Discussing Tolerance with Dr. Tobias Buchborn

Tobias Buchborn (PhD) studied Psychology at the OvG University, Magdeburg Germany, and within his Diploma thesis investigated the antidepressant-like properties of repeated LSD administration in an animal model of depression. His PhD project explored the behavioural and molecular biological correlates of tolerance to LSD, DMT, and DOB. In 2016, dr. Buchborn started to work as a Marie Curie Research Fellow at Imperial College London, where his research has been devoted to the hemodynamics and pyramidal-cellular corticodynamics of psychedelic drug action.

In March 2019, dr. Buchborn gave a lecture for APRA about his own research, focusing on psychedelics and tolerance. In this context, tolerance is a state or process in which the body develops strategies to counteract or compensate the effects of a drug. After the lecture, Isolde de Jong and Jennifer Them interviewed dr. Buchborn about his work and research interests. The content of the interview is reported below.

 

Isolde & Jennifer: Originally you started your PhD in psychology in Magdeburg, and your current research is focusing towards the psychopharmacological effects of psychedelics, in particular tolerance. What brought you to this research?

Tobias:  My first love has always been the psyche, so I studied and graduated in Psychology in the first place. Then I went on to run my PhD project in Neuroscience at the Institute of Pharmacology and Toxicology (IPT) in Magdeburg. The interface between these three disciplines indeed is what intrigues me the most. Drugs –as described by Pharmacology– always head for the molecular level, interacting for instance with proteins in the membrane of a neuron and affecting how the neuron handles its “housekeeping”. Since neurons are neatly interconnected changes in the housekeeping of one neuron may affect the housekeeping of other neurons. Information may spread from local units to cross-regional circuits, and eventually determine how different brain areas communicate with one another. As communication patterns of the brain are altered by the drug, bringing Psychology into the arena, shifts in perception, cognition, affectivity, and behaviour occur. Understanding how the different levels of such a physiopsychological hierarchy are interrelated is driving me as a neuropharmacological researcher.

My way into psychedelic research started way back when I was a student. In the lecture series “Clinical Psychology”, I was presented with the pharmacodynamic model of why SSRIs need months (despite quite imminent in inhibiting the reuptake of serotonin) before they actually start ameliorating depression. I remember one of these catchy cartoons from “Stahl’s essential Psychopharmacology”; certain adaptations, such as the desensitisation of somatodendritic 5-HT1A autoreceptors and the downregulation of postsynaptic 5-HT2A receptors, were shown to occur with a temporal lag only and suggested to be critical for the delayed onset of therapeutic efficacy. I had read into psychedelic research early on and, sitting in this lecture, two studies came to my mind; in these studies, repeated LSD and DOI treatment had in fact been demonstrated to regulate 5-HT receptors the very way suggested relevant for antidepressants. Although it had always seemed plausible to me that drugs that facilitate access to the psyche might be of benefit to psychotherapy, it was then that I for the first time thought that beyond psychology healing potential might already lie within the mere neurochemistry of psychedelic drugs. I was lucky to meet Prof. Gisela Grecksch, an expert in animal models of psychiatric disorders at the IPT. Testing the antidepressant potential of repeated LSD treatment in an animal model of depression became the theme of my Diploma thesis, and further down the road my first publication. Given the repetitiveness of drug application within this first project and the fact that the IPT at that time had a major research focus on tolerance arising from repeated opioid treatment, it only stood to reason to me that my PhD project would then be set around tolerance to psychedelics.

 

What would you say is a common misconception in the general public and/or scientific community when it comes to psychedelics and tolerance?

 When repeatedly confronted with a drug that interferes with the body’s functioning, the body usually adapts in the function targeted by the drug. A common way of such an adaptation is called “tolerance”; a state or process in which the body develops strategies to counteract the interference from the drug. Psychedelics interfere, amongst others, with psychological functioning and upon repeated application (of LSD for instance), the body quickly finds ways to keep the psyche stable despite the presence of the drug. Tolerance is quite tricky, though, and critically dependent upon the doses and intervals of drug application, and sometimes quite different between drugs of the same class. Although both similarly psychedelic to the human mind, the body seems to more readily adapt to LSD than to DMT, for example. Whereas rigorous scientific knowledge about tolerance usually derives from standardised experiments, recreational drug use in the general public is often hardly controlled in terms of purity of drug, dose, and interval of drug intake. As to this, it now and again becomes quite difficult to predict whether the repeated application of a psychedelic drug at flexible doses and/or intervals, or the interchangeable use of mechanistically akin drugs (e.g., the 5-HT2A agonistic psychedelics and the indirectly 5-HT2A agonistic entactogens) will actually potentiate and/or dampen the respective drug effect upon next administration. Another aspect to bear in mind is that tolerance to a (psychedelic) drug can develop differentially, which means that some effects might vanish upon repeated intake whereas others might persist or sensitize. One might, for instance, be tempted to increase the dose of the drug in order to overcome tolerance to its psychedelic effect; instead of bringing back psychedelia, however, the drug might only be heavy on other monoamine receptor expressing organs (such as the cardiovascular system) and/or the metabolic apparatus. Such concerns might particularly apply to some of the newer, highly potent synthetic phenethylamine psychedelics with increased toxicity.

