How do hallucinogens work on the brain?

How do hallucinogens work on the brain?

Robin Carhart-Harris, Mendel Kaelen and David Nutt consider a big question on several levels

The ‘classic’ hallucinogens – such as LSD (derived from ergotamine found in ergot fungi), dimethyltryptamine (DMT, the major hallucinogenic component of ayahuasca) and psilocybin (from magic mushrooms) – possess a unique and arguably unrivalled potential as scientific tools to study the mind and the brain.

For those of us who are currently fortunate enough to be researching them, there is a real sense that we are exploring something destined to become the ‘next big thing’ in psychopharmacology. But how much do we really know about how they act on the brain to produce their many unusual effects? Here, we summarise the relevant research, beginning at the level of single neurons and moving towards networks in the brain.

The level of single neurons

All classic hallucinogens stimulate a particular serotonin receptor subtype expressed on neurons in the brain, the serotonin 2A receptor. This receptor appears to be central to the action of hallucinogens because blocking it (with another drug called ketanserin) abolishes the occurrence of the hallucinatory state (Vollenweider et al., 1998). Also, the affinity (or ‘stickiness’) of different hallucinogens for the serotonin 2A receptor correlates positively with their potency, or ‘strength’; for example, LSD has an extremely high affinity for the serotonin 2A receptor and is remarkably potent (Glennon et al., 1984). That hallucinogens ‘stimulate’ serotonin 2A receptors means that they mimic the action of serotonin at the receptor by binding to it, altering its conformation or ‘shape’, and ultimately altering the internal conditions and therefore behaviour of the neuron it sits on.

For the serotonin 2A receptor, the key functional effect of its stimulation is an increase in the excitability of the hosting neuron. Serotonin 2A receptors are primarily expressed on an important type of neuron or brain cell in the brain, excitatory pyramidal neurons. More specifically, serotonin 2A receptors are especially highly expressed on excitatory pyramidal neurons in ‘layer 5’ of the cortex. The cortex is organised into layers of different cell types, like the different layers of a cake, and layer 5 is a deep layer, nearer the base than the icing (Weber & Andrade, 2010). Layer 5 pyramidal neurons are especially important functional units in the brain as they are the principal source of output from a cortical region. They project to hierarchically subordinate, or ‘lower’, cortical and subcortical regions (e.g. from a visual association region to the primary visual cortex).

Layer 5 pyramidal neurons project heavily onto inhibitory interneurons and so the net effect of their excitation seems to be inhibitory (Bastos et al., 2012). This is important because hallucinogen-induced excitation of layer 5 pyramidal cells has been interpreted by some as evidence of a more general excitatory effect of these drugs, but as will be discussed in the forthcoming sections, recent animal electrophysiological and human neuroimaging recordings have cast further doubt on the assumption that hallucinogens have a general excitatory effect on cortical activity (Carhart-Harris et al., 2012; Wood et al., 2012).

Captured by the idiom ‘failing to see the woods for the trees’, these results are a reminder that one should not be too hasty to extrapolate from the activity of certain single units in the brain, since the interconnected nature of cortical circuits means that local excitation can translate into net inhibition, or rather ‘disorder’, at a higher level of the system. If John Donne was a neuroscientist, he might have said: ‘no neuron is an island, entire of itself’.


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  • Chris noton on The administration of psilocybin to healthy hallucinogen experienced volunteersHello, I’m am 43 year old male living in oxford and suffered from depression and anxiety for 20 some years and I am a chronic suffer. I am very interested in participating on this type of drug trial. In my 20’s I have picked my own mushrooms once or…
  • Anonymous on Are you having a psychedelic experience in the near future?Hi All, I suffer from depression and anxiety and have done so for many years. After being placed on anti-depressants (again), I had a very bad response and the side effects of increased suicidal thoughts became unbearable. It was an everyday battle o…
  • J Moran on Help us treat depression!Hello, I am wondering if you have completed your research into the use of psychedelics to aid with depression. I suffer with it myself and want to know if you are still looking for volunteers? I am currently 20 years old, turning 21 in September. I a…
  • Leo Tognetti on The administration of psilocybin to healthy hallucinogen experienced volunteersHi Drew Thanks for sharing. What was your method?
  • Richard NAUGHTON on Help us treat depression!These mushrooms have powers beyond the understanding of the modern world that have been lost in translation since the dawn of man . I've used them and felt drawn to them and felt it was a calling . I collected them myself for 15 years ate them , drie…
  • Garry Tickell on Are you having a psychedelic experience in the near future?My name is Garry.I have been using LSD (truffles)every day for the last fortnight.I have bi;polar disorder,and asbergers.I have several different thoughts on what im doing,and why,the hell i have to do it illegally.Right now,i have to start work,so d…

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