidence for the effects of ketamine in the treatment of depression, even when study samples were still relatively small. In any case, the results support the further exploration of administering ketamine to individuals with a severe and therapy resistant depression diagnosis. Ruud Kortekaas, a Dutch neuroscientist at the UMCG (Universitair Medisch Centrum Groningen), is now conducting a study into the long term effects (twenty weeks) of ketamine administration to people who don’t react [5] to regular antidepressants. Kortekaas attributes the effects of ketamine in his patients to a heightened activity in the prefrontal lobe. “It’s like all of those rusty taps in the brain”, says Kortekaas in the Volkskrant (Mudde, 2012), “are completely opened in one go. Often patients experience a strong improvement within several hours. Substances like Prozac, if they work, only start having effects after weeks. Here there is an immediate effect which lasts for days, in small pilot studies in eight out of ten patients”. Ketamine stimulates, in rather low dosages, the process of synaptogenesis which increases the plasticity of the brain (Zarate 2006, Duman 2012). Rasmussen et al. published in Journal of Psychopharmacology (2013) that a low dose of ketamine intravenously is effective in alleviating depressive symptoms in half of their subjects. Rupert McShane, researcher at Oxford Health NHS Foundation Trust, even rapports an effect of several months in a small study published in Journal of Psychopharmacology (2012). In Kortekaas’s study the focus will be on examining the different nuances of different dosages. The study is unique because an oral form of administering ketamine was choses while most other studies based their results on intravenous, intramuscular or nasal forms. An oral form will, according to Kortekaas, result in a strong growth of ketamine’s applicability as antidepressant. Also, the low dosages which are used in the study are hardly psychoactive, and therefore will almost have no influence on normal functioning. The study is set up as a randomized controlled trial (RCT) with 100 participants (50 placebo) in which individuals will receive a functional magnetic resonance imaging scan (fMRI) before ketamine administration and after completing three weeks. “If this study is successful”, says Kortekaas, “it would mean the first step in getting a large amount of people, which don’t react to conventional substances, back into society”. “It’s exciting”, says psychiatrist and neurobiologist Duman (2012), “the hope is that this new information about ketamine is really going to provide a whole array of new targets that can be developed that ultimately provide a much better way of treating depression”.

There aren’t a lot of substances which had its utility reconsidered as often as ketamine. Moreover, the different paradigms surrounding ketamine aren’t mutually exclusive. It’s possible that the same substance could be regarded as an antidepressant in low dosages, a psychedelic in higher dosages and in the highest dosage range a total anesthetic. The nuances between these states must be carefully examined in the future, certainly when ketamine will become available to greater amounts of people as an antidepressant.

 
[1] Ketamine as a model for schizophrenia (Fletcher et al., 2006), ‘body ownership’ (Fletcher et al., 2011), analgesic (Menigaux et al., 2001), ‘sense of agency’ (Moore et al., 2013), perception of time (Coul et al., 2011), morphine synergism (Schulte et al., 2004).
[2] Recreational use of ketamine was first documented in the beginning of the 70s in the underground publication The Fabulous Furry Freak Brothers.
[3] He borrowed this term from computer science where metaprogramming is the writing of a computer program which itself is able to write or manipulate programs.
[4] Psychonautics refer to the paradigm in which the phenomenology of psychoactive substances is examined.
[5] Individuals that don’t react to SSRI’s (selective serotonin reuptake inhibitors) and TCA’s (tricyclic antidepressant).
 
References
Abrams, L. (2012). The Biggest Breakthrough in Depression Research in 50 years is… Ketamine? The Atlantic. Retrieved at: http://www.theatlantic.com/health/archive/2012/10/the-biggest-breakthrough-in-depression-research-in-50-years-is-ketamine/263400/
American Psychiatric Association. (2014). APA 167th annual meeting proceedings. Washington, DC: Author. Retrieved at: http://psychnews.psychiatryonline.org/newsarticle.aspx?articleid=1816463
Baumeister, D., Barnes, G., Giaroli, G., & Tracy, D. (2014). Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles. Therapeutic Advances in Psychopharmacology, 2045125314527985.
Coull, J. T., Morgan, H., Cambridge, V. C., Moore, J. W., Giorlando, F., Adapa, R., Corlett, P. R., Fletcher, P. C. (2011). Ketamine perturbs perception of the flow of time in healthy volunteers. Psychopharmacology (Berl) 218(3):543-56.
Diamond, P. R., Farmery, A. D., Atkinson, S., Haldar, J., Williams, N., Cowen, P. J., … & McShane, R. (2014). Ketamine infusions for treatment resistant depression: a series of 28 patients treated weekly or twice weekly in an ECT clinic. Journal of Psychopharmacology, 0269881114527361.
Duman, R. S., & Aghajanian, G. K. (2012). Synaptic dysfunction in depression: potential therapeutic targets. Science, 338(6103), 68-72.
Fletcher, P. C., Honey, G. D. (2006), Schizophrenia, ketamine and cannabis: evidence of overlapping memory deficits. Trends in the Cognitive Sciences 10(4):167-174.
Jansen, K. (2001). Ketamine: Dreams and Realities. MAPS (Multidisciplinary Association for Psychedelic Studies).
Khorramzadeh, E., & Lotfy, A. O. (1973). The use of ketamine in psychiatry. Psychosomatics, 14(6), 344-346.
Krupitsky E., Burakov, A., Romanova, T., Dunaevsky, I., Strassman, R., Grinenko A. (2002). Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up. Journal of Substance Abuse Treatment, 23, 273-283.
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Rasmussen, K. G., Lineberry, T. W., Galardy, C. W., Kung, S., Lapid, M. I., Palmer, B. A. & Frye, M. A. (2013). Serial infusions of low-dose ketamine for major depression. Journal of Psychopharmacology, 2

