Recent advances in the neuropsychopharmacology of serotonergic hallucinogens

“…that psilocybin reduces activity and connectivity in core nodes of the default-mode network, brain regions that are active during the resting state and potentially involved in introspective processes (for more information, see: Raichle et al., 2001; Mason et al., 2007; Buckner et al., 2008).”

“…that psilocybin reduces activity and connectivity in core nodes of the default-mode network, brain regions that are active during the resting state and potentially involved in introspective processes (for more information, see: Raichle et al., 2001; Mason et al., 2007; Buckner et al., 2008).”

“CSTC loops are parallel, anatomically segregated circuits relaying information between the basal ganglia, thalamus, and cortex (Alexander et al., 1986, 1990).”

“Since cortical oscillations play a fundamental role in a diverse set of mental processes and are required for the coordination of neural processing (Gray et al., 1989; Singer, 1999; Buzsaki and Draguhn, 2004; Sejnowski and Paulsen, 2006; Fries, 2009; Klimesch, 2012), it is tempting to speculate that the reduction of n…”

“One potential explanation is that the hemodynamic responses measured by fMRI are actually better correlated with cortical oscillatory activity than with neuronal firing (Mathiesen et al., 1998; Logothetis et al., 2001; Behav Brain Res.”

“Since cortical oscillations play a fundamental role in a diverse set of mental processes and are required for the coordination of neural processing (Gray et al., 1989; Singer, 1999; Buzsaki and Draguhn, 2004; Sejnowski and Paulsen, 2006; Fries, 2009; Klimesch, 2012), it is tempting to speculate that the reduction of n…”

“Under anesthesia or during slow-wave sleep, cortical networks display slow (0.5–1 Hz) and delta (1–4 Hz) oscillations (Steriade et al., 1993a,b; Steriade, 1997) that reflect alternations between periods of silence (DOWN states) and periods of depolarization with repetitive spiking (UP states).”

“Since cortical oscillations play a fundamental role in a diverse set of mental processes and are required for the coordination of neural processing (Gray et al., 1989; Singer, 1999; Buzsaki and Draguhn, 2004; Sejnowski and Paulsen, 2006; Fries, 2009; Klimesch, 2012), it is tempting to speculate that the reduction of n…”

“The 5-HT2 receptor class was later reorganized to include three subtypes: 5-HT2A (equivalent to the site known historically as the 5-HT2 receptor or the D receptor), 5-HT2B (formerly known as the 5HT2F receptor), and 5-HT2C (formerly known as the 5-HT1C receptor) (Hoyer et al., 1994).”

“GABAergic interneurons expressing parvalbumin and calbindin are sources of perisomatic inhibition that synchronize the oscillatory firing of large ensembles of pyramidal neurons (Bartos et al., 2007; Freund and Katona, 2007; Buzsaki and Wang, 2012).”

“…that psilocybin reduces activity and connectivity in core nodes of the default-mode network, brain regions that are active during the resting state and potentially involved in introspective processes (for more information, see: Raichle et al., 2001; Mason et al., 2007; Buckner et al., 2008).”

“…the active waking state, which is characterized by fast rhythms in the gamma range (30–80 Hz) that play a putative role in a multitude of perceptual and cognitive functions (Tallon-Baudry et al., 1998; Fries et al., 2001; Herrmann et al., 2004; Schroeder and Lakatos, 2009; Roux and Uhlhaas, 2014).”

“Since cortical oscillations play a fundamental role in a diverse set of mental processes and are required for the coordination of neural processing (Gray et al., 1989; Singer, 1999; Buzsaki and Draguhn, 2004; Sejnowski and Paulsen, 2006; Fries, 2009; Klimesch, 2012), it is tempting to speculate that the reduction of n…”

“…that schizophrenia patients show deficits of gamma oscillations and synchrony (Spencer et al., 2003; Cho et al., 2006; Minzenberg et al., 2010; Uhlhaas and Singer, 2010) and reductions in slow-wave sleep (Yang and Winkelman, 2006), and it has been hypothesized that these abnormalities play an…”

“GABAergic interneurons expressing parvalbumin and calbindin are sources of perisomatic inhibition that synchronize the oscillatory firing of large ensembles of pyramidal neurons (Bartos et al., 2007; Freund and Katona, 2007; Buzsaki and Wang, 2012).”

“CSTC loops are parallel, anatomically segregated circuits relaying information between the basal ganglia, thalamus, and cortex (Alexander et al., 1986, 1990).”

“Under anesthesia or during slow-wave sleep, cortical networks display slow (0.5–1 Hz) and delta (1–4 Hz) oscillations (Steriade et al., 1993a,b; Steriade, 1997) that reflect alternations between periods of silence (DOWN states) and periods of depolarization with repetitive spiking (UP states).”

“Since cortical oscillations play a fundamental role in a diverse set of mental processes and are required for the coordination of neural processing (Gray et al., 1989; Singer, 1999; Buzsaki and Draguhn, 2004; Sejnowski and Paulsen, 2006; Fries, 2009; Klimesch, 2012), it is tempting to speculate that the reduction of n…”

“Another notable difference between ketamine and serotonergic hallucinogens is that ketamine does not produce mystical experiences (Lofwall et al., 2006), whereas hallucinogens induce these states with some reliability (Pahnke, 1969; Griffiths et al., 2006, 2008, 2011; Lyvers and Meester, 2012).”

