Exploring the LSD-Derivative With Potential for Treating Mood Disorders

Biotechnology company BetterLife Pharma focuses on developing and commercializing cutting-edge treatments for psychiatric and neurological disorders with high unmet needs, using non-hallucinogenic psychedelic derivative compounds. Classical psychedelics like lysergic acid diethylamide (LSD) are in early clinical trials for conditions such as depression, anxiety and cluster headaches.

BetterLife Pharma’s lead candidate, BETR-001 (2-bromo-LSD), is a non-hallucinogenic derivative of LSD that mimics the projected therapeutic properties of LSD without negative side effects such as heart damage. A recent study published in Cell Reports characterized some of the pharmacological effects of BETR-001 compared to LSD in mice, and human clinical trials are expected to begin in 2024.

To learn more about BETR-001 and its potential therapeutic applications, Technology Networks spoke with BetterLife Pharma’s chief operating officer, Dr. Hooshmand Sheshbaradaran, and head of preclinical research, Dr. Abdi Ghaffari.

Ruairi J Mackenzie (RM): Can you summarize some background on BetterLife's compounds?

Abdi Ghaffari (AG): 2-bromo-LSD is not a new drug or new analog; it was synthesized by Albert Hoffman back in the 1940s and 50s and was found to be non-hallucinogenic in humans. It was found to block the effects of LSD, but beyond that, there was really no characterization of its pharmacology. Back then, there were very few tools available to look at its receptor activation profile, so it was mainly thought to be an antagonist and an uninteresting compound.

Human studies – mostly case studies with a small number of subjects – have shown that 2-bromo-LSD has a good safety profile, with mild side effects at relatively high doses compared to other compounds in this class. More recent studies in 2010 showed the efficacy of 2-bromo-LSD in cluster headache patients, which got us and others interested in looking at the therapeutic benefits of this compound.

BetterLife has patent protection on the composition, synthesis, methods of use and formulation of our 2-bromo-LSD – which will be called BETR-001. It is not the same as the 2-bromo-LSD compound [called BOL-148] used in historical studies; ours is a hemi-tartrate salt of 2-bromo-LSD and a specific (6R,9R) stereoisomer. We're the first group that has extensively characterized the pharmacology of a pure stereoisomer of 2-bromo-LSD.

RM: You mentioned that BETR-001 is not the same compound as was analyzed in the 50s – it's not even clear what that was. Is it the same compound from the 2010 study?

AG: We don't know, because there is no certificate of analysis for the compounds in that study. Authors stated it was 2-bromo-LSD (BOL-148), synthesized by THC pharm GmbH (Frankfurt, Germany), but there's really no description or information on its stereochemistry, which is important for the activity of 2-bromo-LSD as well as LSD. For example, iso-2-bromo-LSD which is 6R,9S has almost no activity at these receptors, whereas the (6R,9R)-2-bromo-LSD does.

We don't know what exactly the 2-bromo-LSD used in the 2010 study was, but the authors showed the drug was effective in cluster headaches. That's one of the few in vivo clinical studies that shows the activity of 2-bromo-LSD. Based on our data, we have to assume that it was mainly the (6R,9R) stereoisomer, as the ISO shouldn't have much activity at target receptors. 

Hooshmand Sheshbaradaran (HS): For clarity, I would add that 2-bromo-LSD has two chiral centers, so there are four possible stereoisomers. We are working on a publication that shows these isomers have very different pharmacological properties. For example, ketamine has one chiral center and two stereoisomers. With two chiral centers, you have RR, RS, SR and SS, so it's very similar to the ketamine story, and the stereoisomers are pharmacologically quite different.

We don't know what BOL-148 was in the 2010 study; no one knows. What we can tell you from our experience is that when you make 2-bromo-LSD you get a mixture of stereoisomers, and what we call BETR-001 is the (6R,9R) stereoisomer. You have to use nuclear magnetic resonance (NMR) to determine the stereoisomers – you cannot use optical rotation because RR and RS are both D-isomers, meaning they rotate light in a particular direction. One rotates more than the other, but they are both D-isomers, while the other two are L-isomers. We also found that these have different properties, and people have not been focusing on that – they assume that all compounds labeled as 2-bromo-LSD are the same, which is not the case.

So, there are four stereoisomers, and, in our opinion, one is the active one, which is the one we're developing. What has been done by others is a black box.

RM: Are you exploring this compound for cluster headaches? If not, why?

HS: We have tested BETR-001 in animal models of depression and anxiety, where it was shown to have efficacy, so we believe it will work in depression in humans, but we haven't yet tested that. We believe it will work in anxiety – LSD does – so there's no reason why this shouldn't. We also have tested it in pain models for nerve injury (neuropathic pain) in rats, and it is as effective as gabapentin.

With neuroplasticity, there is the theory that you can rewire the brain, so BETR-001 should have an effect on various neuropathic pain models such as cluster headaches and migraines. It hits receptors known to be involved in headaches, particularly migraines.

We have the 2010 case study from Germany with five cluster headache patients in which three doses of BOL-148 were found to be effective for their headaches, so it is definitely on our list of indications to explore. There are a lot of other possible indications, such as post-traumatic stress disorder (PTSD) or fibromyalgia, but for us, the priority is depression, anxiety and cluster headaches.

There is a lot of interest in PTSD from patient advocacy groups because of need, and they don't want something that causes hallucinations. As BETR-001 doesn't cause hallucination, and potentially doesn't have the scheduled substance regulations, patients with PTSD can take it at home. We also have to look at financial bandwidth as we're not a large pharma, so we can only do one or two things.

RM: Do you see BETR-001 as being something people have to take regularly, or as single doses with several-week intervals? Have you looked at duration of effect?

AG: We have two different dosing models. One is a fairly high dose, but less frequent – such as once weekly for maybe four to six weeks. Data from animals suggests that, unlike for LSD, repeated daily BETR-001 treatment in mice does not lead to tolerance. Based on these findings, we will explore daily dosing at lower levels, for up to four to six weeks. This would be ideal for patient self-administration at home.

RM: Do you have any designs on combining this drug with psychotherapy?

HS: We've discussed this a lot internally; our current model is that this will be added to the standard of care in terms of psychotherapy. When you take a selective serotonin reuptake inhibitor (SSRI), for example, you don't drop psychotherapy. Neuroplasticity gives you the opportunity to reconsider yourself, and that's when you need the therapist's help as you reform your thoughts and work on your identity, so we see it as adjunctive to psychotherapy.

Abdi Ghaffari and Hooshmand Sheshbaradaran were speaking to Ruairi J Mackenzie, Senior Science Writer for Technology Networks.