World Ayahuasca Conference 2014

December 6, 2021 / Articles, Ayahuasca, Events, History, Publications / By

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Het laatste decennium is de belangstelling voor ayahuasca wereldwijd ontzettend toegenomen. Tot haar “recente” ontdekking door de westerse wereld in 1851 bleef ayahuasca, in Zuid-Amerika ook bekend als “la grande medicina”, verborgen in de dichte begroeiing van het Amazonewoud.

Anno 2014 is de wetenschappelijke belangstelling voor ayahuasca niet louter meer een zaak van etnografen en plantkundigen. Meer en meer is het middel de aandacht gaan trekken van allerlei wetenschappers die de effecten, risico’s en therapeutische mogelijkheden ervan willen bestuderen. Deze beweging klinkt als een verre echo van de vroege jaren ’60, toen onderzoek naar psychedelische middelen als LSD op volle toeren draaide, omdat men vermoedde dat ze konden helpen bij een heilzame verkenning van de geest.

Waarom nu? Ayahuasca wordt veel gebruikt als sacrament binnen Santo Daime en União do Vegetal, twee Braziliaanse religieuze bewegingen. Toen vele kerkleden zich in de VS en Europa gingen vestigen begon de kennis over de plant zich in het collectieve bewustzijn te verspreiden – zelfs Sting had het tegenover Rolling Stone Magazine over zijn ervaringen. Vele mensen beschouwen de plant niet als een recreatieve drug, maar als een serieuze en heilige meesterplant. Vanzelfsprekend is samen met de publieke bewustwording ook de belangstelling van wetenschappers toegenomen.

In september aanstaande wil de World Ayahuasca Conference in Ibiza (Spanje) de discussie stimuleren over de rol van de plant in de wetenschap, geneeskunde, therapie en cultuur door vooraanstaande wetenschappers, farmacologen, antropologen, sjamanen en juridische experts samen te brengen. Op het congres zullen ook belangrijke juridische, ethische en duurzaamheidsvraagstukken aan bod komen die verband houden met ayahuasca.

Onder andere sprekers zullen aanwezig zijn: Dennis McKenna, die al meer dan 40 jaar lang medicinale planten bestudeert, Glenn H. Shepard Jr., etnobotanist, medisch antropoloog en filmmaker, en Anya Loizaga-Velder, klinisch psycholoog, die het therapeutisch potentieel van psychedelische planten onderzoekt. De workshops gaan onder andere over het meest recente wetenschappelijk onderzoek naar ayahuasca, het traditionele en religieuze gebruik ervan, de impact van de globalisering op de consumptie van ayahuasca, en over de rol van vrouwen in de wereld van ayahuasca.

Aangezien het gebruik van ayahuasca blijft groeien is een dergelijke multidisciplinaire dialoog noodzakelijk. Vele mensen gebruiken ayahuasca om hun spirituele horizon te verbreden, anderen om depressie en verslaving te bestrijden. Hoewel verder gedetailleerd klinisch onderzoek naar ayahuasca nodig is en er al heel wat op til staat, is het duidelijk dat de populariteit van en de wetenschappelijke belangstelling voor ayahuasca ons veel vertellen over het aanzienlijke potentieel dat deze plant lijkt te hebben voor de genezing van lichaam, geest en ziel.

Klik hier voor meer informatie over de World Ayahuasca Conference.

Psychedelic Resurgence

December 6, 2021 / Articles, Background articles, Publications, Research / By

This year’s first edition of The Journal of Psychoactive Drugs is a special issue dedicated to the resurgence of psychedelic research. In roughly five themes (LSD, MDMA , ayahuasca, cannabis, research issues and institutes) the journal provides a glance at past and present matters related to research and therapeutic uses of psychedelics.