“…do not produce head twitches in response to mescaline, DOI, DOM, LSD, DMT, 5-MeO-DMT, psilocin, or 1-methylpsilocin (González-Maeso et al., 2007; Keiser et al., 2009; Halberstadt et al., 2011), although the response can be rescued by selectively restoring the 5-HT2A receptor gene to cortical…”

“The LC also receives excitatory input from the prefrontal cortex (PFC), both directly and indirectly (Sesack et al., 1989; Jodo and Aston-Jones, 1997; Jodo et al., 1998), and the excitatory effects of hallucinogens on the LC may be mediated by those pathways.”

“After introduction of the dopamine antagonist radioligand [3H]spiperone, it was recognized that [3H]spiperone binds to 5-HT receptors distinct from the sites labeled by [3H]5-HT (Peroutka and Snyder, 1979).”

“The D receptor was eventually shown to be equivalent to the 5-HT2 receptor, whereas the M receptor is pharmacologically distinct from 5-HT1 sites and was later classified by Bradley and coworkers (Bradley et al., 1986) as the 5-HT3 receptor.”

“The values reported by Grob et al. (2011) were reanalyzed using the 11 new homogenous APZ subscales developed by Studerus et al. (2010).”

“Likewise, hallucinogens enhance memory recall (Carhart-Harris et al., 2012b), sometimes producing extremely vivid recollections.”

“There has been some debate about the exact number of CSTC loops (Middleton and Strick, 2001; Di Martino et al., 2008), but at least five have been putatively identified, each serving a different function.”

“It was proposed in 1982 that the mescaline-induced HTR is mediated by the 5- HT2A receptor, based on the fact that the relative potency of 5-HT antagonists to block the behavior is correlated (r = 0.875) with their 5-HT2A affinity (Leysen et al., 1982).”

“Importantly, PPI is regulated by components of the limbic CSTC loop, including mPFC, NAc, and VP (Swerdlow et al., 2001).”

“Among patients with Parkinson's disease, approximately 22% experience complex visual hallucinations (Fenelon et al., 2000).”

“The excitation of V1 is presumably driven by 5- HT2A receptors because ketanserin blocks the visual hallucinations induced by psilocybin (Vollenweider et al., 1998; Kometer et al., 2013).”

“Since 5-HT2C editing can influence the downstream coupling of the receptor (Burns et al., 1997), the nature of the interactions between 5-HT2A and 5-HT2C could potentially vary by mouse strain.”

“The PFC exerts top-down executive control over processing in temporal and parietal cortices (Tomita et al., 1999; Simons and Spiers, 2003; Merchant et al., 2011; Crowe et al., 2013).”

“Two clinical trials have shown that the selective 5-HT2A inverse agonist pimavanserin reduces the severity of hallucinations in Parkinson's disease (Meltzer et al., 2010; Cummings et al., 2014).”

“Another notable difference between ketamine and serotonergic hallucinogens is that ketamine does not produce mystical experiences (Lofwall et al., 2006), whereas hallucinogens induce these states with some reliability (Pahnke, 1969; Griffiths et al., 2006, 2008, 2011; Lyvers and Meester, 2012).”

“The IL subregion of mPFC impairs fear conditioning by inhibiting central amygdaloid nucleus output neurons, which project to brainstem and hypothalamic sites responsible for expressing fear responses (Quirk et al., 2003).”

“Abbreviations: AA, arachidonic acid; 2-AG, 2-arachidonoylglycerol; ARF, ADP-ribosylation factor-1; DAG, diacylglycerol; DGL, diacylglycerol lipase; ERK1/2, extracellular-regulated kinases 1 and 2; GRB, growth factor receptor-bound protein 2; IP3, inositol triphosphate; p38 MAPK, p38 mitogenactivated protein kinase; ME…”

“…the active waking state, which is characterized by fast rhythms in the gamma range (30–80 Hz) that play a putative role in a multitude of perceptual and cognitive functions (Tallon-Baudry et al., 1998; Fries et al., 2001; Herrmann et al., 2004; Schroeder and Lakatos, 2009; Roux and Uhlhaas, 2014).”

“Psilocybin can induce highly meaningful spiritual experiences (Griffiths et al., 2006), and some subjects have reported experiencing positive changes in mood and behavior that persist for many months (Griffiths et al., 2008).”

“…the active waking state, which is characterized by fast rhythms in the gamma range (30–80 Hz) that play a putative role in a multitude of perceptual and cognitive functions (Tallon-Baudry et al., 1998; Fries et al., 2001; Herrmann et al., 2004; Schroeder and Lakatos, 2009; Roux and Uhlhaas, 2014).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript Niessing et al., 2005; Nir et al., 2007; Viswanathan and Freeman, 2007).”

“Evidence has emerged that mGlu2 and 5- HT2A receptors can form heteromeric complexes in cortex (Gonzalez-Maeso et al., 2008; Moreno et al., 2012), and these complexes may mediate the crosstalk that occurs between these receptors.”

“…the active waking state, which is characterized by fast rhythms in the gamma range (30–80 Hz) that play a putative role in a multitude of perceptual and cognitive functions (Tallon-Baudry et al., 1998; Fries et al., 2001; Herrmann et al., 2004; Schroeder and Lakatos, 2009; Roux and Uhlhaas, 2014).”

“Recent clinical trials have investigated whether psilocybin has efficacy against anxiety in terminal cancer patients (Grob et al., 2011), and LSD has been tested as a potential adjunct for psychotherapy (Gasser et al., 2014).”

