#2 Let's Get Brainy

How do psychedelics actually work? In this edition we take a deep-dive into the classes of psychedelics and your beautiful, magical brain.

Tiger got to hunt, bird got to fly;
Man got to sit and wonder 'why, why, why?'
Tiger got to sleep, bird got to land;
Man got to tell himself he understand.”
― Kurt Vonnegut, Cat's Cradle

Hey pal, how are you doing? How are you keeping yourself sane during these weird times? Do you need a hug? You know what, I'll give you one anyway.

I'll be honest with you, I've been struggling. I was already going through a really tough time before this pandemic hit, and now, just like you, I'm worried about the health of my parents, my finances and the impact this will have on our lives as a society. But I'm trying to have more good days than bad. A mix of yoga, meditation, sleep, nice food, learning and reading, video calls with friends and crying a lot seems to work for me. My neuroscientist-meditation-teacher-friend Lars is leading short and beautiful meditations every evening live on Facebook and Instagram, which I can't recommend enough. I also just got my Reiki I diploma, which earned me another good ritual in the mornings and before bed. This self-reiki practice really gets me into my body and soothes the random aches that feed my anxieties. If you'd like to give it a go, the course I'm doing is only £29 this month. 

And if, like me, you've struggled to be productive or creative during this time, be kind to yourself. This isn't about who wins the Pandemic Olympics or Self-Isolation League. Life seems to really knock us down sometimes, take away the things we cherished most, and then make us fall and sprain our one good ankle (wait, was that just me?). And then we can choose to struggle with it, or to listen and flow with what's happening. Or both! My hope is that we'll come out of this as more resilient, compassionate and kind. And if you're skeptical about it, maybe this amazing essay will change your mind.

So, come on , let's pick ourselves up, dust ourselves off and learn how that magical brain of yours can create altered states on psychedelics. I've tried my best to simplify the complicated neuroscience I understand, but if you want to learn more, I've included plenty of links that go deeper at the end of this newsletter.

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Classification Board 

Before we get into anything, let’s note that not all psychedelics are equal. Different substances work on different receptors in your brain, and create different effects. It’s important to know this especially when it comes to how your body might respond to them, when and how you should take them, or whether you should take them at all. 

There are five classes of psychedelics (although some people only reserve the name psychedelic to refer to tryptamines, and there's a bit of cross-over anyway, but hey-ho):

  • Tryptamines: LSD, psilocybin, DMT, Ayahuasca, Ibogaine

  • Phenylethylamines: Mescaline, MDMA, MDA, the 2-C drugs and 25-NBOME

  • Empathogens: MDMA

  • Dissociatives: Ketamine, PCP, Dextromethorphan

  • Deliriants: Atropa Belladona, Brugmansia or Angel’s Trumpet, Datura stramonium, Scopolamine.

Tiny disclaimer: Please keep in mind that when I talk about the benefits of these substances I am using data from controlled clinical studies that use super-pure stuff in a controlled environment, with trained guides, often with ongoing therapeutic support. Getting the same effects by yourself at home is pretty unlikely, and can be risky. Know yourself, know the substance and learn about safe practices. Promise? :)

Tryptamines are your classic hallucinogens, and what most people, including myself, mean when they say psychedelics: LSD (lysergic acid diethylamide), magic mushrooms (psilocybin), Ibogaine, DMT and Ayahuasca. There's a ton to talk about for each of these medicines, but in this edition I'll focus on psilocybin to illustrate how tryptamines work in your brain for two reasons: it's the most studied substance at the moment, and my medicine of choice. Now, there's a short explanation that won’t make much sense just yet (but might make you look real smart when you repeat it to others), and the long one right after.

So, basically…

Psychedelics act like agonists at 5-HT2A serotonin receptors in the brain and create new patterns of communication by decreasing activity in the Default Mode Network.

