The neuroscience behind ayahuasca’s efficacy

 

By Katherine Loritz

 

Ayahuasca is an Amazonian tea traditionally used by shamans for making contact with the spirit world, as well as for sorcery, divination, religious ceremonies, and healing. The decoction, which typically combines the vine Banisteriopsis Caapi with another plant containing dimethyltryptamine (DMT) like Psychotria Vidris, has been growing in popularity in Europe and North America over the past two decades for its powerful therapeutic effects.

Research studies have been rolling in to confirm innumerable anecdotal reports of ayahuasca’s ability to heal disorders like depression, addiction, and PTSD. With the psychedelic renaissance underway, entheogens are the hottest new area of research in mental health. Not just ayahuasca, but magic mushrooms and LSD are being researched at universities and consumed medicinally in legal and underground settings around the world. However the benefits of ayahuasca are rumored to be above and beyond those of its counterparts. At least one study has found that ayahuasca experiences are more positive and their effects more enduring than experiences with LSD, psilocybin, or plain old DMT. Ayahuasca users also tend to have higher levels of well-being than LSD or psilocybin users.

If you’ve seen a documentary featuring Dr. Gabor Maté, like The Wisdom of Trauma, you may know that ayahuasca has also received attention for its potential to heal cancer and other chronic diseases.

So what makes ayahuasca so powerful? Does the answer lie in biology? Or could environmental factors explain ayahuasca’s extra magic? Could this panacea’s efficacy come from the supernatural realm?

Is it even possible to know?

Does it matter?

Maybe not. However by looking at the various factors influencing the ayahuasca experience (biological, physical, social, cultural, and spiritual) we can at least hope to gain some new insights and ideas about why we trip, and how to trip well.

I’ll begin by summarizing the science of the so-called civilized, with a deepish dive into the neurobiology of ayahuasca.

 

 

The neuroscience of ayahuasca

 

Disconnecting & transcending

 

What’s the first thing you do when your computer doesn’t work? Restart it, right? You may even unplug the machine in hopes that a short break from the electrical current will reset it. We don’t know why this works. So why should we understand a million year old process between our brains and nature?

Humans have been resetting our brains for thousands of years with psychedelics. And they work. Like a switch that lights up your unconscious – maybe you see your shadow, your guardian angel, your spirit animal or your inner child. Turn it off and on again, and the next day when you wake up you may find that your depression has lifted. You may even have a death and rebirth experience. You may find that the experience changes you profoundly as a person. It’s okay to say goodbye to people we were or parts of ourselves – that’s how we grow. Hanging on to the ego is where trips can sometimes go south. We have to let go and trust in the plant spirits. Or the science, if you prefer.

Like other tryptamines, DMT disrupts major neural networks, those well-worn pathways connecting different brain regions. One such network is called the default mode network (DMN), and its disconnection is liberating. Known as the seat of the ego (and of depression), at higher doses DMT and other psychedelics thoroughly deactivate the DMN, decoupling its various nodes, inducing ego death and unleashing intensely meaningful and mystical experiences.

The DMN’s main nodes in the brain are the medial prefrontal cortex (the mPFC), the posterior cingulate cortex (PCC), and the angular gyrus. Together, these nodes are responsible for many of our mental processes – especially dysfunctional ones.

The DMN directs our attention internally – but not in the same way ayahuasca turns us inwards. The DMN is active when we’re daydreaming, recalling our pasts,  planning for the future, and entertaining complex social thoughts like ethical judgments or mentalization about another’s state of mind. The construction and maintenance of a stable sense of self also takes place in the DMN. So it’s not unimportant – but the DMN has a real dark side.

At the center of the DMN is the PCC. The PCC is implicated in just about every disorder of the mind you could think of from Alzheimer’s to depression, anxiety, ADHD, autism, and traumatic brain injury.