“…and it is possible the crosstalk is purely functional and occurs at the circuit level. mGlu2 receptors function predominantly as presynaptic autoreceptors (Schoepp, 2001), so mGlu2 activation could potentially suppress 5-HT2Ainduced spontaneous EPSCs by reducing Glu release from axon terminals.”

“Vollenweider and colleagues have conducted a psychometric assessment of APZ-OAV data pooled from 43 studies with psilocybin, (S)-ketamine, and the entactogen 3,4methylenedioxymethamphetamine (MDMA, “Ecstasy”) (Studerus et al., 2010).”

“, 2009) and the trace amine receptor (Bunzow et al., 2001), and are substrates for the 5-HT transporter (SERT) (Nagai et al.”

“Additionally, there is a very strong correlation (r = 0.90–0.97) between 5- HT2A receptor affinity and human hallucinogenic potency (Glennon et al., 1984; Titeler et al., 1988; Sadzot et al., 1989).”

“…phenomenon where a weak prestimulus presented prior to a startling stimulus will attenuate the startle response; PPI is often used as an operational measure of sensorimotor gating, and reflects central mechanisms that filter out irrelevant or distracting sensory stimuli (Swerdlow and Geyer, 1998).”

“Along these lines, there is evidence that schizophrenia patients show deficits of gamma oscillations and synchrony (Spencer et al., 2003; Cho et al., 2006; Minzenberg et al., 2010; Uhlhaas and Singer, 2010) and reductions in slow-wave sleep (Yang and Winkelman, 2006), and it has been hypothesized that these abnormalit…”

“…neurons: there is a moderate depolarization, spike-frequency accommodation is reduced, and the afterhyperpolarization (AHP) that normally follows a burst of spikes is replaced by a slow depolarizing afterpotential (sADP)(Araneda and Andrade, 1991; Tanaka and North, 1993; Arvanov et al., 1999).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript Niessing et al., 2005; Nir et al., 2007; Viswanathan and Freeman, 2007).”

“The PFC exerts top-down executive control over processing in temporal and parietal cortices (Tomita et al., 1999; Simons and Spiers, 2003; Merchant et al., 2011; Crowe et al., 2013).”

“Several theoretical explanations for geometric visual hallucinations have been proposed based on retinocortical mapping and the architecture of V1 (Ermentrout and Cowan, 1979; Behav Brain Res.”

“Along these lines, there is evidence that schizophrenia patients show deficits of gamma oscillations and synchrony (Spencer et al., 2003; Cho et al., 2006; Minzenberg et al., 2010; Uhlhaas and Singer, 2010) and reductions in slow-wave sleep (Yang and Winkelman, 2006), and it has been hypothesized…”

“The values reported by Grob et al. (2011) were reanalyzed using the 11 new homogenous APZ subscales developed by Studerus et al. (2010).”

“Almost all prefrontal pyramidal neurons express the 5-HT2A receptor, with the receptor localized primarily to the proximal apical dendrites (Willins et al., 1997; Jakab and Goldman-Rakic, 1998; Cornea-Hébert et al., 1999; Xu and Pandey, 2000).”

“Certain indolealkylamines, most notably DMT and some of its derivatives, bind to σ1 receptors (Fontanilla et al., 2009) and the trace amine receptor (Bunzow et al., 2001), and are substrates for the 5-HT transporter (SERT) (Nagai et al., 2007; Cozzi et al., 2009).”

“The 5- HT1A antagonist WAY-100635 does not alter LSD discrimination in rats (Appel et al., 2004; Reissig et al., 2005; Gresch et al., 2007), but the 5-HT1A receptor may make an more prominent contribution to the LSD cue in mice because discrimination can be partially blocked by administration of either WAY-100635 or M…”

“There is evidence that excitation of Brodmann area (BA) 19 and BA 37 can produce complex visual hallucinations (Ffytche et al., 1998; Holroyd and Wooten, 2006; Kazui et al., 2009).”

“) produces broadband reductions in cortical oscillatory power (Muthukumaraswamy et al., 2013).”

“Likewise, in rats, a large percentage of the cells in the superficial, middle, and deep layers of the secondary motor, anterior cingulate (ACA), prelimbic (PrL), and infralimbic (IL) areas express 5-HT2A mRNA (Amargos-Bosch et al., 2004; Santana et al., 2004).”

“6), and acts as an agonist at a variety of serotonergic, dopaminergic, and adrenergic receptors (Leysen, 1989; Piercey et al,. 1996; Egan et al., 1998; Marona-Lewicka et al., 2002; Millan et al., 2002; Nichols et al., 2002).”

“…mPFC inhibits the amygdala because the projection is glutamatergic (Amaral and Insausti, 1992; Smith et al., 2000), the mechanism is now believed to involve excitation of GABAergic neurons in the intercalated nuclei of the amygdala (Berretta et al., 2005; Likhtik et al., 2008; Pinard et al., 2012).”

“Visual input stabilizes network activity in V1 by driving inhibitory interneurons (Ozeki et al., 2009).”

“Another instrument is the Hallucinogen Rating Scale (HRS), which was specifically designed to measure the effects of parenteral DMT (Strassman et al., 1994) Double-blind studies have confirmed the APZ and the HRS can distinguish the effects of psilocybin and mescaline from those of…”

“In contrast to those findings, another group has reported that higher doses of DOI (3–5 mg/kg, i.p.) tend to inhibit the firing of pyramidal cells in ACA and the ventral, dorsolateral, and lateral orbitofrontal cortices of behaving rats (Wood et al., 2012).”