All eyes on serotonin

You have more than 100 different types of neurotransmitters in your brain. Serotonin is one of them, and often referred to as 5-HT (short for 5-hydroxytryptamine). Most of the serotonin receptors are found in high level structures of the cortex, in regions that do more general things rather than being focused on a specific function like vision, or movement. Serotonin is a very important neurotransmitter. Not only does it modulate the release of other important neurotransmitters, it also controls sleep, mood, cognition, sexual behaviour, aggression, impulsivity, appetite, nausea, pain, thermoregulation, circadian rhythm and memory. Raising serotonergic activity makes you happy, social and active. Lowering it makes you depressed, irritable and more prone to mental illness. 

The Serotonin 5-HT2A receptors

Both antidepressants (Selective Serotonin Reuptake Inhibitors, or SSRIs) and tryptamine psychedelics target this serotonergic system in the brain. Of all the 14 serotonin receptors in your brain, research has found that these substances mainly go for the 5-HT2A receptors. These regulate addiction, anxiety, appetite, cognition, imagination, learning, memory, mood, perception, sexual behaviour, sleep, thermoregulation and vasoconstriction. 

(from Sapien Soup)

But here’s the coolest thing. If you look at psilocin, the molecule psilocybin metabolises to, you’ll notice how similar it is to serotonin - which makes us wonder why nature would produce a substance that fits our receptors so well, and expands our minds beyond our egoic smallness? The same applies to LSD - and, in fact, it turns out that LSD sticks to these receptors even better than serotonin does, which explains why an acid trip can last up to 12 hours.

Agonists at the 5-HT2A receptors

An agonist is a chemical that binds to a receptor and activates it to produce a biological response (as opposed to an antagonist, which blocks activity). Normally, your neurons are transmitting serotonin from one to another. Some of it gets absorbed by the receiving neuron, and the rest goes through a sort of recycling process called reuptake - where it gets reabsorbed by the first neuron and broken down. SSRIs and psychedelics inhibit this reuptake, which means that more serotonin is available to activate receptors in neurons. This creates some of the interesting effects we get on psychedelics.

Decreasing activity in the DMN

The Default Mode Network (DMN) is a very interesting part of your brain. First of all, it’s metabolically hungry: it receives a lot of bloodflow and consumes a lot of glucose in the brain. Secondly, it’s very interconnected. Regions in this network serve as transit hubs, a sort of orchestrator for brain function. Here, information is collected and organised in ways that make sense with your pre-existing patterns.

The DMN is engaged during self-reflection, complex mental-imagery, mental time travel (thinking into the future or contemplating the past), theory of mind (trying to understand or make inferences of someone else’s thoughts) and metacognition (thinking about thinking). It's been compared to a screensaver that randomly shuffles through images of your past, future, your to-do list, and all the things you regret having said or eaten. It's also been called the orchestrator of the self, and it may even be the seat of our personality, or our ego.

Firing the conductor to let the orchestra play

Using fMRIs, scientists have noticed that psychedelics lower bloodflow to the DMN, reducing the activity here. Set free from the orchestrator, the brain starts to communicate in new ways. Think of it as London Bridge closing down: you have to make more connections to get to where you wanted to go, and you might end up in places you normally don’t visit.

(a) your brain connections normally and (b) the brain on a psychedelic 

Regions that normally don’t speak to each other suddenly connect, making you more creative. You break free from thought patterns. Your sense of self may dissolve, causing the almost fetishised “ego dissolution”.

Of course, you don't actually feel part of your brain taking it easy. Instead, you notice that your perception of reality starts to shift. You may see changes in shapes and colours, visual distortions, open or closed eye visuals, and you may even experience synaesthesia, where music can become a colour (piano music is blue for me). You may feel physical changes like drowsiness, blurred vision, dizziness, an increase in your heart rate, different body temperature, and sometimes nausea or shaking which are related to mechanisms of releasing trauma. Psychologically, you may notice changes in mood, from euphoria to panic, distortions of how you perceive time or space, changes in thoughts, dream-like states and a deeper sense of connection with the world around. You'll still be you, just slightly different for a few hours.

Dissociatives (in this case Ketamine) work primarily on theNMDA receptors in your glutamate system, along with dozens of other systems like your dopamine and opioid systems. Ketamine itself is a tiny molecule, totally synthetic, and a derivative of PCP.

