Exploring psychedelic chemistry

BY JASMIN FOX-SKELLY | 8 MAY 2024

Psychedelic or mind-bending compounds are most usually associated with mushrooms. But it’s likely that humans produce them too, while recent research suggests they could even be responsible for near death and ‘out of body’ experiences, reports Jasmin Fox-Skelly

Around 3500 years ago on the banks of the River Ganges, it’s thought that members of the ancient Vedic religion gathered to make a sacrifice to their warrior god Indra. Worshippers sipped soma, a ritual drink believed to contain a hallucinogenic from the fly agaric mushroom, Amanita muscaria. The ancient Greeks likewise gave attendees of their secret religious rites a drink made from wheat infected with ergot fungi – containing a natural form of LSD. While mushrooms are the most prolific manufacturers of psychedelic or mind-bending compounds, some plant species can produce them too, while even toads, frogs and fish have been known to make psychedelics. In the 1960s, scientists discovered something strange. They found traces of the psychedelic compound N,N-dimethyltryptamine (DMT) in human cerebral spinal fluid. So, could humans also make psychedelics?

To find out, Steven Barker, a professor emeritus at Louisiana State University teamed up with Jimo Borjigin, professor of neurology at the University of Michigan, both in the US. In 2013, they found DMT in the pineal gland and visual cortex of the brain of live rats ^[1]. DMT is also found in several other animal and plant species, and is the active ingredient in the drink ayahuasca, a popular brew drunk by Amazonian tribespeople. A study in 2019 led by Borjigin’s grad student Jon Dean detected the compound in the rat’s cerebral cortex, at concentrations similar to the neurotransmitters serotonin and dopamine ^[2]. It’s difficult to conduct these experiments in humans, as to do so would require collecting spinal fluid via a lumbar puncture – a procedure not many are willing to volunteer for. However, Dean’s 2019 study showed that the enzymes needed to make, store, and release DMT are also present in neurons of the human cerebral cortex, providing indirect evidence that DMT is produced there too. But what is DMT doing in the human brain? Some scientists, including Barker, believe it is acting as a neurotransmitter, although this has yet to be universally accepted by the scientific community.

‘The concentrations of DMT in the rat brain are equivalent, or in some cases more than, other common neurotransmitters such as serotonin, dopamine, GABA, you name it,’ says Barker. ‘We know that DMT can be synthesised in the brain, so you can check that box. DMT can also be taken up into neuronal vesicles, it can be released from vesicles, and it can send a signal across the synapse through binding to other receptors on the next neuron.’

According to Barker, the distribution of the enzymes also seems to follow the path we would expect from the effects of DMT. For example, to manufacture DMT, first you need to convert tryptophan to tryptamine. That job is performed by the enzyme tryptophan decarboxylase (TDC). Tryptamine is then methylated by another enzyme called indole-N-methyltransferase (INMT). If DMT is acting as a neurotransmitter, then both those enzymes should be located in the same place, and very close to the site of action of DMT – as otherwise any DMT produced could be rapidly broken down.

The concentrations of N,N-dimethyltryptamine in the rat brain are equivalent, or in some cases more than, other common neurotransmitters such as serotonin, dopamine, GABA, you name it.
Steven Barker, professor emeritus at Louisiana State University, US

And they were. ‘We saw them [the enzymes] in the frontal cortex and visual cortex – places where you would expect DMT to act – but not so much in other areas like the motor cortex where it wouldn’t have any expected role,’ says Barker.

