Solving the Puzzle of Neurodegeneration:

When I first entered the world of research, my goal was to solve some of biology's most complicated puzzles. As an amateur scientist, it is easy to get excited about tackling these mysteries and realize just how little we actually know. To approach any scientific question, we must start with what’s already known. At first this can feel daunting; brushing through the weeds, reading stacks of primary literature articles and reviews, sometimes unsure where to begin. But after diving in, you start to uncover the gaps in our knowledge; the missing puzzle pieces. 

When friends and family asked about my doctoral work, I’d remind them that I was only working on a tiny piece of what feels like an infinitely sized puzzle. Our work is meaningful, but it is nothing without the collective effort of researchers pulling their own weight. And when you finally reach that pinnacle moment of solving your precious single puzzle piece– amid failure, reevaluation, and eventual success– you realize how much more there is to learn. 

“I am smart enough to know that I am dumb.” - Richard Feynman

In the world of Neurodegenerative diseases and Neuropsychiatric disorders, we are at a crucial point of reevaluation. One particularly intriguing frontier in puzzle solving lies in the potential of treating neurodegeneration with psychedelics.

Current Neurodegenerative Treatments

There are no current treatments that can effectively stop or reverse the progression of Alzheimer’s and Parkinson’s disease. Traditional therapies primarily manage symptoms rather than modifying the disease itself. All clinical trials for Alzheimer’s treatment have failed, with some work involving fabricated data. Equally unsettling is the fact that much of this false data became the foundation for subsequent research. While this highlights our desperation for a suitable treatment, it also shows how failed research can set us back. In reality, we don’t know as much as we might hope and we should consider thinking outside the box to solve these embarrassingly complex puzzle pieces. 

What are we missing?

Time and time again, mental health has proven to be significant in disease prognosis. Whether it’s having a support system or a healthy coping mechanism, mental health plays a crucial role. While the exact connection between mental health and disease progression remains elusive, it is definitely not something to be ignored. 

A Controversial Treatment: Psychedelics

Psychedelics are gaining recognition for their potential to treat depression, PTSD, and substance use disorders. Banned worldwide in the 1960s and 1970s, they were once thought to have no medical value. However, recent clinical trials show promise for these drugs as potential therapeutics. Psychedelics have been repeatedly found to reduce neuroinflammation, modulate immune function, and enhance neuroplasticity; all of which are important in counteracting neural loss and cognitive decline. The FDA has even designated certain psychedelics as “Breakthrough Therapies” for psychiatric disorders, though not yet for neurodegeneration. 

What are psychedelics?

“Classical” psychedelics (“mind manifesting”), including LSD and psilocybin, are hallucinogens that target the 5-HT2A receptor in the brain. These receptors are crucial for cortical neuron health and are dysregulated in neurodegenerative diseases such as Alzheimer’s. In addition, these drugs increase levels of proteins essential in neuronal survival and growth (BDNFs), glutamate and oxytocin, and show anti-inflammatory effects. These effects have been the basis for explanations for effective treatment of disorders ranging from depression to addiction.

So why do “magic mushrooms” (psilocybin) make you hallucinate? Psilocybin affects what is called the default mode network (DMN) of the brain. As you can imagine, the brain has a baseline resting state. When you aren’t performing a task or thinking about something, what is your brain doing? What’s super interesting is that during a resting state, several brain areas have been shown to be consistently and collectively active. Research suggests that they are part of the same special network, which is now defined as the DMN. Psilocybin alters the activity and connectivity of the DMN brain areas, increasing and diversifying functional connectivity. Of those brain areas, several of them make up the visual and sensory networks, explaining why you might “see things”.

Studies on Psychedelics: Less is More

Two major studies from 2016 demonstrated groundbreaking results from a one-time administration of psilocybin. Cancer patients who received the drug in combination with psychotherapy showed improvements in well-being, with positive effects persisting through the duration of the 6-month long studies. Sure, feeling better is one thing, but if you’ve met a cancer patient, you know just how important this can be to their treatment. Many cancer patients develop aggressive mental health disorders, like major depressive disorder (MDD), that only worsen their physical state. 

A long-term follow up study from 2020, showed positive outcomes lasting at least 4.5 years; from just 1-2 doses of psilocybin (effective doses ranged from ~0.3 - 0.43 mg/kg). How much better is this than the current standard of care? SSRIs (selective serotonin reuptake inhibitors) are the current standard of care for treating depression and other mental health disorders. In a 2021 study, researchers compared psilocybin to an SSRI (escitalopram, better known as lexapro) to treat MDD. Both approaches had similar effects in the 6 week study; however, only two total doses of psilocybin were needed to create that effect, compared to a daily dose of an SSRI. Ongoing studies are now exploring psychedelics for PTSD, addiction, headaches, and MDD in individuals with Alzheimer’s disease, to better inform the broader applications of these drugs. 

Using Psychedelics for Neurodegenerative diseases

You may have heard of “microdosing”, a dosing method in which you take very low concentrations of the drug that do not reach the threshold needed for behavioral effects. Normally, this is 10% of active recreational doses (~0.1-0.3g of dry psilocybin) taken up to three times per week. This technique is believed to improve creativity, thinking, and well-being. However, there have been few rigorous studies of microdosing. The results are questionable and these improvements could be associated with the “placebo effect”.

Though only effective at normal doses, this hot topic in science right now has prompted the creation of regulation centers offering psychedelic-assisted therapy (PAT). These centers provide a controlled environment for treatment, with clinical supervision and rigorous data collection. With the FDA’s designation of psilocybin, MDMA, and LSD as “Breakthrough Therapies”, we are able to expedite therapy development that may be similarly aimed at neurodegenerative diseases. 

The Controversy

Psychedelics have little to no addictive potential, as shown by studies from 2018. These drugs are typically not used “day-to-day”, but rather “once in a lifetime”. Many describe their experience as an “awakening” that is appreciated but not meant to be revisited. Unfortunately, psychedelics’ association with counterculture led to a negative public perception, contributing to the war on drugs. Of course, no drug comes without potential consequences. Studies show that some psychedelics could pose risks for individuals with psychotic disorders, although studies looking at clinical applications tend to exclude at-risk individuals. 

Breaking the Stigma

Public perception remains a major barrier. Even if psychedelics are approved for clinical use, changing public opinion will be a challenge. Despite scientific backing, shifting attitudes about these drugs may be the next puzzle piece to solve.