Glutamate is an essential neurotransmitter that powers your brain and controls pain, memory, perception and cognitive function. At high doses, Ketamine is an antagonist at these receptors, blocking their activity, which makes sense with its longstanding use as an anaesthetic. But at smaller doses, it works as an agonist, stimulating them. As the category suggests, Ketamine can disconnect you from the environment, your thoughts, and can even replace your reality in higher doses. It's highly hallucinogenic, and it can create new connections between synapses, restoring a stressed brain to its normal state. Under Ketamine you may feel disconnected from your body, and the boundaries between you and the environment often disappear, as you merge into the visions you've been contemplating.

Ketamine is short-acting, and a rapid-acting treatment of depression. Due to its efficacy and safety Ketamine is now offered as legal treatment for depression (Ketamine itself is not legal!). It's a great mood regulator for people with organic depression, although the effects are temporary, and frequent use is not recommended. At higher doses it can be very psychedelic, and many people have mentioned "feeling the presence of God" during administration. 

Ketamine Clinics are offering a wide range of recurring treatments using intravenous, intramuscular infusions (which are approved by the DEA), lower-dose lozenges for talk therapy, or the nasal spray produced by Johnson & Johnson, which was also approved by the Food and Drug Administration. In combination with ongoing therapy, Ketamine therapy is proving to be a very efficient option for treating depression (unfortunately also very costly, and limited in the US and UK).

The more I learn about it, the more fascinated I am with its properties, and there will surely be an entire newsletter only dedicated to it in the near future. Here's a great intro video about it.

Empathogens, or entactogens, are known for creating the feelings of emotional openness, love and social connection. You're probably familiar with MDMA (3,4-Methyl​enedioxy​methamphetamine) as an everpresent recreational drug in the clubbing scene as Ecstasy or Molly. So let's talk about how it works.

MDMA is a great multi-tasker. Like Ketamine, it works on a few of your systems to create the alchemy of effects we know. The biggest impact is on your serotonergic system (mainly the 5-HT1A, 5-HT1B, and 5-HT2A receptors): it increases serotonin, which leads to better mood and creative thinking, and a decrease in depression, anxiety, fear, aggression and defensiveness. Second to that, it increases dopamine and noradrenaline, which create more stimulation, like an increased level of alertness, arousal, and a faster heart rate. It also increased alpha-2 activity which controls thermoregulation promotes relaxation, and stimulates your hypothalamus to release oxytocin, which creates the increased sense of empathy and bonding (basically why you wanna hug everyone).

MDMA also works on the limbic system, the part of your brain that deals with emotions and forming memories. Studies have shown that MDMA decreases activity in your limbic system, and promotes communication between the medial temporal lobe and medial prefrontal cortex, as well as the amygdala and the hippocampus, creating the opposite communication patterns you see in people suffering from anxiety and PTSD. In fact, MDMA-assisted therapy has already been granted breakthrough therapy for the treatment of PTSD by the FDA in the States, and it's on its way to be legalised for medical use by next year.

Here's a great overview of MDMA from UK's leading researcher Ben Sessa.

Deliriants are the worst of the bunch. I mean it. They’re antagonists at different receptors, particularly the acetylcholine receptor - but who cares, because you’ll never touch these, right? While on must drugs you still remember you took something, deliriants create hallucinations that the user doesn’t realise they’re drug induced. You can end up chatting to a fictional person, smoke a cigarette that isn’t there, or in the worst cases see spiders or insects crawling around that aren’t really there. You may also not see things that are actually there, which is not ideal if you’re out and about. It's very likely you'll respond badly to things, become aggressive and get into a lot of trouble. I told you, they suck big time. These drugs are very dangerous, and most experiences are bad. 

 Dept. of Further Investigation 

Comission of Celebrations 

Happy Fantastic Fungi Day!

What are you doing tonight? That's right, you're watching this fascinating documentary along with thousands of peeps around the world, packed with juicy stories about mushrooms and the intelligent network of fungi that's keeping the world alive, just underneath our feet. Rent it or buy it here.

Audit Division 

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