The structure of DMT is similar to the neurotransmitter serotonin, so much so that it binds to the same serotonin receptors (5HT2a) on the neuronal cell membrane. In fact, psychedelics across the breadth of the animal, plant and fungi kingdoms are all remarkably conserved. This conservation of structure suggests that whatever the function of the compounds, they must be important for survival. One theory is that DMT could protect neurons from the harmful effects of stress. For example, in a 2022 study, Parker Kelley, a molecular neuroscientist at Louisiana State University, and his team gave DMT to rats who were suffering a form of PTSD after living in unstable housing conditions for 30 days and periodically exposed to cats ^[3]. The scientists found that after suffering from prolonged stress, levels of reactive oxygen species (ROS) and inflammation increased in the brain. ROS can damage and kill neurons if left unchecked. However, after being given DMT, levels of ROS fell, protecting the neurons in the prefrontal cortex from death.

‘We’ve hypothesised that stress and hypoxia cause lots of DMT to be produced in the brain,’ says Barker. ‘It seems its role is to try to save you, and to protect your brain if at all possible.’

Hallucinogenic effects

If our brains produce psychedelics to protect neurons from dying, this may also help to explain reports of people experiencing hallucinations shortly before death – so called ‘near death experiences’. In the 1990s, Rick Strassman, professor of psychiatry at the University of New Mexico, US, injected 60 volunteers with DMT. Over half the volunteers subsequently described encounters with angelic, demonic and even alien ‘entities’. These descriptions seemed to mirror the hallucinations reported by people who had undergone near-death experiences.

Strassman calculated that to induce hallucinations and out of body experiences, blood concentrations would have to rise to at least 65nM. While it has not been possible to establish actual whole brain or brain area concentrations under these conditions, we do know DMT is normally only present in the rat brain in tiny amounts (17-35nm) – not enough to produce any psychedelic effects. Nonetheless, work in the 1980s showed that housing rats in ‘solitary confinement’ for 30 days led to whole brain concentrations of DMT up to 500nM. Group-housed rats had almost undetectable levels of DMT.

So, could extreme stress cause a rapid and substantial increase in DMT? In their 2019 study, Jon Dean and Jimo Borgijin induced cardiac arrest in rats to create a state of extended hypoxia. They found that DMT did rise significantly in the brain when the animals were close to death.

‘It’s an interesting hypothesis that I don’t think we can discount,’ says Barker. ‘Studies have shown that the DMT psychedelic experience is closer to the near-death experience than anything else. But I think we would need to do some more work to confirm it.’

Depression therapy

It’s long been known that psychedelics have mind bending properties. But until recently scientists weren’t allowed to study these banned, recreational drugs. These laws have now lifted, and studies are finally shining light on their effects on the brain. It appears that psychedelics alleviate depression by encouraging new neurons and neural connections to form, whilst maintaining and repairing existing neurons. For example, scientists at Imperial College London, UK, have given volunteers psilocybin and DMT and imaged their brains using functional MRI scans. Their research has shown that the psychedelics massively increase connectivity across brain regions ^[4].

‘What they have seen is a huge increase in connectivity, so new networks, and new neurons being formed, as well as parts of the brain talking to each other that don’t normally talk to each other,’ says Doug Drysdale, CEO of Canadian biopharmaceutical company Cybin. ‘When you look at traditional antidepressants, they create small amounts of neuroplasticity too, as does psychotherapy. But what we see with psychedelics is a really significant burst of plasticity that lasts for a period of time.’

Meanwhile a 2023 study, by David Olsen, professor of biochemistry at University of California, Davis, US, suggests that psychedelics may promote neuroplasticity by activating a special class of serotonin 2A receptors found inside neurons [5]. These receptors then go on to encourage the formation of new dendrites – tree-like branches found on the end of neurons that are responsible for the connections between brain cells. As serotonin itself is a polar molecule, it can’t cross the lipid bilayer cell membrane and interact with the receptors inside. However, chemicals like DMT and psilocybin are methylated, making them hydrophobic enough to make the journey.

To support the theory, in a series of experiments, Olsen’s lab attached fluorescent proteins to serotonin 2A receptors inside rat cortical neurons. They then chemically modified DMT and psilocin so they could no longer cross the cell membrane. They found that only membrane-permeable compounds could promote neuroplasticity and the growth of new dendrites. Now Olson’s lab is developing compounds called psychoplastogens that have a similar antidepressant action to psychedelic drugs, but which don’t cause hallucinogenic trips. So far, his lab has produced analogues of DMT and ibogaine, with human tests beginning in May 2023.