“LSD and other ergoline hallucinogens display high affinity for 5- HT receptors, as well as dopaminergic and adrenergic receptors (reviewed by: Halberstadt and Geyer, 2011; Nichols, 2012).”

“However, although the ability of 5-HT to induce EPSCs is lost after deletion of the 5-HT2A gene (htr2A−/− mice), the effect can be rescued by selective restoration of 5-HT2A receptors to pyramidal neurons in the forebrain (Weisstaub et al., 2006).”

“Under anesthesia or during slow-wave sleep, cortical networks display slow (0.5–1 Hz) and delta (1–4 Hz) oscillations (Steriade et al., 1993a,b; Steriade, 1997) that reflect alternations between periods of silence (DOWN states) and periods of depolarization with repetitive spiking (UP states).”

“It is also a component of ayahuasca, an infusion or decoction prepared from DMT-containing plants in combination with species of Banisteriopsis containing β-carboline alkaloids that act as monoamine oxidase inhibitors (McKenna et al., 1984).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript Niessing et al., 2005; Nir et al., 2007; Viswanathan and Freeman, 2007).”

“, fenfluramine and p-chloroamphetamine), and therefore the behavior is not specific to hallucinogens (Corne et al., 1963; Matthews and Smith, 1980; Singleton and Marsden, 1981; Yamaguchi et al., 1987).”

“One potential explanation is that the hemodynamic responses measured by fMRI are actually better correlated with cortical oscillatory activity than with neuronal firing (Mathiesen et al., 1998; Logothetis et al., 2001; Behav Brain Res.”

“Likewise, in rats, a large percentage of the cells in the superficial, middle, and deep layers of the secondary motor, anterior cingulate (ACA), prelimbic (PrL), and infralimbic (IL) areas express 5-HT2A mRNA (Amargos-Bosch et al., 2004; Santana et al., 2004).”

“The exact nature of the experience is highly variable and depends on the mood and expectations of the subject (the “set”) as well as the environment in which the drug is ingested (the “setting”) (Bercel et al., 1955; Osmond, 1957; Faillace and Szára, 1968; Freedman, 1968).”

“The excitation of V1 is presumably driven by 5- HT2A receptors because ketanserin blocks the visual hallucinations induced by psilocybin (Vollenweider et al., 1998; Kometer et al., 2013).”

“Moreover, 5-HT2A receptors are expressed at high to moderate densities in temporal and parietal cortical areas (Pazos et al., 1987; Lidow et al., 1989; Gross-Isseroff et al., 1990a,b; Hall et al., 2000), so the influence exerted by the PFC would act in concert with any local response induced by…”

“Additionally, there is a very strong correlation (r = 0.90–0.97) between 5- HT2A receptor affinity and human hallucinogenic potency (Glennon et al., 1984; Titeler et al., 1988; Sadzot et al., 1989).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript is part of the dorsal visual stream and generates multiple egocentric representations of space (Stein, 1992; Vallar et al., 1999; Schindler and Bartels, 2013).”

“It has been theorized that hallucinogen-induced altered states may arise in part through effects on cortico-striato-thalamo-cortical (CSTC) feedback loops (Vollenweider, 1994, 1998; Vollenweider and Geyer, 2001).”

“Hallucinogens also induce head twitches in rats, but in that species the behavior often involves both the head and the trunk (Yamamoto and Ueki, 1975; Bedard and Pycock, 1977).”

“For example, DOI activates serotonergic neurons in the dorsal raphe nucleus indirectly by exciting the projection from mPFC (Martín-Ruiz et al., 2001; Puig et al., 2003).”

“The atypical antipsychotics clozapine and risperidone, which block the 5-HT2A receptor, are also effective against the visual hallucinations (Kahn et al., 1991; Meco et al., 1997; Pollak et al., 2004).”

“An fMRI BOLD study in healthy volunteers revealed that psilocybin (0.16 mg/kg p.o.) reduces activation of the amygdala by negative and neutral pictures, and the BOLD signal change was inversely correlated with reports of increased positive mood (Kraehenmann et al., 2014).”

“Although hallucinogens act in a relatively unspecific manner (Grof, 1980), and hence a broad range of experiences are possible, previous clinical studies have confirmed that there is also a great deal of similarity between the effects of different hallucinogens.”

“…and inhibitory neurons in the amygdala express 5-HT2A receptors (McDonald and Mascagni, 2007; Bombardi, 2011), and DOI and other 5-HT2A agonists act locally to produce direct excitatory and indirect inhibitory effects in the amygdala (Rainnie, 1999; Stein et al., 2000; Sokal et al., 2005).”

“…1 DOI-induced head twitch response 1 5-HT2A antagonist ↓ M100907 Aghajanian & Marek, 1997 Beique et al., 2007 Benneyworth et al., 2007 ↓ M100907 Schreiber et al., 1995 5-HT2C antagonist Ø SB242084 Marek & Aghajanian, 1999 Beique et al., 2007 Ø SB242084 Vickers et al., 2001 Fantegrossi et…”

“…(Vollenweider et al., 1998), prepulse inhibition of acoustic startle (Quednow et al., 2012), N170 visual-evoked potentials (Kometer et al., 2013), semantic interference in the Stroop test (Quednow et al., 2012), and recognition of emotional facial cues in a go/nogo task (Kometer et al., 2012).”

