Why LSD Tolerance Happens | Brain Mechanisms & Microdosing | Tobias Buchborn, PhD

Scientific concepts & nature/brain phenomena presented

Core pharmacology: tolerance, sensitization, and withdrawal

• Repeated drug use changes effects over time:
  • Tolerance: early effects (e.g., euphoria) diminish with continued dosing.
  • Sensitization: some effects can become more pronounced over repeated use (e.g., craving).
  • Withdrawal syndrome: upon stopping, symptoms may appear that are opposite of acute effects.
• LSD-specific point:
  • Tolerance is prominent for LSD.
  • Taking psychedelic doses too frequently is unlikely in real-world patterns, and withdrawal is described as unheard of for LSD (per speaker).

LSD tolerance in animals: key determinants

• Dose interval matters
  • Re-dosing every 4 hours leads to much higher tolerance by day 4 than re-dosing with longer gaps (e.g., 8h, 24h).
• Dose amount matters
  • Tolerance often shows dose dependency.
  • In multi-day regimens, animals develop tolerance only when dose is increased to medium/high on multiple occasions.
• Effect-type differences (“biased tolerance”)
  • Tolerance develops differently across behaviors/physiological outcomes:
    • Shaking behavior (psychedelic signature) develops tolerance under one condition.
    • Hypothermia may not develop the same tolerance unless dosing conditions (e.g., higher doses) are adjusted.

Desensitization mechanism (pharmacodynamic tolerance)

• A major mechanism proposed:
  • Receptor desensitization: the drug’s target receptor stops responding after repeated exposure.
• Proposed cellular/biochemical phases of desensitization:
  • receptor uncoupling from its downstream signaling cascade
  • receptor internalization
  • receptor degradation
  • inhibition of new receptor synthesis
• Primary receptor target for LSD/psychedelics:
  • LSD and related psychedelics act primarily via serotonin (5-HT) 2A receptors.
• Receptor complex / interaction idea:
  • The speaker mentions that 5-HT2A receptors can form complexes with mGlu2 receptors (based on animal studies).

Brain receptor adaptations found (animal experiments)

• 5-HT2A receptor adaptations:
  • Binding capacity decreased in tolerant animals.
  • Coupling to G proteins decreased (reduced “capacity to buy G proteins”).
  • Desensitization of mGlu2 receptors was also reported as notable.
• Downstream glutamate system adaptations:
  • Lower overall glutamate receptor binding was observed after tolerance development (suggesting involvement of downstream networks).
• Dose dependency
  • In some higher-dose hypothermia experiments, 5-HT2A desensitization was detected, supporting a link between dose and tolerance magnitude.

Therapeutic implications: effects in depression-like models

• Pathology model: “actizyed” (likely “limbic-disrupted”) rats
  • Limbic system is described as important for:
    • allocating emotional value to cues
    • learning context for avoidance/behavior
  • These animals are described as unable to learn avoidance of an aversive situation.
• Behavioral assay described (tone → current → escape option)
  • Animals hear a tone.
  • After the tone, a non-painful but strong tickle-like current is delivered.
  • They can escape by jumping to a pole.
  • Disrupted-limbic (“pathological”) rats cannot do this avoidance, but chronic antidepressants enable learning.
• Repeated LSD effects
  • LSD did help the pathological animals (speaker frames it as similar to antidepressants).
  • Healthy animals did not benefit from LSD → “specific/normalizing effect” rather than enhancement.
• Hippocampus & receptor signaling
  • Bubba (likely “bilateral”) bubectomy/hippocampal lesion associated with reduced/altered 5-HT2A signaling.
  • LSD reportedly normalized this in healthy animals.
  • The normalization effect is described as specific to the 5-HT2 receptor family, not showing regulatory activity at:
    • 5-HT1A (mentioned as “overall metabotropic serotonin signaling” showing no regulatory activity)
• Net implication
  • tolerance mechanisms and therapeutic-like normalization effects may be condition-dependent (works in pathology, not in healthy baseline).

Microdosing and “affinity”/receptor occupancy considerations

• The speaker discusses a pharmacology parameter:
  • Affinity: drug concentration needed to bind a receptor and induce activity.
• How affinity is measured (conceptual assay)
  • Radiolabeled ligand binds receptors in “wells”/cell preparations.
  • Adding a psychedelic (unlabeled/competing) displaces the radioligand.
  • Increase psychedelic concentration until displacement is maximal.
  • Affinity defined as the concentration producing 50% displacement (IC50-like concept).
• Receptor occupancy assumption challenged
  • Microdosing is often suggested to aim for ~40% occupancy at 5-HT2A.
  • But LSD/“psychedelics” are described as not selective for 5-HT2A.
    • Example given: higher preference for 5-HT1B than 5-HT2A.
  • Therefore, achieving ~40% 5-HT2A occupancy could imply ~80% occupancy of another receptor (5-HT1B), raising safety/side-effect concerns depending on what that other receptor does.

Summary takeaways (mechanistic and safety)

• LSD tolerance depends on:
  • dose interval (shorter intervals → more tolerance)
  • dose (higher doses → more tolerance)
  • which effect is measured (biased tolerance)
• Tolerance mechanisms involve:
  • 5-HT2 family desensitization
  • possibly adaptations in downstream pathways, including the glutamate system and interaction partners (e.g., mGlu2)
• For therapeutic and microdosing contexts:
  • short-term LSD might have beneficial learning/integration-like effects (speaker framing), potentially relevant to depression/other psychiatric conditions
  • microdosing studies should include:
    • not only psychological outcomes
    • but also monitoring other organs and receptor populations over time (months), due to non-selective receptor binding and possible long-term adaptations

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Researchers / sources featured

• Tobias Buchborn, PhD (speaker; biopsychologist at Imperial College London)

No other specific researchers, paper titles, or institutions are explicitly named in the subtitles beyond the speaker’s affiliation.