The PCC is highly sensitive to our emotions, which triggers it to call forth relevant autobiographical memories. This could be a way of monitoring our experiences and comparing them to our pasts, thereby ensuring the continuity of the ego by reinforcing our self-concept and bringing the same person, thoughts, or behaviors into the present.

However a hyperactive PCC will take that self-referential thought and go wild. It will obsess – turning attention not just inwards but against oneself with negative self-criticism, self-aggression, and doubts, leading to a spiral of rumination that makes it difficult to pay attention to what’s going on outside ourselves. Creating our own personal hell.

 

It seems to me that the PCC is like a muscle; the more you use it, the more it grows – and it grows into monster.

Meditation, however, deactivates the PCC. And if your PCC begins to shrink, well praise be – you may become a boddhisatva after all. You’re on your way to Nirvana.

A recent study found that members of the Santo Daime, the Brazilian ayahuasca church (where ‘daimistas’ may take ‘daime’ as frequently as once a week during religious rituals), have significantly thinner PCCs than the rest of us, according to a recent study. The thinness of the daimistas’ PCCs was directly correlated with the duration of their use and the quantities of daime they consumed. And the thinner their PCCs, the higher the daimistas scored on a scale measuring “self-transcendence.”

 

 

 

Freeing our depths from logical repression

 

The neocortex is the outer layer of the brain, where our gray matter and logical thoughts live. Under normal circumstances, the neocortex controls the rest of the brain through neural networks like the DMN. Serotonergic psychedelics like DMT deactivate and decouple these networks, disabling the top-down control that the neocortex usually exerts over the more ancient, emotional limbic midbrain. This allows repressed feelings and memories to surface from deeper brain areas without being suppressed by the thinking, judging neocortex.

DMT also deactivates our right amygdala and binds to the serotonin 5-HT1A receptor , which is thought to decrease anxiety. These are like safety mechanisms that help protect us from being frightened by any traumatic content arising from our unconscious, or from being overwhelmed by whatever other vision ayahuasca may present us with. These mechanisms may also help us feel safe enough to confront and process any sensitive material that comes up for us in new and creative ways.

The inhibition of top-down cortical control also allows a more anarchic, “entropic,” pattern to form in the brain. Not only do psychedelics disconnect normal neueal pathways, but new ones begin to emerge, as nodes that don’t usually talk start to communicate. This opens us to new ways of thinking, ideas, and insights.

Like other psychedelics, DMT binds to the serotonin-glutamate combination receptor 5-HT2A/mGlu2. How does this play out in the brain? Serotonin doesn’t have its own special type of neuron, but is expressed on many different neurons. The 5-HT2A/mGlu2 combo receptors are expressed on both excitatory pyramidal cells (which release the excitatory neurotransmitter glutamate) and inhibitory interneurons (which release the inhibitory neurotransmitter GABA) in the neocortex. However the mGlu2 receptor is an inhibitory glutamate receptor, and it prevents the release of glutamate into the next neuron. So the activation of this receptor creates an inhibitory pattern in the brain. This is what quiets the neocortex, and opens the brain up to information buried deep within.

DMT’s activation of the 5-HT2A/mGlu2 receptor also causes the release of what’s called a G protein at the receptor. The protein is released into the neuron, spurring a series of intracellular processes that end up stimulating the production of brain-derived neurotrophic factor (BDNF), a protein that’s essential for the development and sustained health of neurons.

In pathologies such as depression, stress, and PTSD, neurons fry and their dendrites wither. Through a dramatic uptick in BDNF in the brain, neurons begin to flourish – growing new dendrites, forming new connections at synapses, and nourishing baby neurons from the dentate gyrus. This neuroplasticity means there are more neurons, and they’re healthier and more able to communicate with each other, and new connections form in the brain, creating new neural networks and thought patterns. These new neural networks provide an escape from the well-worn, dysfunctional thought loops of the DMN that we may have been trapped in. If we nurture these new thoughts, they can turn into permanent changes in our attitudes, behavior, and lifestyles. We can shed our old skins and become new people.

