Psychedelics (including dissociative anesthetics, e.g. Ketamine) mood, and depression

Albert Hoffman ( ) In 1943, invented LSD-25 and took the first acid trip.

Albert Hoffman is a different guy from Abbie Hoffman ( )—social activist and member of “The Chicago Seven” who helped disrupt the Democratic National Convention in 1968.

That first trip Share – – The Guardian, Thursday 1 May 2008The Guardian Article history On April , Hofmann administered to himself the first experimental dose of his creation LSD-25. He recorded what happened on that now legendary "bicycle day" in his book, LSD - My Problem Child: "I had to struggle to speak intelligibly. I asked my laboratory assistant, who was informed of the self-experiment, to escort me home. We went by bicycle, no automobile being available because of wartime restrictions on their use. "On the way home, my condition began to assume threatening forms. Everything in my field of vision wavered and was distorted as if seen in a curved mirror. 'I also had the sensation of being unable to move from the spot. Nevertheless, my assistant later told me that we had travelled very rapidly

"We arrived at home. I had to lie down on a sofa. My surroundings had now transformed themselves in more terrifying ways. Everything in the room spun around, and the familiar objects and pieces of furniture assumed grotesque, threatening forms... The lady next door, whom I scarcely recognised, brought me milk. "She was no longer Mrs R, but rather a malevolent, insidious witch with a coloured mask... I was taken to another world, another place, another time. My body seemed to be without sensation, lifeless, strange. Was I dying? "Slowly I came back from a weird, unfamiliar world to reassuring everyday reality. The horror softened and gave way to a feeling of good fortune and gratitude... I could begin to enjoy the unprecedented colours and plays of shapes that persisted behind my closed eyes. Kaleidoscopic, fantastic images surged in on me, alternating, variegated, opening and then closing themselves in circles and spirals, exploding in coloured fountains."

5D-ASC The Altered States of Consciousness rating scale 5DASC (Dittrich, 1998; Dittrich et al., 1999) consists of 94 items that are visual-analogue scales of 10 cm length. These items measure alterations in mood, perception, experience of self in relation to environment, and thought disorder. Scores of each item range between zero (‘No, not more than usually’) and ten (‘Yes, much more than usually’). The ASC items are grouped into five main factors comprising several items. (1) ‘oceanic boundlessness’ (OB) measures derealization and depersonalization accompanied by changes in affect ranging from heightened mood to euphoria and/or exaltation as well as alterations in the sense of time. The corresponding item clusters are ‘positive derealization’, ‘positive depersonalization’, ‘altered time sense’, ‘positive mood’, and ‘mania-like experience’. (2) ‘anxious ego dissolution’ (AED) measures ego disintegration associated with loss of self-control, thought disorder, arousal, and anxiety. The item clusters are ‘anxious derealization’, ‘thought disorder’, ‘delusion’, ‘fear of loss of thought control’, and ‘fear of loss of body control’. (3) ‘visionary restructuralization’ (VR) includes the item clusters ‘elementary hallucinations’, ‘visual (pseudo-) hallucinations’, ‘synesthesia’, ‘changed meaning of percepts’, ‘facilitated recollection’, and ‘facilitated imagination’. (4) ‘auditory alterations’ (AA) refers to acoustic hallucinations and distortions in auditory experiences and (5) the dimension ‘reduction of vigilance’ (RV) relates to states of drowsiness, reduced alertness, and related impairment of cognitive function.

“Quantifying altered states of consciousness was problematic in the early years of hallucinogen research. Today, however, there are validated instruments for assessing various aspects of consciousness. According to Dittrich, hallucinogen-induced altered states of consciousness can be reliably measured by the five-dimensional altered states of consciousness (5DASC) rating scale. This scale comprises five primary dimensions and their respective subdimensions (see the figure). The primary dimensions are ‘oceanic boundlessness’ (shown by orange boxes), referring to positively experienced loss of ego boundaries that are associated with changes in the sense of time and emotions – ranging from heightened mood to sublime happiness and feelings of unity with the environment; ‘anxious ego- disintegration’ (shown by purple boxes), including thought disorder and loss of self-control; ‘visionary restructuralization’ (shown by blue boxes), referring to perceptual alterations (such as visual illusions and hallucinations), and altered meaning of percepts; acoustic alterations (not shown), including hypersensitivity to sound and auditory hallucinations; and altered vigilance (not shown).”

Magic Mushrooms

Some of these states of mind, such as “boundlessness,” are directly linked to increased neural activity in fMRI studies. They conclude: “The clinical findings and current understanding of the mechanisms of action of classical hallucinogens and dissociative anaesthetics converge on the idea that psychedelics might be useful in the treatment of major depression, anxiety disorders and OCD.”

Recently ketamine was shown to activate the mTOR (mammalian target of rapamycin) pathway

mTOR Pathway The mTOR pathway involves the regulation of a protein kinase variously known as: FKBP12-rapamycin-associated protein (FRAP); mammalian target of rapamycin (mTOR) or rapamycin and FKBP12 target 1 (RAFT1) and its downstream effectors. This kinase is a component of two functional complexes; TORC1 and TORC2. TORC1 is the rapamycin-sensitive mTOR complex responsible for regulation of protein translation initiation and efficiency. TORC1 contains; mTOR, the kinase; raptor (KOG1), a scaffold protein that mediates the association of mTOR with its substrates; LST8; and Tco89. TORC1 is sensitive to nutrients, especially amino acids such as leucine. This sensitivity involves the small GTPase Ras homologue, Rheb. TORC1 is activated by phosphatidic acid (PA) that results from the induction of phospholipase D by mechanical stimuli. TORC1 is activated by growth factor receptors through the phosphatidylinositol-3-kinase (PI3K); protein kinase D1 (PDK1); protein kinase B (Akt/PKB) pathway.

Activated mTOR (TORC1) phosphorylates protein phosphatase 2A (PP2A), p70S6K (S6K1) and eIF4E-BP (PHAS-1). Phosphorylation of PP2A prevents the dephosphorylation of p70S6K and eIF4E-BP. The phosphorylation of eIF4E-BP releases eIF4E which can then participate in the formation of the protein translation complex involving capped mRNAs. Phosphorylated p70S6K can phosphorylate the ribosomal S6 subunit which enhances the translation of 5'-terminal oligopyrimidine (TOP)-mRNAs. Enhanced translation of TOP-mRNAs leads to increased synthesis of proteins required for protein synthetic machinery. The combined effect of increased translation initiation and increased ribosomal and other translational proteins leads to enhanced protein synthesis and cell growth.

Ketamine caused rapid and transient activation of the mTOR pathway Phosphorylated mTOR Phosphorylated eukaryotic initiation factor 4E binding protein1 (4E-BP1) Phosphorylated p70S6 kinase

Dose-dependent activation of mTOR pathway by ketamine

Blockage of AMPA recptors blocks ketamine activation of mTOR, extracellular regulated kinase (ERK), and a serine/threonine specific kinase (AKT)

Inhibitors of either ERK or AKT blocked ketamine activation of mTOR

Ketamine enhanced synaptic proteins via mTOR pathway

Ketamine enhanced synaptic spines in the prefrontal cortex 24 hrs after treatment

Ketamine enhanced EPSCs via mTOR Hypocretin

Rapamycin blocked ketamine antidepressant effects on behavioral tests

NR2b antagonist Ro mimics ketamine

Coherence of Antidepressants