Research Briefing: LSD back in vogue

This research briefing is co-published with the excellent Report on Psychedelics (RoP). As RoP is restructuring its activities, these blogs may come in at a slightly altered schedule for now.

March 15th, 2022

In the Research Briefing

• LSD safe to give in a novel, cost-effective, therapeutic framework
• Can you distinguish LSD from psilocybin, a new study says no
• The challenges ahead for psychedelics as medicine

LSD safely administrated in a more scaleable treatment protocol

When we think of integrating psychedelic-assisted psychotherapy (PAP) into clinical practice, it may be limited in its reach due to the labour-intensive nature of the current PAP paradigm. In the current paradigm, patients require many hours with psychotherapists in preparation sessions as well as integration sessions following the psychedelic experience. Together, these intensive approaches may render psychedelics expensive and difficult to access, especially for those living with economic disadvantages. Thus, in order to scale PAP, a different approach may be needed.

In the present study, researchers tested the safety and tolerability of escalating doses of LSD in healthy subjects within a novel intervention paradigm which was considered to be more scaleable than the current PAP treatment protocols. This study, sponsored by Eleusis, was divided into two parts: 1) an open-label dose-escalating study involving experienced psychedelic users to evaluate the tolerability and pharmacokinetics (PK) of different LSD doses and determine the appropriate LSD doses for use in the second part of the study; 2) a double-blind placebo-controlled part to allow for the comparison of protocol measurements taken during LSD administration to placebo as well as within-subject comparison of different LSD doses.

The Novel Intervention Paradigm

• Participants spent full days at the research site, and their participation was framed around exploring creativity vis-à-vis a work-related problem they described at their screening visit. This framing required participants to focus on improving an aspect of their life (i.e. productivity on a professional problem) and provided an opportunity to develop an operational protocol for an interventional trial.
• The specific problem-solving aspect of this trial sets it apart from previous studies administering classic psychedelics to healthy participants which have largely been laboratory studies with the sole objective of evaluating safety, pharmacokinetics, and related assessments and/or neuroimaging.
• The design used a single attendant to assist each participant during each drug administration, employed remote monitoring of the rooms used for drug administration, fostered group interactions, and a strong collaborative ‘interpersonal atmosphere’ over a single day prior to drug administration and required no ongoing interaction between participants and attendants after the drug administration day.

Part One

• In part 1, 13 participants were enrolled and received 50µg (n=3, no women, mean age = 28), 75µg (n=7, one woman, mean age = 28) or 100µg (n=3, no women, mean age = 32) LSD on a single occasion.

Part Two

• In part 2, the experimental group (n=9, two women, mean age = 27) received two sequential single doses of LSD (50µg followed by 75µg), with dosing separated by seven drug-free days.
• The placebo-controlled group (n=10, one woman, mean age = 31) received a placebo followed, after seven drug-free days, by a single dose of 75µg LSD.

For both parts 1 and 2, altered states of consciousness were measured using three questionnaires administered at the end of the day of the drug administration session after dinner: the five-dimensional altered states of consciousness (ASC) scale, the ego dissolution inventory (EDI), and the mystical experience questionnaire (MEQ).

The Findings

• LSD was found to be well tolerated in the population studied, with 30 of 33 participants (91%) completing all aspects of the current study.
• There were no serious adverse events while 28% of participants (n=9) experienced at least one expected treatment-emergent adverse advents which included vomiting/nausea, headache and fatigue, among others.
• Compared to placebo, LSD largely produced greater subjective effects than placebo reflected in elevations in ASC, EDI, and MEQ scores with the authors stating that the current report is the first to demonstrate such elevations produced by 50µg LSD specifically.
• A review of the safety and tolerability suggests that the aforementioned novel intervention paradigm may not affect the physical or psychological safety of healthy participants while the observed subjective effects suggest these changes may not inhibit the transcendent, mystical-type experiences that are thought to mediate therapeutic outcomes.
• Qualitative analysis of participants’ accounts can be found here.