 

O Sigma-1

 

All serotonergic psychedelics are understood to work in the ways described above, not just ayahuasca or DMT. However DMT binds not only to the 5-HT2A/mGlu2 receptors, but a receptor called Sigma-1. The Sigma-1 receptor “has so far been implicated in illnesses like Alzheimer’s disease, Parkinson’s disease, cancer, cardiomyopathy, retinal dysfunction, perinatal and traumatic brain injury, frontal motor neuron degeneration, amyotrophic lateral sclerosis, HIV-related dementia, major depression, and psychostimulant addiction.”

Activation of the Sigma-1 receptor through DMT may be a way to prevent, heal, and even cure some of the diseases listed above. How? Well, Sigma-1 protects against oxidative stress, low grade inflammation (LGI), and endoplasmic reticulum stress. All of these cellular stresses are closely related to and exacerbate one another. Oxidative stress can lead to cancer and apoptosis (cell death). Research increasingly implicates LGI in most chronic diseases, including disorders of the brain. The endoplasmic reticulum is responsible for protein folding, which goes awry in diseases like Alzheimer’s. Sigma-1 also supports mitochondrial activity and cellular survival, thus promoting neuroplasticity and preventing the neural degeneration typical of many brain disorders.

 

B. Caapi to the rescue

 

Banisteriopsis Caapi, the vine that constitutes half of a typical ayahuasca recipe, contains no DMT, but shamans have long considered it to be the key ingredient in ayahuasca. It contains alkaloids that prevent the immediate breakdown of DMT in the gut, allowing us to enjoy the trip for a few hours instead of seconds. These alkaloids have also been found to stimulate neurogenesis – the growth of new neurons in adults.

What could be better for your brain? I mean, maybe bolstering the brain’s immune system to kill free radicals and prevent cell death, which B. Caapi also does. It turns out the vine also has compounds with anti-inflammatory effects in microglia, protecting and strengthening the brain’s immune system. So ayahuasca doesn’t just heal by way of DMT, and scientists are now studying B. Caapi to find ways to prevent neurological diseases.

 

This short neuroscientific overview may explain some of ayahuasca’s proclaimed magic, its curative powers – but there are more variables at play in the complex interactions that occur between the biological, personal, physical, and social worlds.

In Part II, I’ll introduce the epistemologies of Peruvian shamans (though I’ll hardly be able to do them justice), before returning to Western thought and looking at aspects of set and setting in ayahuasca ceremonies. Hopefully, Spirit will guide me away from too much reductionism or empiricism in the realm of the personal, social, and spiritual, where most things are invisible and immeasurable.

 

mdma as a cure for ptsd

 

MDMA, PTSD & the Revision of our Pasts

 

 

MDMA, or ecstasy, is what you take before you go clubbing, right?

Or during your therapy session – which we may all need after Covid. And by the time it’s finally over, MDMA-assisted psychotherapy may actually be available.

MDMA isn’t a classic psychedelic like LSD. It doesn’t exactly alter your reality (though it might be able to change your past). The drug, which makes you feel happier, confident, and more empathetic, was synthesized in 1912, but wasn’t used until the 1970s, when it enjoyed a brief therapeutic career. In the 1980s it was sold on the street as a party drug, and was swiftly criminalized in 1985.

On the street, ecstasy is seldom pure MDMA; it’s usually cut with other drugs like amphetamine. It’s true that it’s not as harmless as classic psychedelics like LSD or psilocybin, and overdose or heavy, long-term use can have serious consequences. Its use at raves earned it a negative reputation in the press, but pure MDMA – when used sparingly – is relatively safe, and less addictive than most illicit drugs.

Anyways, now that psychedelics are becoming more acceptable, the media is changing its mind and shedding light on MDMA’s seemingly magical powers to alleviate – if not cure – PTSD. And these days, there’s more trauma than ever.