“Two clinical trials have shown that the selective 5-HT2A inverse agonist pimavanserin reduces the severity of hallucinations in Parkinson's disease (Meltzer et al., 2010; Cummings et al., 2014).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript Tass, 1997; Bressloff et al., 2001, 2002; Baker and Cowan, 2009).”

“Since cortical oscillations play a fundamental role in a diverse set of mental processes and are required for the coordination of neural processing (Gray et al., 1989; Singer, 1999; Buzsaki and Draguhn, 2004; Sejnowski and Paulsen, 2006; Fries, 2009; Klimesch, 2012), it is tempting to speculate that the reduction of n…”

“[PubMed: 23135605] Marek GJ. Behavioral evidence for mu-opioid and 5-HT2A receptor interactions.”

“However, compared with σ1 and SERT, tryptamines are more potent at 5-HT1A and 5-HT2A receptors by several orders of magnitude, so the former sites probably do not contribute to the hallucinogenic response.”

“…example, a PET imaging study with [18F]setoperone found that visual hallucinations in Parkinson's patients are associated with unusually high levels of 5-HT2A binding in the inferooccipital gyrus (BA 19), fusiform gyrus (BA 20 and BA 37), and inferotemporal gyrus (BA 20) (Ballanger et al., 2010).”

“Psilocybin and TCB-2 have been shown to facilitate the extinction of fear conditioning in C57BL/6J mice (Catlow et al., 2013; Zhang et al., 2013), which could be a consequence of activating the projection from IL to the intercalated nuclei.”

“Psilocybin also alters performance on laboratory measures of timing (Wittmann et al., 2007).”

“…lines, there is evidence that schizophrenia patients show deficits of gamma oscillations and synchrony (Spencer et al., 2003; Cho et al., 2006; Minzenberg et al., 2010; Uhlhaas and Singer, 2010) and reductions in slow-wave sleep (Yang and Winkelman, 2006), and it has been hypothesized that…”

“These interactions have been demonstrated most extensively for the HTR (see Table 3), a 5-HT2A-mediated behavior that can be provoked by infusion of DOI directly into the mPFC (Willins and Meltzer, 1997; Ciccocioppo et al., 1999).”

“Mice show a similar behavior, known as the head twitch response (HTR), after administration of hallucinogens (Corne and Pickering, 1967;Silva and Calil, 1975; Darmani et al., 1990).”

“is part of the dorsal visual stream and generates multiple egocentric representations of space (Stein, 1992; Vallar et al., 1999; Schindler and Bartels, 2013).”

“Similar patterns of brain activation were found in subjects administered ayahuasca as part of a SPECT study (Riba et al., 2006).”

“The 5-HT2A receptor is expressed heavily in the PFC and adjacent cortical regions, particularly in lamina V (Mengod et al., 1990; LopezGimenez et al., 1997; Jakab and Goldman-Rakic, 1998; Cornea-Hébert et al., 1999).”

“…measures in humans, including tests of spatial working memory (Vollenweider et al., 1998), prepulse inhibition of acoustic startle (Quednow et al., 2012), N170 visual-evoked potentials (Kometer et al., 2013), semantic interference in the Stroop test (Quednow et al., 2012), and…”

“5-HT2A receptor activation also increases the frequency of spontaneous IPSCs in pyramidal neurons (Zhou and Hablitz, 1999), an effect that is mediated by activation of neighboring GABAergic interneurons (Weber and Andrade, 2010; Zhang et al., 2010).”

“Likewise, hallucinogens enhance memory recall (Carhart-Harris et al., 2012b), sometimes producing extremely vivid recollections.”

“…on the OB, AED, and VR dimensions of the APZOAV and 5D-ASC are completely blocked by pretreatment with either the 5-HT2A/2C antagonist ketanserin or the mixed 5-HT2A/D2 antagonist risperidone (Vollenweider et al., 1998; Carter et al., 2005, 2007; Kometer et al., 2012, 2013; Quednow et al., 2012).”

“Schmid and colleagues have reported that β-arrestin-2 is not required for the behavioral effects of DOI and 5-MeO-DMT (Schmid et al., 2008; Schmid and Bohn, 2010).”

“Although the nucleus paragigantocellularis in the ventrolateral rostral medulla is a major source of excitatory input into the LC (Ennis and Aston-Jones, 1986; Chiang and Aston-Jones, 1993), the ability of somatosensory stimuli to excite the LC is unaffected by lesions of nucleus…”

“Although one study found haloperidol can block the PPI disruption produced by hallucinogens (Sipes and Geyer, 1994), this was not replicated by subsequent investigations (Varty and Higgins, 1995; Behav Brain Res.”

“…have shown that DOI (0.05–0.8 mg/kg, i.v.) and 5-MeO-DMT (0.1 mg/kg, i.v., in combination with the monoamine oxidase inhibitor clorgyline) produce a net excitatory effect on pyramidal neurons in the PrL, IL, and ACA regions of mPFC (Puig et al., 2003; Wang et al., 2009; Riga et al., 2014).”

“…5-HT2A-induced sEPSCs in layer V pyramidal neurons 1 DOI-induced head twitch response 1 5-HT2A antagonist ↓ M100907 Aghajanian & Marek, 1997 Beique et al., 2007 Benneyworth et al., 2007 ↓ M100907 Schreiber et al., 1995 5-HT2C antagonist Ø SB242084 Marek & Aghajanian, 1999 Beique et al.,…”

“The kinematics of the HTR induced by DOI have been characterized in C57BL/6J mice and Sprague-Dawley rats (Halberstadt and Geyer, 2013).”

