- 🔑 Paper Claims Psychedelics Exert Antidepressant Effects By Binding to TrkB, Not 5-HT2A
- 💵 Kentucky Earmarks $42 Million for Ibogaine Research
- 🔐 Reunion Neuroscience Announces Take-Private Transaction
- 🧭 Compass Patents Upheld
- ⚖️ Psychedelic Policy Reform Updates
and lots more…
Psychedelic Sector News
Paper Claims Psychedelics Exert Antidepressant Effects By Binding to TrkB, Not 5-HT2A
A paper in Nature Neuroscience caused quite a stir last week. A group of researchers at University of Helsinki claim that LSD and psilocin “directly bind to TrkB with affinities 1,000-fold higher than those for other antidepressants”, binding to “distinct but partially overlapping sites within the transmembrane domain of TrkB dimers.”
TrkB is the receptor for brain-derived neurotrophic factor (BDNF), which is instrumental in the growth and survival of neurons and the promotion of neuroplasticity, among other functions.
An earlier paper from the group claimed that both fluoxetine and ketamine act by directly binding to TrkB (Casarotto et al., 2021), too.
The group’s thesis appears to fly in the face of a prominent tenet in some corners of psychedelic research that maintains it’s the 5-HT2A receptor primarily mediating the apparent therapeutic effects of psychedelics. “To date, most papers focusing on psychedelics’ neurotrophic actions never provided a convincing alternative path to 5-HT2A of this magnitude”, psychedelic researcher and drug developer Mario de la Fuente told Psychedelic Alpha.
Speculating on why this paper has sparked so much discussion within the psychedelics research community, de la Fuente said that the researchers, “didn’t fill in the gap with a mechanistic speculation, they provided biophysical evidence of a direct interaction between LSD, psilocin, lisuride and the BDNF receptor TrkB… and they did so with a compendium of methodologies.”
What’s more, the group claims that the effects of LSD and psilocin on “neurotrophic signaling, plasticity and antidepressant-like behavior in mice” are not only dependent on TrkB binding and the associated promotion of endogenous BDNF signalling, but that these effects are independent of 5-HT2A activation. This was ascertained by employing 5-HT2A antagonists. LSD-induced head twitching, meanwhile, is independent of TrkB binding but dependent on 5-HT2A activation.
Put simply, the group is implying that TrkB is responsible for the therapeutic effects of the psychedelics under study, while 5-HT2A is responsible for the psychedelic effects (using head-twitch in mice as a proxy).
The upshot is that the group believes there may be potential in developing non-hallucinogenic psychedelic-inspired antidepressants that work by binding to TrkB but lack 5-HT2A activity. In this sense, they might resemble something akin to ‘better’ or ‘stronger’ SSRIs. Indeed, the paper discloses that seven of the co-authors are inventors on a patent application related to the filings.
In the past decade, some groups have sought to develop TrkB Positive Allosteric Modulators (PAMs) for neurodegenerative disorders, though research remains sparse.
Elsewhere, Semax—a drug that’s almost exclusively used in Ukraine and its occupier, Russia—rapidly increases levels of BDNF and expression of TrkB in the hippocampus of animals studied. It’s used to aid recovery from stroke and transient ischemic attack as well as hypoxia and other conditions. Aside from its apparent neuroprotective properties it’s found further interest among biohacker enthusiasts for its potential cognitive enhancing effects, where it’s often categorised as a nootropic. In 2007, a psychiatrist based at the Catholic University of Korea College of Medicine, in Seoul, wrote that further research into the potential role of Semax in treating depression was warranted. There have been no published trials of Semax outside of the former Soviet sphere.
Back to the present discussion: it’s much too early to throw out other theories of psychedelics’ primary mechanism of action just yet, given that the findings are yet to be replicated and the fact that we’re looking at mouse brains at this stage. But, this paper has generated healthy discussion surrounding the uncertainty of psychedelic mechanisms of action.
Given the magnitude of the findings, it won’t be long before we see peers attempting to replicate this work, expand on the hypothesis and evaluate the specificity of Moliner et al.’s findings with other chemotypes”, de la Fuente told us.
It looks like it might not be too long before we start to hear from labs looking to replicate the findings. University of North Carolina’s Bryan Roth told Psychedelic Alpha that his lab is attempting to do just that, and as de la Fuente points out: they surely won’t be alone.
Editor’s note: Shortly before this bulletin went to press, another potential unifying mechanism was put forward by Gül Dölen et al. in a heavily-anticipated Nature publication. Dölen and colleagues suggest that psychedelics—and that term can be used broadly as the researchers not only tested LSD and psilocybin but also MDMA (an empathogen), ibogaine (an atypical psychedelic) and ketamine (a dissociative anaesthetic), with cocaine and saline used for comparison—appear to reopen the social reward learning critical period in mice.