The more we talk about PTSD, the more it shows up. One could even say we live in a traumatized society. Around 10% of people in the US are estimated to have PTSD at some point in their lives, and about 3.5% of the population in any given year. But those are the official estimates.

PTSD as a diagnosis was created to describe the symptoms of Vietnam War veterans. However we’re now learning that not only war, but everything from bullying, to living in poverty, to racism, to having Covid can cause PTSD. It’s also common in first responders like paramedics, who have to witness traumatic events on a daily basis. Whether or not we catch the “disease” depends less on the objective event as it does on the person, how they experience it, and the support they receive immediately afterwards.

Oppressed groups such as racial minorities and people in poverty are more likely to experience long-term stress and traumatic events. And those who don’t know they have PTSD are at greater risk of being retraumatized. This can lead to its new, stronger variant, C-PTSD (trauma is also mutating).

The only currently approved treatments for PTSD are SSRIs and psychotherapy, in particular exposure therapy. In exposure therapy, the patient recalls the traumatic event(s) in safe contexts over time. This is supposed to promote “fear extinction,” or an unlearning of the fear response. But it turns out that PTSD patients don’t like remembering their traumas over and over again, so exposure therapy has high dropout rates. Neither antidepressants nor exposure therapy are very effective in treating PTSD, with only around half of patients responding.

MAPS, an organization founded in 1986 to promote the research of psychedelics, has been at the forefront of MDMA research. MAPS decided early on to focus on MDMA because it’s the drug that best lends itself to therapy, and it had potential to treat PTSD, which has no strong treatment alternatives. They’ve been trying to conduct research with veterans since 1990, with no luck because of the stigma, despite the huge need; over one million veterans are on disability for PTSD.

“The real motivation, why I’ve kept going for so long, is that humanity as a whole is, I would say, massively mentally ill,” said MAPS founder Rick Doblin in an interview.

 

Towards an understanding of PTSD

More and more people with anxiety, depression, and addictions are realizing that these problems are rooted in trauma. This was the approach of early psychoanalysts, that psychological problems sprang from childhood trauma (though people like Freud created some weird theories around it).

Behavioral psychology and medical explanations have dominated since the mid-20th century, because it’s more profitable to treat human beings like lab rats than traumatized subjects. Acknowledging the sources of trauma would also mean addressing the deep inequities in our society. However the popularity of people like the doctor Gabor Maté, who says that all addiction is rooted in trauma, has helped bring trauma theory back.

And now that we now know a lot more about the brain, there’s some biological understanding of how PTSD works (and MDMA, too).

PTSD changes our brain structure. As we revisit the memory or it’s cued in our environment by a “trigger,” our bodies secrete stress hormones like adrenaline and cortisol to respond to the threat, and our bodies reactivate the fight, flight, freeze, or fawn response. Our hippocampus measures and regulates cortisol, but too much wears it down, and so it shrinks. Meanwhile, cortisol continues to signal the the amygdala, which processes emotions like fear, and grows as we maintain a state of hypervigilance. The ventromedial prefrontal cortex (vmPFC), which regulates the amygdala, emotional responses, and our self-control, also shrinks and becomes hypoactive, leading to difficulties with emotional regulation. A deactivated vmPFC and smaller hippocampus in PTSD translates to deficits in thinking, learning, and memory, while a larger amygdala makes people more sensitive to fear. 

Of course this hypervigilant state was meant to respond to real threats in our environment, but PTSD is usually maladaptive, playing traumatic memories or their reminders and fear responses on loop.

It’s worth noting that memories aren’t only visual. As a study of traumatic experience notes:

“Episodic memory can present itself in parts… [it] might appear as an inner vision, a sound, or just a hint – a brief sensation in the belly or a strong pain in the chest.”

 

MDMA-assisted therapy offers hope

“We know from brain scans of PTSD patients that PTSD changes people’s brains, and MDMA can change it back in almost the exact same way,” said Doblin. 