“…mPFC inhibits the amygdala because the projection is glutamatergic (Amaral and Insausti, 1992; Smith et al., 2000), the mechanism is now believed to involve excitation of GABAergic neurons in the intercalated nuclei of the amygdala (Berretta et al., 2005; Likhtik et al., 2008; Pinard et al., 2012).”

“Receptor Ligand pharmacology 5-HT2A-induced sEPSCs in layer V pyramidal neurons 1 DOI-induced head twitch response 1 5-HT2A antagonist ↓ M100907 Aghajanian & Marek, 1997 Beique et al., 2007 Benneyworth et al., 2007 ↓ M100907 Schreiber et al., 1995 5-HT2C antagonist Ø SB242084 Marek & Aghajanian, 1999 Beique et al., 20…”

“…et al., 1994) Double-blind studies have confirmed the APZ and the HRS can distinguish the effects of psilocybin and mescaline from those of (+)-methamphetamine, methylphenidate, and 3,4-methylenedioxyethylamphetamine (Hermle et al., 1992; Gouzoulis-Mayfrank et al., 1999b; Griffiths et al., 2006).”

“Although N-alkyl substituted phenylalkylamines are usually inactive as hallucinogens, the addition of a N-benzyl group to phenethylamines can dramatically increase their activity, and N-benzylphenethylamines are a new class of potent hallucinogenic compounds (Braden et al., 2006).”

“One example is the Behavioral Pattern Monitor (BPM), which combines features from activity chambers and holeboards and provides quantitative as well as qualitative measures of the spatial and temporal structure of activity (Geyer et al., 1986; Paulus and Geyer, 1991).”

“…twitches in response to mescaline, DOI, DOM, LSD, DMT, 5-MeO-DMT, psilocin, or 1-methylpsilocin (González-Maeso et al., 2007; Keiser et al., 2009; Halberstadt et al., 2011), although the response can be rescued by selectively restoring the 5-HT2A receptor gene to cortical regions (González-Maeso…”

“In addition to pyramidal neurons, 5-HT2A receptors are also expressed by subsets of parvalbumin- and calbindin-positive interneurons (Willins et al., 1997; Jakab and Goldman-Rakic, 2000; Santana et al., 2004; De Almeida and Mengod, 2007; Puig et al., 2010; Weber and Adrade, 2010).”

“…in the dorsal pons, is the source of almost all noradrenergic projections in the CNS. LC neurons are responsive to sensory stimuli, especially of a novel or arousing nature, and the firing of LC neurons is markedly increased by noxious stimulation (reviewed by: Singewald and Philippu, 1998).”

“Indoleamine and phenylalkylamine hallucinogens bind to 5-HT2 sites with moderate to high affinity (Shannon et al., 1984; Lyon et al., 1988; Sadzot et al., 1989; McKenna et al., 1990).”

“Almost all prefrontal pyramidal neurons express the 5-HT2A receptor, with the receptor localized primarily to the proximal apical dendrites (Willins et al., 1997; Jakab and Goldman-Rakic, 1998; Cornea-Hébert et al., 1999; Xu and Pandey, 2000).”

“…study comparing DMT and the NMDA antagonist (S)-ketamine found DMT produces effects that more closely resemble the positive symptoms of schizophrenia, whereas the effects of (S)-ketamine are more similar to the negative and catatonic symptoms of schizophrenia (Gouzoulis-Mayfrank et al., 2005).”

“Extensive testing has confirmed this pattern of effects in the BPM is highly specific to hallucinogens (Geyer et al., 1986, 1987; Mittman and Geyer, 1989; Callaway et al., 1990; Lehmann-Masten and Geyer, 1991).”

“…and all legal disclaimers that apply to the journal pertain. anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript hallucinogens produce similar discriminative stimulus effects (Glennon et al., 1982) and act as agonists of the serotonin-2A (5-HT2A) receptor (Glennon et al., 1983).”

“…neurons: there is a moderate depolarization, spike-frequency accommodation is reduced, and the afterhyperpolarization (AHP) that normally follows a burst of spikes is replaced by a slow depolarizing afterpotential (sADP)(Araneda and Andrade, 1991; Tanaka and North, 1993; Arvanov et al., 1999).”

“Although it was not initially clear how mPFC inhibits the amygdala because the projection is glutamatergic (Amaral and Insausti, 1992; Smith et al., 2000), the mechanism is now believed to involve excitation of GABAergic neurons in the intercalated nuclei of the amygdala (Berretta et al., 2005;…”

“Although one study found haloperidol can block the PPI disruption produced by hallucinogens (Sipes and Geyer, 1994), this was not replicated by subsequent investigations (Varty and Higgins, 1995; Behav Brain Res.”

“) produces a hyperfrontal metabolic pattern, especially in the right hemisphere (Hermle et al., 1992).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript and p38 MAP kinase), Akt, and phospholipase D (dependent on the small G protein ADPribosylation factor-1 (ARF1)) (Kurrasch-Orbaugh et al., 2003a; González-Maeso et al., 2007; Schmid and Bohn, 2010; Barclay et al., 2011).”

“Similarly, there is a consensus in the literature that the ability of DOI to induce the HTR is not blocked by selective 5-HT2C antagonists or mixed 5-HT2C/2B antagonists (Kennett et al., 1994; Schreiber et al., 1995; Wettstein et al., 1999; Vickers et al., 2001; Fantegrossi et al., 2010).”

