Twitter Peer Review
Discover more from The Trip Report by Beckley Waves
Twitter Peer Review
Plus updates from Freedom to Operate, the DEA, Health Canada, and the industry's first acquisition
Several developments in the psychedelic arena this week are worth exploring, including:
A request of Compass Pathways to disclaim a patent
The DEA plans to schedule two additional compounds that serve essential research functions for psychedelic researchers
But first, a longer piece about a recent study that compared psilocybin to the SSRI Escitalopram using the brain imaging technology fMRI.
Psilocybin vs. Escitalopram with fMRI
On Monday, this announcement from the UCSF News Center came across my newsfeed.
It is a high-level summary of results from a new study titled Increased global integration in the brain after psilocybin therapy for depression by lead author Robin Carhart-Harris and colleagues at Imperial College London.
From UCSF News Center:
“The discovery points toward a general mechanism through which psychedelics may be acting therapeutically on the brain to alleviate depression and possibly other psychiatric conditions that are marked by fixed patterns of thinking…
The scans, which were done before and after treatment, showed the psilocybin treatment reduced connections within brain areas that are tightly connected in depression, including the default mode, salience, and executive networks, and increased connections to other regions of the brain that had not been well integrated…
No such changes were seen in the brains of those who received escitalopram, suggesting that psilocybin acts differently on the brain than SSRIs.”
The paper marks a significant milestone in psychedelic science because it is the first comparison of a psychedelic against another treatment, the SSRI Escitalopram (Lexapro), using an objective marker of neurophysiological changes with Functional Magnetic Resonance Imaging (fMRI)
(See What if the 'Psilocybin vs. Escitalopram' trial used Digital Biomarkers to measure results? for discussion of the original paper.)
Notably, the findings suggest a different mechanism for how psilocybin works for depression compared to SSRIs.
The authors note in the paper (emphasis added):
“the antidepressant response to psilocybin was rapid, sustained and correlated with decreases in fMRI brain network modularity, implying that psilocybin’s antidepressant action may depend on a global increase in brain network integration. Network cartography analyses indicated that 5-HT2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after psilocybin treatment. The antidepressant response to escitalopram was milder and no changes in brain network organization were observed.”
Not long after, I stumbled upon this from UNC psychopharmacologist Brian Roth.
The takeaway at this point seemed that while both psilocybin and Escitalopram assisted therapy reduce symptoms of depression, only psilocybin does so through neuroplastic modulation of brain regions associated with depression.
In other words, as the title of the UCSF press release puts it, psilocybin rewires the brain; Escitalopram doesn’t.
So far, it seems like an exciting finding that supports the commonly accepted idea that psychedelics promote neuroplastic changes in impaired circuits and regions of the brain to achieve their therapeutic benefit.
Given the significance of comparing psilocybin to escitalopram with objective biomarkers through fMRI, I sensed we were in for a deluge of commentary about these findings. So I started to track responses:
Twitter: The New Peer Review
If you’re not on Twitter, God Bless you—you’re doing yourself a favor. Seriously.
But if you are, you will have certainly realized that the social media platform, in addition to being the new public square, is also the New Peer Review Process.
And this paper was reviewed pretty harshly.
First, I happened upon this from Johns Hopkins researcher Manoj Doss:
Then this from Yale’s Phil Corlett:
Then I started to track several other critiques, including this and this.
Sensing a trend and not understanding why there was so much pushback, I asked for an explanation.
What followed was a lively exchange between Drs. Corlett, Carhart-Harris, and others that interested readers are free to view, even if you’re not on Twitter (remember, you’ve been warned).
Comments from Jacob Aday and Sandeep Nayak were constructive for me.
After all of this, the take-home message is that the psilocybin group showed a statistically significant change in modularity (the biomarker of neuroplastic changes) from baseline, and the Escitalopram group did not.
However, the difference between the two groups, while approaching statistical significance—was not, in fact, statistically significant—therefore, we cannot conclude that neuroplastic changes caused the psilocybin’s antidepressant effects.
In other words, we can’t conclude that psilocybin works differently than Escitalopram, but we have intriguing data that lends itself to guiding replication efforts and further exploration.
An Open Letter to Compass Pathways
From the Freedom to Operate (FTO) newsletter on Thursday, April 4th:
“This week, FTO has published an open letter to Compass Pathways’ CEO, George Goldsmith, regarding the invalidity of one of Compass’ U.S. patents on psilocybin. To date, Compass has obtained patent claims on two psilocybin polymorphs, Polymorph A and Hydrate A. FTO has previously filed petitions with the U.S. Patent and Trademark Office for post-grant review of three patents that include claims directed to the first of these polymorphs, Polymorph A. The letter to Compass, which marks the most recent occasion on which FTO has disputed the validity of a Compass patent on psilocybin, serves to put Compass on notice that FTO believes U.S. Patent No. 11,149,044 is also invalid as relating to a known form of crystalline psilocybin that was publicly used prior to the date on which the patent for the claimed invention was first filed.”
Conventional pharmaceutical drug development looks like this:
A company identifies or discovers a new molecule they think has therapeutic potential.
Then they test it in FDA-sanctioned clinical trials for safety and efficacy.
The FDA approves it if it is safe and effective, and then doctors can prescribe it.
Classical Psychedelics, and related compounds like MDMA, on the other hand, are not new and have been used in various contexts for millennia.