“So, where PTSD increases activity in the amygdala, MDMA decreases activity in the amygdala. PTSD decreases activity in the prefrontal cortex, MDMA increases activity in the prefrontal cortex. PTSD makes people feel isolated, alone, and mistrustful, but MDMA builds trust and connection.”

MDMA increases the availability of the neurotransmitters serotonin, norepinephrine, and dopamine, while releasing hormones including oxytocin, cortisol, prolactin, and vasopressin.

This neurobiological cocktail puts subjects in an ideal therapeutic state. It provokes a sense of peace and safety, makes them more introspective and open, and more trusting in their relationship with their therapists.

And in combination with psychotherapy, it appears that MDMA heals trauma in about two-thirds of cases.

It wasn’t with veterans, but MAPS was finally able to conduct their first study in 2008. Their trials were such a success that the FDA granted MDMA-assisted psychotherapy Breakthrough Therapy Designation in 2017, fast-tracking the research. 

In 2020, MAPS aggregated the follow-up data for six phase 2 trials of MDMA-assisted psychotherapy.  All of the trials were conducted similarly, with participants undergoing eight psychotherapy sessions, two of which lasted eight hours and involved MDMA. 

At treatment exit, 56% of participants no longer met the criteria for PTSD. However in the one year follow-up this number had increased, and 67% of participants no longer met the criteria, while over 90% had a clinically significant reduction in symptoms. These are magical numbers. A follow up of an older study is even more promising, suggesting that the benefits of MDMA treatment for PTSD canlast at least 3.5 years.

MDMA-assisted psychotherapy for PTSD is now in phase 3 trials, which are expected to be completed in 2022, and the therapy could be approved by the FDA as soon as 2023.

In case the government wasn’t sold on the benefits, MAPS produced a separate study estimating that making MDMA-assisted psychotherapy available to just 1,000 patients with PTSD would reduce general and mental health care costs by $103.2 million over 30 years. For a million veterans, it would save $103.2 billion.

 

Positively changing our memories

MDMA & PTSD

MDMA-assisted psychotherapy is thought to treat PTSD through memory reconsolidation. It increases the connectivity between the hippocampus and amygdala, which may indicate a heightened capacity to emotionally process fear-related memories.

It turns out that when we recall memories, they become malleable. There’s a small window in which they “reconsolidate” and we can modify and update them. The events themselves may not change, but the way we remember them, and especially the feelings we have associated with them, do.

We do this all the time. For example if you once looked back on a fun experience with a partner fondly, but then found out that partner cheated on you, you might remember that same experience differently – perhaps with sadness, anger, or a sense of betrayal.

When we recall trauma memories and our adrenal receptors in the amygdala are activated, those memories are reinforced from a place of fear. Continually recalling the same memories with the same emotions may be what underlies the long-term nature of PTSD.

MDMA therapy is like the opposite of that. The key is reconsolidating memories in a positive state. First you enter a safe, happy state of mind, and only then do you recall memories with your therapist, process them, and reconsolidate them.

MDMA allows us to visit the ghosts from our pasts from a place of empathy or compassion. Without fear, we can see through them and give them new meanings. We can make peace with them, and lay them to rest.

Can you use MDMA to treat yourself? You can try, but I wouldn’t recommend it. You’ll need the psychotherapy not only to help you process your trauma and integrate your experience, but to pick up the pieces of your life that trauma has left in its wake.

Doblin says the end goal of the MAPS project is “mass mental health.” If phase 3 trials are successful and MDMA-assisted psychotherapy is approved by the FDA, MAPS plans to focus on researching group therapy for PTSD, as well as other indications for MDMA.

Because MDMA is thought to stimulate prosocial behavior, MAPS is also studying MDMA-assisted psychotherapy as a treatment for social anxiety in autistic adults. It’s also being investigated for couples therapy and addiction.