Interestingly, the length of time for which the critical period remains open appears to be correlated to the duration of subjective effects, with ketamine providing the shortest opening, and ibogaine the longest.
Kentucky Earmarks $42 Million for Ibogaine Research
On May 31, Attorney General Daniel Cameron opened a Kentucky Opioid Abatement Advisory Commission press conference. “We cannot continue to lose over two-thousand Kentuckians [to addictions] each year”, Cameron said. This is why, he added, the state Attorney General’s office has sought to tackle the opioid epidemic over the past years.
“I look forward to the Commission’s exploration of possibilities”, he said, hoping that they might find “the next big breakthrough”.
Bryan Hubbard, who chairs the state’s Opioid Abatement Advisory Commission, then announced that, “we are here to announce the arrival of Kentucky’s breakthrough opportunity”: ibogaine.
“Ibogaine is an alkaloid derived from three plant sources” found in West African countries. “Anecdotal evidence that is a mountain high and decades wide suggests that ibogaine, within 48 to 72 hours of administration in safe, clinically-controlled conditions, resolves opioid withdrawal syndrome”, Hubbard explained.
“If this anecdotal evidence can be clinically validated, ibogaine would represent a transformative therapeutic or treatment of opioid use disorder”, he added.
Next, Lieutenant General Martin R. Steele took to the podium. “While ibogaine might not be the right option for everyone”, for those not touched by existing options this should serve as “a reason for hope”, Steele noted, invoking the name of the organisation he co-founded.
Later in the conference, Hubbard explained that “over the coming months, the commission will explore the possibility of devoting no less than $42 million over the next six years to the creation of public-private partnerships which can incubate, support and drive the development of ibogaine all the way through the FDA approval process.”
“Kentucky will also seek to develop the platinum standard model for an ibogaine recovery protocol by hosting multi-site clinical trials right here at home”, he added.
“We must overcome the opioid epidemic by any and all humanitarian means necessary. Our history demands it.”
This funding, which remains subject to a vote, is largely the product of campaigning and education by Reason for Hope and the Veteran Mental Health Leadership Coalition.
Reunion Neuroscience Announces Take-Private Transaction
On June 1st, Reunion Neuroscience announced that it has entered into a take-private agreement with MPM BioImpact, whereby the publicly-traded company would be acquired in an all-cash transaction valued at around $13 million.
The transaction would take the company private, with shareholders receiving $1.12 per share. This represents a 62% premium on the closing price of REUN shares the day prior to the announcement. Since the announcement, the stock has remained above $1, suggesting some level of confidence that the transaction will be completed.
In order to complete the transaction, among other conditions Reunion must have no less than $8 million in cash immediately prior to the closing of the deal. As such, MPM’s $13.1m purchase price represents just a $5.1m premium over the company’s worst-case cash reserves.
While Reunion had around $32m in cash and cash equivalents at the end of the 2022 calendar year, it made a comprehensive loss of $12.4m during its most recently filed quarter (ending December 31, 2022). Projecting this forward, Reunion might come close to the $8m cash limit in the agreement.
Still, MPM’s offer was welcomed by Reunion’s CEO Greg Mayes, who said Reunion is “thrilled that MPM recognizes the value and differentiation” of the company’s pipeline.
That differentiation has been called into question as of late, as it emerged that Reunion’s lead candidate had been claimed in a Mindset Pharma patent application with an earlier priority date. Seemingly backed into a corner, Reunion responded by suing Mindset, alleging that it “knowingly copied” its lead candidate (read our analysis).
Then, in April, NASDAQ informed Reunion that it was heading towards being delisted, as it was failing to meet a minimum price of $1 per share.
The transaction is expected to close in Q3.
Compass Patents Upheld
In June 2022, the U.S. Patent Trial and Appeal Board (PTAB) denied institution of two post-grant reviews (PGRs) of Compass Pathways’ ‘257 and ‘259 patents, which cover Polymorph A. PTAB found that each of Freedom to Operate’s (FTO) invalidity arguments were unsupported and unpersuasive. For more information, see our earlier coverage in Bulletin 108.
FTO sought to have the situation revisited by requesting a rehearing. However, PTAB has again rejected FTO’s calls to institute PGRs. In the conclusion of the decision letter explaining the refusal, the assigned Administrative Patent Judges determined that, “Petitioner has failed to show that we abused our discretion in declining to institute a post-grant review of the challenged claims of the ’257 patent or the ’259 patent.” Therefore, it was ordered that the petitioner’s requests for rehearing be denied.