“It is likely that the nucleus prepositus hypoglossi (PrH), an area known to provide direct GABAergic inhibitory input into the LC (Ennis and Aston-Jones, 1989a,b), mediates the hallucinogen-induced inhibition of spontaneous LC activity.”

“Phenylalkylamines, including DOI, mescaline, and TCB-2, inhibit investigatory behavior and alter locomotor activity in a dose-dependent manner, increasing activity at low to moderate doses and reducing activity at high doses (Halberstadt et al., 2009, 2013).”

“Studies using the Addiction Research Center Inventory (ARCI) instrument (Haertzen et al., 1963) have confirmed that the effects of LSD are dissimilar from those of (+)-amphetamine (Rosenberg et al., 1963) and Δ9tetrahydrocannabinol (Isbell and Jasinski, 1969).”

“The stimulus effects of hallucinogens can be blocked by the selective 5-HT2 antagonists ketanserin and pirenperone (Colpaert et al., 1982; Glennon et al., 1983; Glennon, 1986; Cunningham and Appel, 1987; Appel and Callahan, 1989).”

“Psilocybin and TCB-2 have been shown to facilitate the extinction of fear conditioning in C57BL/6J mice (Catlow et al., 2013; Zhang et al., 2013), which could be a consequence of activating the projection from IL to the intercalated nuclei.”

“respectively, effects that would likely influence dendritic integration (Carr et al., 2002; Day et al., 2002).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript and p38 MAP kinase), Akt, and phospholipase D (dependent on the small G protein ADPribosylation factor-1 (ARF1)) (Kurrasch-Orbaugh et al., 2003a; González-Maeso et al., 2007; Schmid and Bohn, 2010; Barclay et al., 2011).”

“…Marek et al., 2000 Klodzinska et al., 2002 ↓ LY354740 Gewirtz and Marek, 2000 Klodzinska et al., 2002) ↓ LY379268 Klodzinska et al., 2002 antagonist ↑ LY341495 Marek et al., 2000 ↓ LY341495 Gewirtz and Marek, 2000 Adenosine A1 agonist ↓ N6-cyclopentyladenosine Stutzmann et al., 2001 ↓…”

“Extensive testing has confirmed this pattern of effects in the BPM is highly specific to hallucinogens (Geyer et al., 1986, 1987; Mittman and Geyer, 1989; Callaway et al., 1990; Lehmann-Masten and Geyer, 1991).”

“…and can occur during a variety of hallucinatory states, including migraine aura (Sacks, 1995), epilepsy (Horowitz et al., 1967), sensory isolation (Heron et al., 1956), viewing flickering light (Becker and Elliott, 2006; Allefeld et al., 2011), and electrical cortical stimulation (Knoll et al.,…”

“…of hallucinogens is admittedly speculative, it does receive some support from the fact that hallucinogens disrupt PPI in humans and in animal models (Sipes and Geyer, 1994; Padich et al., 1996; Vollenweider et al., 2007; Pálenícek et al., 2008; Halberstadt and Geyer, 2010; Quednow et al., 2012).”

“Receptor Ligand pharmacology 5-HT2A-induced sEPSCs in layer V pyramidal neurons 1 DOI-induced head twitch response 1 5-HT2A antagonist ↓ M100907 Aghajanian & Marek, 1997 Beique et al., 2007 Benneyworth et al., 2007 ↓ M100907 Schreiber et al., 1995 5-HT2C antagonist Ø SB242084 Marek & Aghajanian, 1999 Beique et al., 20…”

“Chiang and Aston-Jones (1993) reported that the decrease in LC spontaneous firing induced by DOI could be blocked by the GABAA receptor antagonists bicuculline and picrotoxin, whereas the ability of DOI to enhance sensory-evoked LC responses was blocked by the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid…”

“…any glutamatergic mPFC neurons that were driven to fire action potentials by 5-HT2A activation, it was initially thought that the increase in Glu release was caused by local activation of the terminals of glutamatergic thalamocortical afferents (Lambe and Aghajanian, 2001; Marek et al., 2001).”

“…mGlu2/3 agonists and AMPA antagonists also block the ability of DOI to increase cortical expression of BDNF and the immediate-early genes c-fos, erg-2, and Arc (Scruggs et al., 2000; Gewirtz et al., 2002; Zhai et al., 2003; Pei et al., 2004; GonzalezMaseo et al., 2008; Wischhof and Koch, 2012).”

“According to another study conducted post-mortem, Parkinson's patients with visual hallucinations show elevated levels of 5-HT2A binding in the inferolateral temporal cortex (BA 21) (Huot et al., 2010).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript Phenylalkylamine hallucinogens are selective for 5-HT2 receptors, including 5-HT2A, 5- HT2B, and 5-HT2C sites (Titeler et al., 1988; Leysen, 1989; Pierce and Peroutka, 1989).”

“In contrast to those findings, another group has reported that higher doses of DOI (3–5 mg/kg, i.p.) tend to inhibit the firing of pyramidal cells in ACA and the ventral, dorsolateral, and lateral orbitofrontal cortices of behaving rats (Wood et al., 2012).”

