This research briefing is co-published with the excellent Report on Psychedelics.

July 23rd, 2021

In The Research Briefing:

• LSD increases empathy via oxytocin independent of serotonin receptor activity
• Low dose LSD engenders therapeutic processes by inducing suggestibility alongside psychosis-like pheneomena and mystical experiences
• Novel gene repression method improves the yield of psilocybin biosynthesis by over 300%

EMPATHY

LSD increases empathy and oxytocin partially independent of 5-HT2A receptor activity

MDMA produces prosocial bonding and strong empathogenic effects, but these phenomena have received comparatively less attention with respect to other psychedelic substances. A recent line of research has shown that LSD enhances emotional empathy and sociality, a complex phenomenon that is typically assessed by showing pictures of other people with emotional content. For instance, by showing someone a picture of a crying child within a war scene, and asking them to rate how much they feel for the other person (i.e., explicit emotional empathy) and how much arousal they feel in response to each scene (i.e., implicit emotional empathy).

The current study sought to investigate how LSD increases implicit and explicit empathy, whether these effects are mediated by the 5-HT2A receptor, or by proxy of increased oxytocin circulating in the blood flow. The study used a double-blind, placebo-controlled, crossover design and administered a wide dose range (25, 50, 100, and 200μg) across multiple sessions. Additionally, they included a ketanserin pretreatment condition in conjunction with 200μg LSD to selective block 5-HT2A activity. The empathy test was administered 6 hours after LSD administration.

What did they find?

• Explicit and implicit emotional empathy were enhanced by LSD and only by the highest 200 μg dose and not by doses of 100 μg or lower. This was only weakly attenuated by ketanserin
• LSD alone significantly increased plasma oxytocin concentrations at the 200 μg dose, whereas a dose of 100 μg LSD did not increase plasma oxytocin levels in another study
• Ketanserin prevented the moderate LSD-induced increase in plasma oxytocin, indicating that the effects of LSD on the oxytocin system involve 5-HT2A receptors
• LSD-induced increase in oxytocin was only 1.25 to 3-fold higher compared with placebo, compared to MDMA which increases plasma oxytocin levels 3 to 11-fold compared with placebo

Taken together, the present findings indicate that LSD-induced empathogenic effects are neither mediated via oxytocin release nor via direct 5-HT2A receptor activation. LSD also binds with high affinity to 5-HT1A and dopamine receptors, although similar empathogenic effects have also been observed for psilocybin (Pokorny et al., 2017), which does not have an affinity to dopamine receptors. The involvement of other factors and receptors in emotion processing are thus likely to contribute to this process. The question of whether LSD also enhances empathy in patients with impairments in social functioning awaits further investigation!

PSYCHOSIS & HEALING

Mystical experiences may be the bridge between the psychosis model and the therapeutic model of psychedelics

Research on LSD is notoriously multifaceted as scientists have characterized its subjective as either psychosis-like, mystical, or mind-revealing across various stages of its historic development. In fact, Humphrey Osmond who coined the term ‘psychedelic’ in conjunction with Aldous Huxley, sparked his interest in the substance upon noticing that it induces similar effects as the symptoms of schizophrenia. And although many researchers were interested in utilizing the mind-manifesting psychedelic properties of the substance to treat alcoholism and mood disorders, these research efforts were undercut by the cultural shift which propagated the myth that psychedelics can induce psychosis. Although this myth is largely discredited, the psychotomimetic model remains one of the most well-studied paradigms that compares the similarities and differences between psychedelics and psychosis (Geyer & Vollenweider, 2008).

As the word psychotomimetic implies, psychedelics mimic some of the most salient features of psychosis, such as altered perception of senses, self, body, time, altered emotions, impaired cognition, loss of intentionality, magical thinking, among others. But given the proximity of these symptoms to a state of psychosis, how is it that the same subjective effects take up such a central role within psychedelic-assisted psychotherapy? The current study sought to address this nuanced issue by examining how low-dose LSD (50 μg) occasions these experiences within the same cohort, in order to investigate the relationships that underly these different constructs within a randomized, double-blind, placebo-controlled, crossover study.

What did they measure?

• Psychotic experiences were assessed within the model of aberrant salience, which is broadly defined as the process of placing inappropriate significance toexternal objects or internal representations, which gives rise to hallucinations and delusions in psychotic phenomena
• Therapeutic potential was assessed by suggestibility (Creative Imagination Scale, CIS) and mindfulness (Five Facet Mindfulness Questionnaire, FFMQ; Mindful Attention Awareness Scale, MAAS; Experiences Questionnaire, EQ)
• Psychedelic experiences were assessed assessed with four questionnaires: Altered State of Consciousness Questionnaire, Mystical Experiences Questionnaire, Challenging Experiences Questionnaire, and the Ego-Dissolution Inventory

What was the relationship between these experiences?

• LSD-induced aberrant salience which highly correlated with altered state of consciousness, mystical experiences, and ego-dissolution
• LSD increased suggestibility but not mindfulness

What does this reveal?

