Engineering Psychoplastogens: Toward a Safer Alternative for Treating Depression

Identification of psychoplastogenic isoDMT analogs is a concrete step forward in using psychedelics for treating patients who suffer from depression.

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“[…] Hence the malaise, ‘’mal de vivre’’ that only exceptional minds once knew, and that today involves great masses.” — George Minois

Depression is the most common and debilitating mental disease, causing various symptoms that affect both the way a person feels and their daily activities.1 It induces excessive rumination in patients who also start to manifest a decrease in self-confidence and increases in guilt and helplessness. 

A  recent report from the World Health Organization stated that at a global level, over 300 million people are estimated to suffer from depression.2 This is equivalent to about 4.4% of the world’s population.

Although traditional antidepressants such as selective serotonin reuptake inhibitors (SSRIs), norepinephrine reuptake inhibitors (NERIs), and tricyclics have  been enjoying some success in treating people with this disorder, two main issues need to be addressed:

  1. Approximately one-third of patients do not show response to any class of antidepressant, while others respond only partially.1 
  2. Their effects on plasticity in the brain are quite slow and require chronic administration.3 

Neural Plasticity and the Neurotrophic Hypothesis

Neural plasticity is the ability of the brain to change and adapt in response to stimuli2. Its dysregulation has been identified as a contributing factor to depression.1

In fact, the neurotrophic hypothesis posits that a loss of trophic support in the prefrontal cortex (PFC) and the hippocampus leads to atrophy of these brain regions, which ultimately disrupts critical mood-regulating circuits.2 Traditional antidepressants can counteract these structural changes, such as the retraction of neurites, loss of dendritic spines, and elimination of synapses. And, by increasing the expression of brain-derived neurotrophic factor (BDNF), they promote the growth of neurons in both PFC and hippocampus.3 

Nevertheless, in a 2018 paper, Calvin Ly et al. suggested another class of compounds called psychoplastogens that might have value as fast-acting antidepressants with efficacy in patients who do not respond to traditional ones.4

What Are Psychoplastogens?

The term psychoplastogen was first introduced in 2018 by a research team led by Calvin Ly.4  It describes a growing number of compounds capable of rapidly promoting structural and functional neural plasticity. Coming from Greek words  psych-= mind, –plast= molded, and –gen=producing, this class includes psychedelics such as N,N-Dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), and psilocybin as well as the dissociative anesthetic ketamine.3 

Working through a similar molecular mechanism, both serotonergic psychedelics and ketamine produce a measurable change in plasticity (e.g. neurite growth, dendritic spine density, synapse number, intrinsic excitability, etc.) within a short period of time (typically 24-72 hours) following a single administration.1,3   

Molecularly speaking, psychoplastogens appear to induce changes in neuronal structure by activating mTOR, the mammalian target of rapamycin. mTOR belongs to the protein kinase family of enzymes and is involved in cell growth, autophagy, and the production of proteins necessary for synapse formation.3

However, in a 2018 paper, Dr. David Olson pointed out that although extremely promising, ketamine, for example, is still far from an ideal therapeutics as it has the potential for abuse.3 For this reason, he and his colleagues focused their attention on psychedelics as psychoplastogenic compounds that could be used to treat depression. Moreover, Dr. Olson explained that 

Although our cellular studies have shown that a wide variety of psychedelic compounds produce psychoplastogenic effects, our in vivo work thus far has primarily focused on the effects of DMT— the archetype for all tryptamine-containing psychedelics.

However, another issue needed to be addressed by Dr. Olson. Many DMT derivatives such as noribogaine, LSD, and psilocin (shown in Figure A) are well known as potent hallucinogens. This is the main adverse effect in treating patients suffering from depression with psychedelics. 

Figure A: The chemical structure of compounds possessing the DMT pharmacophore.5 The DMT portion (highlighted in black) is the core scaffold of several known psychoplastogenic compounds.

Working On DMT: Engineering isoDMT Analogues

Two years later in a 2020 paper, Lee E. Dunlap collaborated with Dr. Olson to investigate how to decrease the hallucinogenic potential of psychedelics.5

Extending on the extraordinary work of Glennon and colleagues in 1984, Dunlap and his team began by analyzing the efficacy of small series of compounds called isoDMT (N, N-Dimethylaminoisotryptamine) analogs. These molecules are well-validated to be less hallucinogenic than DMT. Nevertheless, their power in maintaining the ability to promote plasticity in depression still works as well as their fast-acting antidepressant properties.

Chemically, isoDMT is identical to DMT except that the indole nitrogen atom of isoDMT is located in the 3-position instead of the 1-position. These arrangements are shown in Figure B.

Figure B: The only difference between the chemical structures of DMT (1) and isoDMT (2) is that the C1 and C3 substituents of the indole are transposed.5

Usually, the synthesis of isoDMT and related analogs requires multiple steps and harsh conditions. On the contrary, Dunlap’s lab developed an operationally simple and robust method for synthesizing a variety of isoDMTs.

In principle, related analogs could be accessed in a single step through N-alkylation of the corresponding indoles or related heterocycles, as Figure C shows.           

Figure C: The chemical optimization of indole N-alkylation.5

The Dendritogenesis Assay

In the same paper, Dunlap and colleagues used a phenotypic assay to test the ability of isoDMTs analogs to increase dendritic arbor complexity in cultures of cortical neurons. The results of the assay (shown in Figure D) compared the ability of DMT, isoDMT, and some isoDMT analogs to increase dendritic arbor complexity.

The data indicated that although isoDMT and its analogs have the indole N-H at a different ring location than DMT, they still increased dendritic arbor complexity. 

Figure D: Images of cortical neurons treated with the compounds indicated.5 VEH = vehicle control. The indole N-H of tryptamine derivatives is not necessary to promote dendritogenesis.

Moreover, Dunlap et al. confirm the hypothesis that a basic nitrogen atom is necessary to promote plasticity. In fact, compounds such as the N,N-dimethylamide analog of isoDMT did not promote neuronal growth.

Hallucinogenic Potential

In the same work, Dunlap and his colleagues analyzed the affinity of isoDMTs for the serotonergic receptor 5-HT2A and their ability to elicit a mouse head-twitch response (HTR), a well-validated behavioral proxy for hallucinations. Two extraordinary results were observed:

  1. Despite their chemical modification, the isoDMTs still retained the affinity for 5-HT2A receptors as compared to their DMT counterparts.
  2. Mice treated with isoDMTs did not produce any HTR, demonstrating that hallucinogenic potential and psychoplastogenity can be decoupled.

Conclusion

In present-day society, depression is at the heart of peoples’ everyday lives shaping their feelings, thoughts, and behaviors. Nowadays, traditional antidepressants are usually prescribed to treat this condition. However, these treatments still lack efficacy sometimes, have a slow mechanism of action, and also require chronic administration. 

Working with psychoplastogens, Drs. Olson and Dunlap and their colleagues have developed molecules with a much safer profile highlighting their efficacy in maintaining a strong therapeutic potential without being hallucinogenic. Taken together, these findings not only offer a glimmer of hope in treating patients suffering from depression, but they may also represent a step forward in the decriminalization and the demystification of psychedelic research.

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