Meanwhile, other trials are also ongoing to see whether psychedelics could alleviate depression. For example, John Kelly, a psychiatrist and clinical senior lecturer at Trinity College Dublin, recently concluded a Phase 2 clinical trial of COMP360, a synthetic formulation of psilocybin for treatment-resistant depression (TRD) ^[6]. In the double-blind trial, 233 participants with TRD were randomly assigned to three groups. The team used the Montgomery–Åsberg Depression Rating Scale (MADRS) to assess each patient’s level of clinical depression, with higher scores indicating more severe depression. The mean MADRS total score at the start of the trial was 32 or 33 in each group. The first group then received a single 25mg dose of psilocybin, the second 10mg, and the third control group received 1mg. Each group also received psychological support from trained therapists. Kelly and his colleagues found that a single 25mg dose of psilocybin improved depression symptoms significantly, with the MADRS score in this group reducing by 12 points. In comparison, the MADRS score for the 10mg group reduced by 7.9 points on average, while the score of the 1mg group reduced by 5.4 points.

On average, SSRIs like Prozac will improve depression symptoms compared to placebo by about two points on the MADRS depression scale, whereas we saw an average of 14 points improvement, from just one dose [of CYB003, a deuterated psilocybin analogue]
Doug Drysdale, CEO of Canadian biopharmaceutical company Cybin

Cybin is also developing psychedelic therapeutics. One candidate, CYB003, is a deuterated form of a molecule derived from psilocybin, while a second, CYB004, is a deuterated form of DMT. ‘What we’ve done is selectively substituted certain hydrogen atoms on each of the molecules with deuterium – a heavier isotope of hydrogen,’ says Drysdale. ‘This has the effect of creating stronger carbon to deuterium bonds, which seems to make the molecules more bioavailable in the body.’ Stronger bonds stop the compounds being broken down too quickly, allowing more of them to cross the blood brain barrier and reach the site of action.

‘In the clinic we are seeing faster onset, and also greater effects at lower doses than we would see with nondeuterated versions,’ says Drysdale. ‘If you inject someone with DMT they might have a 5-10 minute aggressive experience – an up and down rocket ride, if you will. But we have extended that to 90 minutes, and it is a much smoother curve.’

Cybin recently announced positive Phase 2 results for treatment of Major Depressive Disorder (MDD) with CYB003, with 79% of patients in remission from depression after two doses. The company now plans to initiate a Phase 3 study this year. According to Drysdale, the magnitude of improvement seen is far superior compared to approved antidepressants. ‘On average, SSRIs like Prozac will improve depression symptoms compared to placebo by about two points on the MADRS depression scale, whereas we saw an average of 14 points improvement [with CYB003], from just one dose.’

While we may not yet know the exact role that DMT plays in humans, that shouldn’t stop us from reaping the therapeutic benefits of psychedelics. ‘I think it’s quite a paradigm switch in how we treat depression,’ Drysdale says. ‘Moving away from a kind of chronic day to day symptom management to an intervention that can change things very quickly,’

References

Barker, S. A. et al, Biomed. Chromatogr., 2013, doi: 10.1002/bmc.2981
Dean, J. et al, Sci. Rep., 2019, doi: 10.1038/s41598-019-45812-w
Kelley, P. et al, ACS Chem. Neurosci, 2022, doi: 10.1021/acschemneuro.1c00660
Timmermann, C. et al, PNAS, 2023, doi: 10.1073/pnas.221894912
Vargas, M. V. et al, Science, 2023, doi: 10.1126/science.adf04
Goodwin J. M. et al, J. Affective Disorders, 2023, doi: 10.1016/j.jad.2023.01.108