Limitations

• The sample only included healthy participants. Clinical populations may require closer monitoring to ensure patient safety and the best possible therapeutic outcomes. Thus, all components of the intervention paradigm that were tested in this study would need to be re-evaluated in clinical samples before implementation in patient populations.
• The overall sample size is small (32).
• Participants were informed of the identity of the drug, raising the possibility of expectancies influencing the results.
• Some components of the novel paradigm may actually be more costly than currently proposed PAP e.g full days at the study site, overnight stays, provision of meals.

Ultimately, the findings of the present study support the feasibility of new treatment design protocols for drug administration and open the door for larger studies designed to evaluate further refinements and additions to these new treatment designs for the safe and cost-efficient delivery of PAP.

Similar subjective effects between LSD and psilocybin in head-to-head comparison

The city of Basel in Switzerland has a long history with psychedelic substances ever since the discovery of LSD by Albert Hofmann in 1938. Today, research with these substances is continuing at the University of Basel by the team at the Liechti Lab. The team here has conducted clinical trials with substances including MDMA, psilocybin and perhaps most notably, LSD, making significant contributions to advancing psychedelics as medicine for the past number of years. At present, their clinical research with LSD is unparalleled in the field of psychedelics. Their latest endeavour is an interesting one.

The present study sought to evaluate and directly compare the acute subjective, autonomic, and endocrine effects of LSD and psilocybin using two doses of each substance and placebo within the same subject. This is the first study to make such comparisons within the same study and using the within-subject design. A total of 28 healthy participants took part in the study. The study consisted of five 25hr experimental sessions where participants were received a placebo, LSD (100 and 200 µg) and psilocybin (15 and 30 mg) in a randomized order (these doses are similar to those used in therapeutic studies). Experimental sessions were separated by 10 days. Outcome measures included self-rating scales for subjective effects, autonomic effects, adverse effects, effect durations, plasma levels of brain-derived neurotrophic factor (BDNF), prolactin, cortisol, and oxytocin, and pharmacokinetics.

Comparing the results:

• LSD at doses of 100 and 200 µg and the psilocybin dose of 30 mg produced comparable subjective effects. Specifically, 200 µg LSD produced comparable positive drug effects to 100 µg LSD, but the higher dose produced greater ego-dissolution and a trend toward an increase in anxiety.
• The 200 µg dose of LSD increased only ratings of ineffability significantly more than 30 mg psilocybin.
• LSD increased blood pressure and body temperature only moderately, whereas 30 mg psilocybin produced significantly greater increases in blood pressure and body temperature compared with LSD and 15 mg psilocybin.
• Both LSD and psilocybin significantly increased plasma cortisol, PRL, and oxytocin levels. Neither LSD nor psilocybin significantly elevated plasma BDNF levels.
• LSD at both doses had clearly longer effect durations than psilocybin.

Overall, both doses of LSD and the high dose of psilocybin produced qualitatively and quantitatively very similar subjective effects, indicating that alterations of mind that are induced by LSD and psilocybin do not differ beyond the effect duration. In an equal number of male and female participants, this study used two well-characterized doses within-subjects to compare the effects of LSD and psilocybin under double-blind conditions in a laboratory setting. However, the highly controlled setting in which the study took place and the involvement of healthy participants only is also the study’s weaknesses.

In terms of blinding, no participant could distinguish between doses of psilocybin/LSD but the placebo was easily identified by participants. When asked to identify the doses, 15 mg psilocybin was mostly mistaken for 30 mg psilocybin, 30 mg psilocybin was mostly mistaken for 100 µg LSD, 100 µg LSD was mostly mistaken for 15 mg psilocybin, and 200 µg LSD was mostly mistaken for 100 µg LSD. Nonetheless, this study indicates that any differences between LSD and psilocybin are dose-dependent rather than substance-dependent and is another significant contribution to psychedelic medicine by the team at the University of Basel.

The challenges psychedelics as medicine face

Psychedelics are poised to be a game-changer in how we view and treat mental health disorders. These psychoactive substances have a relationship with science and society like no other pharmacological agents. Prior to becoming Schedule I substances following the introduction of the Controlled Substance Act in 1970, researchers were working with these substances. While research from this era pointed toward the therapeutic potential of psychedelics, it was largely marred with methodological flaws and practices that would be considered unethical by today’s standards. If psychedelics are going to become viable therapy options, researchers must now contend with the fallout from this era and must overcome new hurdles that continue to present themselves in this modern age of psychedelic research.