Featured Psychedelic Jobs
- Head of Research at Lionheart Ventures.
- Postdoc Research Associate at University of Utah College of Social Work Center on Mindfulness and Integrative Health Intervention Development.
CNN’s The Whole Story with Anderson Cooper Goes Inside a Jamaican Psychedelic Retreat: This Sunday
One of CNN’s flagship programmes will see correspondent David Culver travel to a psilocybin retreat in Jamaica to “explore the therapeutic benefits of medically supervised consumption of psilocybin” Culver follows a group of “everyday Americans” who attend the retreat for various reasons, and also ingests psilocybin mushrooms himself. “The mushrooms took me on a journey I did not expect”, the said. The episode also sees Culver travel to Oregon.
NIDA Expresses Interest in Funding Research Into Relationship Between Psychedelic Drug Policy Reforms and Public Health Outcomes
In a Notice of Special Interest published on June 13, NIDA expressed a special interest in grant applications that set out to examine the impact of changing state and local psychedelic drug policies. Further information can be found here.
Indigenous Search Team Partook in Yagé Ritual On Morning of Rescue of Four Children in Colombian Amazon
While following the coverage of this remarkable story, we noticed this detail at the foot of a Guardian write-up:
It was perhaps telling that the first people to find the children were members of the Indigenous search team, who had been calling out in native languages. On the morning of the rescue they partook in a ritual with yagé (ayahuasca), a traditional jungle medicine with psychedelic properties.
“They were found by an Indigenous guardian who took yagé and with the support of the army’s technology,” said Luis Acosta, coordinator of the Guardia Indígena. “Those who take yagé see far beyond what we see. He becomes a doctor, a panther, a tiger a puma. He sees beyond because it’s a holistic medicine. He had the capacity to look.”
Speaking on Saturday, Fatima Valencia also credited the spiritual and natural worlds for her grandchildren’s survival.
“I give thanks to Mother Earth, because she released them.”
Psychedelic Alpha’s Josh Hardman to Interview Christian Angermayer at PSYCH Symposium
On July 6th, Josh will be sitting down with atai Life Sciences founder and chairman Christian Angermayer for a fireside conversation. The interview will take place at PSYCH Symposium, hosted at the British Museum in London. Get discounted tickets by using the code HARDMAN15.
Non-LSD Psychedelic Drug Use Nearly Doubles Among 19-30 Year Olds
A study by University of Michigan and Columbia University found that past 12 month use of non-LSD hallucinogens has nearly doubled between 2018 and 2021, from 3.4% to 6.6%. LSD use, meanwhile, remained stable at around 4%. The data was derived from the National Institutes of Health’s Monitoring the Future panel study.
Wired: Scientists Gave People Psychedelics—and Then Erased Their Memory (May 31)
Bio.News: Psychedelics ‘do things to the brain that nothing else does (June 9)
HuffPo: Drew Barrymore Considering Psychedelics To Explore Why She’s Not Open To Relationship (June 6)
Guardian: ‘Beyond the evidence’: media reports overhype ketamine’s use as a depression treatment, review finds (June 8). And, here’s the study in question, published in The British Journal of Psychiatry.
The Times: Australian psychiatrists prepare for magic mushrooms to be legal treatment (June 11)
STAT: Ketamine is comparable to ECT for patients with treatment-resistant depression, study shows (May 23)
ESPN: Former PGA Tour pro Morgan Hoffmann’s nontraditional restorative journey (June 11)
NYT: What Does Good Psychedelic Therapy Look Like? (June 3)
Oprah Daily: Oprah Talks to Scientist Roland Griffiths About the Power of Psychedelics and the Gratitude of Mortality (June 8)
Videos from the UC Davis Health 2023 Psychedelic Summit are now available:
- The Promise of Psychedelics in Medicine
David Lubarsky, UC Davis Health
- Psychedelics and Plasticity-Promoting Neurotherapeutics
David E. Olson, UC Davis
- Neuropsychedelia: From Psychotomimetic to Psychotherapeutics
Mark Geyer, UC San Diego
- Psilocybin Therapy: Current Challenges & Future Prospects
Joshua Wooley, UC San Francisco
- Microdosing: Fact or Fiction?
Harriet De Wit, University of Chicago
- The Cognitive Neuroscience of Psychedelic Drugs
Frederick Streeter Barrett, Johns Hopkins University
- Beyond Psychedelics: Augmenting Mood Enhancing Effects
Dhakshin Ramanathan, UC San Diego
- Probing and Rescuing Dysfunctional Brain Circuits in Depression
Conor Liston, Weill Cornell Medicine
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