Albert Hoffman, famous for discovering LSD, also identified and isolated psilocybin and psilocin as the active ingredients in the psychedelic mushroom species P. Mexicana in 1958, and Merck first synthesized MDMA in 1912.
Therefore, these and other substances are not patentable by the most common (and most defensible) pharmaceutical IP strategy—Composition of Matter patents. So commercial entrants, like Compass, must develop patent strategies in other ways.
In the absence of composition of matter, specific polymorphs—which describe how psilocybin molecules arrange themselves in crystal form—are the novelty for which Compass’ patents have been approved.
FTO is disputing the validity of this approach by presenting evidence that the claim upon which this patent relies is neither new nor novel.
As Shayla Love of Vice notes in a thorough and informative piece on the issue:
“Freedom to Operate believes its research showed that Hydrate A is not a new form of psilocybin—this is significant because patents are only supposed to be granted on new inventions. Research published in the peer-reviewed crystallography journal Acta Crystallographica, and funded by Freedom to Operate, claims that Hydrate A was available as early as 1963 and was used in human clinical trials as early as 2017.”
In light of this, the implication is that the patent awarded to Compass for Hydrate A should not have been granted, and thus the letter from FTO asks Compass to disclaim the patent or issue a Covenant Not to Sue:
“In light of the foregoing, I trust that you will agree that there can be no valid claim to so-called “Hydrate A” of crystalline psilocybin, or its use to treat medical conditions such as depression. I therefore ask that Compass disclaim the ‘044 Patent or, at a minimum, publiclycovenant that it will not attempt to enforce any claim of the ‘044 patent, using the form attached as Exhibit A.”
DEA to Schedule Two Psychedelics Important for Basic Science
From the Federal Register:
“The Drug Enforcement Administration proposes placing two phenethylamine hallucinogens [2,5-dimethoxy-4-iodoamphetamine (DOI) and 2,5-dimethoxy-4-chloroamphetamine (DOC)], as identified in this proposed rule, in schedule I of the Controlled Substances Act. This action is being taken, in part, to enable the United States to meet its obligations under the 1971 Convention on Psychotropic Substances for one of these substances. If finalized, this action would impose the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances on persons who handle (manufacture, distribute, reverse distribute, import, export, engage in research, conduct instructional activities or chemical analysis with, or possess), or propose to handle these two specific controlled substances.”
As I noted back in The Bureaucratic Burden on Psychedelic Science
“However, clinical trials are built on the foundation of basic and translational research, which aims to understand the underlying molecular biology, chemistry, genetics, and safety by conducting experiments with cellular cultures, animals, and other means.
This foundational work in most areas is done at universities or other non-commercial research laboratories. It is funded in the traditional way, namely through grants from government and philanthropic agencies.
However, as we noted, psychedelics because of their Schedule 1 classification are not readily funded by these traditional avenues, and the pipeline of new projects entering clinical trials is stunted.”
Because they are very similar to other psychedelics, especially in their activation site, the 5HT2A receptor, they are an essential tool in building the basic scientific literature for psychedelic research. Adding these compounds to the list of Schedule I substances will impede such work.
The DEA is accepting comments from the public here until June 10th.
Other News and Further Reading
Health Canada announces review of all MDMA trials, as complaint alleges major flaws and safety issues
“The complaint about Health Canada-approved trials conducted by the U.S.-based Multidisciplinary Association for Psychedelic Studies (MAPS) was submitted to the federal agency on March 4 by a group of academics and journalists.
Health Canada confirmed Wednesday that it's now reviewing all trials involving MDMA to ensure patient safety and compliance with regulations.”
Numinus Acquires Novamind
From the Press Release:
“Numinus Wellness Inc. and Novamind Inc., are pleased to announce that they have entered into a definitive arrangement agreement pursuant to which Numinus will acquire all of the issued and outstanding common shares of Novamind in an all-share transaction, by way of a court-approved plan of arrangement, for total consideration of approximately C$26.2 million on a fully diluted in-the-money basis.
Following the Transaction, the combined company will operate 13 wellness clinics and will be positioned as a leading psychedelic-assisted therapy provider in North America, leading its peer group in revenue with approximately C$10 million in annual pro-forma revenue based on the trailing four quarters.”
On Entheogenic Practitioner Duties and Privileges under Oregon’s 109 Program
“Under 109, we are excited to see Oregon blaze the path and set the example for the kind of effective, equitable and affordable regulated access program for the rest of the country to follow. I recently was gratified to read Jon Dennis’s Entheogenic Practitioner proposal which I believe can further optimize and expand the program not only for religious groups, but for group healing generally, while helping make the program more economically accessible and ensuring safety for participants. In particular I want to share the specific policy proposals in his proposal, and point out which are relevant for group healing generally under the program, especially those that will reduce cost and broaden access in a safe way.”
Oklahoma Senators Approve Psilocybin Research Bill But Delete Decriminalization Provision Passed By House
“An Oklahoma Senate committee on Monday unanimously approved a House-passed bill to allow for the cultivation and administration of psilocybin by eligible institutions for research purposes—but the version that senators advanced omits a broader decriminalization provision that had previously been included.
The Senate Health and Human Services Committee advanced the amended legislation from Rep. Daniel Pae (R) in a 9-0 vote. The bill is a committee substitute of an earlier version that originally contained a provision to decriminalize psilocybin for unauthorized use by making it punishable by a fine without the threat of jail time.”
Thanks for reading, and have a great weekend!
Zach