The present paper outlines some of the issues faced by modern psychedelic researchers and provides some thoughts on how the challenges they face can be mitigated. The authors outline issues that are inherent to clinical research as well as the broader research environment, discussing issues such as funding, the current scheduling of psychedelics and the need to be transparent.

Factors related to individual research studies:

• Blinding – Used in clinical trials to limit the occurrence of conscious and unconscious bias although in clinical trials with psychedelics it has proven both difficult to achieve and maintain. Unblinding can affect results due to expectancy effects and therefore, trials must be designed in such a way that participants’ beliefs about whether they are in the treatment arm of the trial are approximately matched across groups.
• Therapeutic alliance – The psychotherapy aspect of many trials with psychedelics has the ability to affect treatment outcomes and may enhance the placebo response. Moreover, a therapist may become aware if a patient has been assigned to the treatment group based on their reaction and could potentially deliver different therapeutic processes based on this.
• Expectancy – Many patients in these trials can have preconceived notions regarding their response to treatment and current positive media coverage of psychedelics may be inflating this issue. Whether or not expectancy effects could be held constant remains open to debate. Furthermore, it is unclear whether there are any drugs that would serve as convincing placebos.
• Statistical Power – Many clinical trials with psychedelics are conducted in small samples which reduces the generalizability of results. Trials with large sample sizes are required and may be possible through multisite studies.

Factors related to the broader research context:

• Real-world evidence should be considered when proving the therapeutic effects of interventions, particularly when considering the aforementioned issues in clinical trials. If used, an adequate set of criteria for and against these therapies would need to be developed.
• Full transparency is needed. One step researchers could take is the publication of full clinical trial protocols in peer-reviewed academic journals.
• Public funding is needed as such trials tend to face a more rigorous peer-review process and scientific assessment when compared to philanthropic endeavours.
• The current scheduling of psychedelics stands at odds with their safety profile and as a result, potential therapeutic applications will continue to impact and create biases in their evidence base. Furthermore, research will remain costly and restricted to the highly controlled research environments unless psychedelics are rescheduled.

Designing research for future use in standard medical practice:

• Psychedelic therapy research design should include techniques to manage the risks relating to the changes in consciousness resulting from the psychedelic experience. Some techniques include multiple practitioners, transparent practices and videotaping sessions.
• Unregulated self-treatment may become more common as the general public increasingly view this class of drugs as viable medicines and ultimately increase the prevalence of adverse events in light of challenging experiences.
• Current models of psychedelic therapy are extremely resource-intensive, creating issues regarding accessibility and entrenching healthcare inequality. There is a need for research into lower-cost alternatives to the current resource-heavy model.
• Incorporating traditional practices into modern research into psychedelics may be of significant therapeutic value and help to maintain the cultural heritage of the indigenous groups who have stewarded much of psychedelic medicine.

Research Report Readout

Maria Bălăet̨ dives deep into the psychedelic state of cognition. She explores what we know, and more importantly, the open questions (and limitations of current research) on psychedelic cognition. How you perceive yourself (disintegrating and reintegrating the self) is explored in another (pre-print) paper.

A large survey with over 2000 participants investigated the naturalistic (outside of the lab) use of psychedelics. For most, the use of psychedelics correlated with positive outcomes on mental health and well-being. For those who do more psychedelics, the outcomes were better. But for those who had perceived harm from use (13%), the health benefits were less pronounced.

In the lab, in an open-label study, participants who had a mystical experience (MEQ), were also the ones who had lasting positive effects (PEQ) three months later.

If psychedelics are to be approved, we need a lot more data on how they interact with other medications. The data is limited and only a few studies have looked at the interaction with mood stabilisers, antidepressants, and antipsychotics. A review brings the current evidence together.

Next to investigating other medications, researchers from MAPS also looked at how MDMA plus therapy (MDMA-AT) can help reduce eating disorders. Reflecting on the data from 90 participants, the researchers found a significant effect on symptoms of eating disorders.