 

What is currently still unknown about tolerance and psychedelics that you would like to know? More specifically, what is/are the question(s) that you most hope to answer with your research, if you could choose one/a few?

Research on tolerance to psychedelics in humans is surprisingly sparse. To date, amongst the serotonergic psychedelics, tolerance most elaborately has been investigated for LSD. Apart from a recent study on acute tolerance by the Liechti-group in Switzerland, however, our knowledge on human tolerance to LSD is exclusively based upon research dating back to the 1950ies and 60ies. These studies do not meet modern standards and have several flaws, including small sample sizes (of mostly psychiatric patients), uncontrolled/unblinded research designs, and sketchy data presentation. For DMT, there are two recent modern-standard studies; for other psychedelics, human literature is thin or non-existing. Although in conjunction with the anecdotal-like reports of the old-days literature it seems safe to say that psychedelic tolerance to LSD in the short run is quick to come, persistent with continuous application, and quick to go upon withdrawal. There is a definite need for modern-standard replications and expansion of research to other psychedelics.

Being a fundamental researcher, my primary interest lies with the mechanism of action of psychedelics, as well as with the mechanism of how the given action becomes subject to tolerance. Apart from a study from my colleague David Erritzoe, where MDMA and/or 5-HT2A agonist users were imaged for 5-HT2A binding sites in the brain, however, there is no literature on correlates and/or mechanisms of tolerance to psychedelics in humans. Research in animals looks somewhat better; the major focus, however, has always been put on the amphetamine-derivative DOI with only little knowledge on classic psychedelics; in particular, it is vastly unknown why LSD rapidly induces tolerance, whereas DMT does not. Pharmacodynamic tolerance is generally thought to arise from regulations around the primary receptor target of a drug. Trying to overcome the gap regarding the classics, my PhD project therefore focussed on processes of 5-HT2A regulation as a possible mechanism of differential tolerance to LSD and DMT. Intriguingly, we found that in all 5-HT2A parameters investigated (incl. binding sites, G-protein interaction, internalisation, mRNA regulation, as well as behavioural and/or autonomic output) LSD and DMT differed, with former behaving in a way indicative of downregulation, and latter being inactive or even upregulatory. Given this association between differential tolerance and differential 5-HT2A regulation, our results provide compelling evidence that tolerance to classic psychedelics indeed seems to have strong pharmacodynamic components. For future research, it would be exciting to elucidate whether differential 5-HT2A regulation translates into differential adaptations of psychedelia-relevant brain circuits, with pyramidal cells losing their responsiveness to repeated LSD, but keeping on response to DMT.

 

In the neuropharmacological literature, psychedelics are defined as serotonergic hallucinogens, i.e. substances that exert hallucinogenic effect via agonism at the serotonin 2A receptor. However, as you mentioned, even within this quite restricted class, major differences in tolerance and duration of action are known, e.g. LSD vs. DMT, suggesting that functional selectivity downstream from the receptor plays a role. Studying this kind of questions may offer insight into cellular mechanisms that are generally important for brain function. What do you think we can learn about the brain in general by studying tolerance to psychedelics? 

Everything starts with a drug binding to its target receptor. The binding of different drugs to the same receptor (even of the same class) is not the same, though, but instead critically dependent on the backbone and side-chains of the drug’s molecule. The simple tryptamine DMT, for instance, is partially buried in the more complex molecule of LSD. The overlap between both molecules is sufficient for them to provide a recognition unit (or “pharmacophore”) for the 5-HT2A receptor and downstream-psychedelia, but also different enough to account for multiple differences in terms of overall receptor binding profile, coupling efficacy, or sensitivity to degrading enzymes. We recently demonstrated, for instance, that LSD via 5-HT2A binding activates an enzyme called phospholipase D (PLD), whereas DMT fails. PLD cuts off the head groups of certain lipids within the membrane and thereby facilitates a “bending” of the cell membrane. Such a bending is an important step for 5-HT2A receptors to be packed into little membrane packages (“vesicles”) that can pinch off from the overall cell membrane and “submerge” into the intracellular space. 5-HT2A receptors, in this process called “internalisation”, are enabled to leave their “work place” and “skip their regular job”. Thus, DMT’s inability to activate PLD and remove 5-HT2A receptors from their work place might well be a reason for its inability to readily induce tolerance. Little differences in molecular structure may give rise to tremendous variance in physiological and/or psychological output of a drug. Intriguingly, tolerance is not only restricted to exogenous compounds provided by the pharmacy or underground drug kitchen. It may develop to endogenous compounds, such as endorphins, in response to behavioural changes. It may also be conveyed by the genes in form of so-called “innate tolerance” and thereby make us prone or resilient to certain disorders. The implications of tolerance reach far, and we are only beginning to understand.

 

Suggested reading

  •       Buchborn T., Grecksch G., Dieterich D. C., Höllt V. (2016). Tolerance to Lysergic Acid Diethylamide: Overview, Correlates, and Clinical Implications. In: Preedy V, editor. Neuropathology of Drug Addictions and Substance Misuse. San Diego: Academic Press, pp 846-858.
  •       Kantak K. M., Wettstein J. G. (2015). Cognitive Enhancement. Heidelberg: Springer.
  •       Passie T. (2019). Science of microdosing psychedelics. London: Psychedelic Press.

 

 Photo by simon peel on Unsplash

 

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