The results suggest that psychedelic and psychotic experiences share a mystical and ego-dissolution phenomenology. LSD spontaneously increased psychosis-like attributes to a greater extent than therapy-related aspects in the psychedelic experiences, which points to common mechanisms. LSD also increased suggestibility but not mindfulness, which indicates that substance does not have intrinsically therapeutic properties, but that therapeutic processes are engendered via therapeutic suggestion.

The authors also suggest a similar mechanism for LSD-induced aberrant salience, which might increase significance attribution and reduce ego boundaries and defence mechanisms, allowing for therapeutic changes in perspectives and attitudes. Hence the process of meaning attribution may elevate psychosis-like phenomena through therapeutic suggestions that foster mystical experiences.

BIOSYNTHESIS

Psilocybin yield from bacteria biosynthesis increased by 300%

The demand for psilocybin is on the rise, yet the cost of pharmaceutical-grade psilocybin is estimated at around $2,000 USD per gram (Fricke et al., 2019) while researchers might pay up to $7,000-$10,000 per gram. This raises the incentive to develop a more cost-effective means of producing the substance. And while the traditional route of chemical synthesis is being pursued most vehemently by COMPASS pathways and the Usona Institute, a number of new companies, such as Psybio Therapeutics, Psygen, Octarine Bio, and CB Therapeutics, are exploring the alternative route of biosynthesis. This involves genetically altering the metabolic networks of yeast or bacteria to convert sugar molecules into the desired compound.

A previous paper that described the first successful attempt of producing psilocybin on the gram scale with the bacteria E. coli, yielded a 32-fold improvement over earlier techniques. But the costs per serving (before any other costs) would then be $40-$50 at 20-30mg per 70kg. This was still higher than the costs of commercially available magic mushrooms or truffles (at $/€10-15). However, the current paper applied a novel gene repression method, which enabled them to selectively inhibit metabolic enzymes that interfere with psilocybin biosynthesis. This effectively improved the yield by an additional 302.9%.

What is novel about this technique?

• The previous attempt to synthesize psilocybin still required expensive precursor materials, given the difficulty of facilitating trypthophan synthesis within E. coli. To solve this problem, they used a more efficient mutation of the tryptophan synthase enzyme and inserted it into E. coli
• The efficiency of psilocybin synthesis was previously limited by the efficiency of methyltranferase enzyme (psiM), so the investigators inserted additional RNA strains into E. coli to overexpress this enzyme
• The investigators identified native pathways in E. coli that interfere with the biosynthesis of psilocybin, for instance transporter enzymes that diminish the cellular concentration of its unfinished precursors. The selective repression of this drug transport enzyme alone increased the production of psilocybin by 107.2%
• The investigators developed a novel RNA-based method that selectively repressess certain genes in a cell-density-dependent manner. Interfering with the genetic make up of the organism itself may otherwise severely impair its natural growth cycle of the host organism and lower its productivity. However, this technique repressess genes on a transcriptional (RNA) level and they were able to repress interference with psilocybin synthesis without impeding on the cellular growth of E. coli

The combined result of these innovations resulted in a 302.9% improvement in their biosynthesis of psilocybin. In reference to previous cost efficiency estimates, this method puts the cost of psilocybin at around $13 – $16.50 at 20-30mg per 70kg. Hence the current study significantly closes the cost gap between psilocybin biosynthesis and growing psilocybin mushrooms/truffles. And although it raises the competitive potential of the biosynthesis method, it is still questionable whether it can match the synthetic method developed by the non-profit Usona Institute that can produce psilocybin even on a large (1kg) scale.

Related Articles:

• Enzymatic synthesis of psilocybin
• Production Options for Psilocybin: Making of the Magic
• In vivo production of psilocybin in E. coli
• Direct Phosphorylation of Psilocin Enables Optimized cGMP Kilogram-Scale Manufacture of Psilocybin

Research Report Readout

The transdiagnostic quality of psychedelics (being effective for many mental health disorders) lies in the ability to increase neuronal and mental plasticity. The combination with therapy can aid adaptation and resilience to lead to long-term well-being.

In this opposing viewpoint to ‘Moving Past Mysticism’, an article which argued that ‘mystical’ constructs are overly laden with beliefs and do not suffice objective measurement, it is argued that ‘mystical experiences’ have a rich history of scientific investigation as the authors lay out a brief summary of their underlying constructs and empiric validation

An interview study with five participants examines the attitudes of palliative care workers towards the use of psilocybin therapy for death anxiety and identified common themes concerning the perceived barriers of treating existential distress and their uncertainty about the risks and benefits of psilocybin.

Psilocybin produces robust perceptual alterations of bodily awareness and self-experience that were related to decreased brain response to surprising tactile stimuli.

The subjective effects of LSD, in one study, significantly overlapped in the phenomenology of psychotic, mystical, and ego-dissolving experiences. The importance of meaning attribution to psychotic experiences explains how these different constructs converge in mystical experiences.

Ketamine’s side effects are mild and self-limiting even among depressed patients with psychosis. While limited in sample size, the available literature does not support the assumption that ketamine will exacerbate psychotic symptoms in predisposed patients.

An observational survey study with over 750.00 respondents investigated the relationship between lifetime classic psychedelic use and cardiometabolic diseases and found that it was associated with a 23% lower odds of heart disease and a 12% lower odds of diabetes in the past year.