“The phenylalkylamines can be subdivided into phenethylamines, such as mescaline from the peyote cactus (Lophophora williamsii), 2,5-dimethoxy-4-bromophenethylamine (2C-B), and 2,5-dimethoxy-4-iodophenethylamine (2C-I); and phenylisopropylamines (“amphetamines”), including DOM, 2,5-dimethoxy-4-iodoamphetamine (DOI), an…”

“…a 5-HT2A antagonist with high selectivity versus the 5-HT2C receptor, blocks stimulus control in animals trained with DOI (Schreiber et al., 1994; Smith et al., 1998, 1999, 2003), DOM (Li et al., 2008; May et al., 2009), R-(–)- DOM (Eckler et al., 2003), LSD (Winter et al., 2004; Benneyworth et…”

“Furthermore, Szabo and Blier (2001) found that the ability of DOI to alter the activity of LC neurons is abolished by M100907.”

“…on the OB, AED, and VR dimensions of the APZOAV and 5D-ASC are completely blocked by pretreatment with either the 5-HT2A/2C antagonist ketanserin or the mixed 5-HT2A/D2 antagonist risperidone (Vollenweider et al., 1998; Carter et al., 2005, 2007; Kometer et al., 2012, 2013; Quednow et al., 2012).”

“…et al., 1994) Double-blind studies have confirmed the APZ and the HRS can distinguish the effects of psilocybin and mescaline from those of (+)-methamphetamine, methylphenidate, and 3,4-methylenedioxyethylamphetamine (Hermle et al., 1992; Gouzoulis-Mayfrank et al., 1999b; Griffiths et al., 2006).”

“…cues involving both 5-HT1A- and 5-HT2A-mediated components (Glennon et al., 1988; Winter et al., 2000; Fantegrossi et al., 2008), 5-HT1A receptors do not play a role in the interoceptive effects of psilocybin (Winter et al., 2007) or 5-methoxy-N,N-diisopropyltryptamine (Fantegrossi et al., 2006).”

“However, compared with σ1 and SERT, tryptamines are more potent at 5-HT1A and 5-HT2A receptors by several orders of magnitude, so the former sites probably do not contribute to the hallucinogenic response.”

“Ayahuasca also elicited significantly greater effects than (+)-amphetamine on 4 of 6 subscales of the HRS (Dos Santos et al., 2011).”

“Evidence has emerged that mGlu2 and 5- HT2A receptors can form heteromeric complexes in cortex (Gonzalez-Maeso et al., 2008; Moreno et al., 2012), and these complexes may mediate the crosstalk that occurs between these receptors.”

“…having different chemical structures, phenylalkylamine, tryptamine, and ergoline hallucinogens produce remarkably similar subjective effects (Isbell, 1959; Hollister, 1961; Wolbach et al., 1962a,b; Hollister and Hartman, 1962; Rosenberg et al., 1964; Abramson and Rolo, 1967; Hollister et…”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript and p38 MAP kinase), Akt, and phospholipase D (dependent on the small G protein ADPribosylation factor-1 (ARF1)) (Kurrasch-Orbaugh et al., 2003a; González-Maeso et al., 2007; Schmid and Bohn, 2010; Barclay et al., 2011).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript and there is eventually nearly a complete loss of response (Abramson et al., 1956; Isbell et al., 1956, 1961; Angrist et al., 1974).”

“Although animals trained with DOM will generalize to lisuride (Glennon and Hauck 1985; Fiorella et al. 1995b), the response to DOM is attenuated when it is co-administered with lisuride (Glennon, 1991).”

“…produced by classical hallucinogens and the κ-opioid receptor agonist salvinorin A from Salvia divinorum, there is evidence that the phenomenology of salvinorin A is unique (Albertson and Grubbs, 2009), and the ARCI is relatively insensitive to the effects of salvinorin A (MacLean et al., 2013).”

“Likewise, electroencephalographic studies have reported that ayahuasca (containing the equivalent of 0.85 mg/kg DMT) reduces cortical oscillatory power across multiple frequency bands (Riba et al., 2002, 2004).”

“One example is the Behavioral Pattern Monitor (BPM), which combines features from activity chambers and holeboards and provides quantitative as well as qualitative measures of the spatial and temporal structure of activity (Geyer et al., 1986; Paulus and Geyer, 1991).”

“…the active waking state, which is characterized by fast rhythms in the gamma range (30–80 Hz) that play a putative role in a multitude of perceptual and cognitive functions (Tallon-Baudry et al., 1998; Fries et al., 2001; Herrmann et al., 2004; Schroeder and Lakatos, 2009; Roux and Uhlhaas, 2014).”

“There is also evidence that the ability of DOI to induce the HTR is significantly attenuated by pretreatment with selective 5-HT2C agonists, including Ro 60-0175, CP-809,101, and mCPP (Schreiber et al., 1995; Siuciak et al., 2007; Fantegrossi et al., 2010; Canal et al., 2013).”

“The classic hallucinogens, which include psilocybin (psilocin) and (+)-lysergic acid diethylamide (LSD), are a structurally diverse group of compounds that are 5-HT2A receptor agonists and produce a unique profile of changes in thoughts, perceptions, and emotions (Halberstadt, 2015; Nichols, 2016).”

“In the study byHalberstadt et al. (2011a), the response to psilocin was not affected by deletion of the 5-HT2A receptor gene.”

“LSD has a high affinity for a range of different neurotransmitter receptors, but its characteristic psychological effects are thought to be mediated by serotonin 2A receptor (5-HT2AR) agonism (7).”

“…this limitation, we also wish to emphasise that the evidence is compelling that 5-HT2AR agonism is key to psychedelics’ most characteristic effects (Halberstadt, 2015), 5-HT1AR agonism attenuates rather than augments these effects (Pokorny et al., 2016; Strassman, 1996) and more selective 5-HT2AR…”