The first article is a review of the past, present and future status of Lysergic Acid Diethylamide (LSD; Smith, Raswyck, & Dickerson Davidson, 2014). The article comprises a chronological overview of how the psychoactive properties of LSD have led to positive and negative appraisal of the substance in therapeutic research, for military purposes, and recreational use. The article finishes with an overview of contemporary research projects. Another LSD-centered article in the journal, is a qualitative study that retrospectively assesses the long-term experiences of Czech psychologists and psychiatrists that involved in self-experimentation with LSD in the 1950’s – 1970’s (Winkler & Csémy, 2014). The article also serves to present arguments for self-experimentation.

Two review papers are dedicated to address the pro’s and con’s of using MDMA in a therapeutic setting and research issues related to the “Ecstacy Paradigm” (Cole, 2014; Parrott, 2014). A consideration of how psychiatry and psychedelics can benefit from each other, is provided by dr. Ben Sessa (2014), who has been working on MDMA-assisted psychotherapy.

In a qualitative study, Loizaga-Velder and Verres (2014) explored the therapeutic effects of ritual ayahuasca use in the treatment of substance abuse. In line with other studies that yielded promising results in exploring the competence of psychedelics in treating addiction (Heffter Institute, 2012; Krupitsky et al., 2007), the main finding was that participation in ritual ayahuasca sessions facilitated substance dependence treatment.

In New-Mexico, the first state that authorized the use of medicinal cannabis for releasing symptoms of Post-Traumatic Stress Disorder (PTSD), Greer, Grob, and Halberstadt (2014) acquired retrospective data in order to portray the result of this law adjustment. The researchers tentatively conclude that cannabis is associated with PTSD reduction in some patients, and express the need for a study with an experimental design.

An inspiring contribution to this special issue, are two articles dedicated to the past and present of the Heffter Research Institute and the Multidisciplinary Association for Psychedelic Studies (MAPS; Emerson, Ponté, Jerome, & Doblin, 2014; Nichols, 2014). As the editor of the journal, Terry Chambers, expresses in the introduction: ‘…this issue of the Journal is not a comprehensive presentation of the activity of those attempting to understand the properties and uses of psychedelic drugs, but it is an indication of the serious and interesting research being done on this subject.’ The resurgence is happening, and we expect that Dutch scientists will follow soon.

The journal is published online and the abstracts can be freely retrieved from our website.

 
References
Cole, J. C. (2014). MDMA and the “Ecstasy Paradigm.” Journal of Psychoactive Drugs, 46(1), 44–56. doi:10.1080/02791072.2014.878148
Emerson, A., Ponté, L., Jerome, L., & Doblin, R. (2014). History and Future of the Multidisciplinary Association for Psychedelic Studies (MAPS). Journal of Psychoactive Drugs, 46(1), 27–36. doi:10.1080/02791072.2014.877321
Greer, G. R., Grob, C. S., & Halberstadt, A. L. (2014). PTSD Symptom Reports of Patients Evaluated for the New Mexico Medical Cannabis Program. Journal of Psychoactive Drugs, 46(1), 73–77. doi:10.1080/02791072.2013.873843
Heffter Research Institute. 2012. Our Research. Available at: http://www. heffter.org/research-hucla.htm.
Krupitsky, E. M., Burakov, A. M., Dunaevsky, I. V, Romanova, T. N., Slavina, T. Y., & Grinenko, A. Y. (2007). Single versus repeated sessions of ketamine-assisted psychotherapy for people with heroin dependence. Journal of Psychoactive Drugs, 39, 13–19. doi:10.1080/02791072.2007.10399860
Loizaga-Velder, A., & Verres, R. (2014). Therapeutic Effects of Ritual Ayahuasca Use in the Treatment of Substance Dependence—Qualitative Results. Journal of Psychoactive Drugs, 46(1), 63–72. doi:10.1080/02791072.2013.873157
Nichols, D. E. (2014). The Heffter Research Institute: Past and Hopeful Future. Journal of Psychoactive Drugs, 46(1), 20–26. doi:10.1080/02791072.2014.873688
Parrott, A. C. (2014). The Potential Dangers of Using MDMA for Psychotherapy. Journal of Psychoactive Drugs, 46(1), 37–43. doi:10.1080/02791072.2014.873690
Sessa, B. (2014). Why Psychiatry Needs Psychedelics and Psychedelics Need Psychiatry. Journal of Psychoactive Drugs, 46(1), 57–62. doi:10.1080/02791072.2014.877322
Smith, D. E., Raswyck, G. E., & Dickerson Davidson, L. (2014). From Hofmann to the Haight Ashbury, and into the Future: The Past and Potential of Lysergic Acid Diethlyamide. Journal of Psychoactive Drugs, 46(1), 3–10. doi:10.1080/02791072.2014.873684
Winkler, P., & Csémy, L. (2014). Self-Experimentations with Psychedelics Among Mental Health Professionals: LSD in the Former Czechoslovakia. Journal of Psychoactive Drugs, 46(1), 11–19. doi:10.1080/02791072.2013.873158