This paper (2011) reviews the evidence that indoleamine hallucinogens act not only on the 5-HT2 receptor group but on a variety of receptors to produce their behavioral effects.
Abstract
“Serotonergic hallucinogens produce profound changes in perception, mood, and cognition. These drugs include phenylalkylamines such as mescaline and 2,5-dimethoxy-4-methylamphetamine (DOM), and indoleamines such as (+)-lysergic acid diethylamide (LSD) and psilocybin. Despite their differences in chemical structure, the two classes of hallucinogens produce remarkably similar subjective effects in humans, and induce cross-tolerance. The phenylalkylamine hallucinogens are selective 5-HT2 receptor agonists, whereas the indoleamines are relatively non-selective for serotonin (5-HT) receptors. There is extensive evidence, from both animal and human studies, that the characteristic effects of hallucinogens are mediated by interactions with the 5-HT2A receptor. Nevertheless, there is also evidence that interactions with other receptor sites contribute to the psychopharmacological and behavioral effects of the indoleamine hallucinogens. This article reviews the evidence demonstrating that the effects of indoleamine hallucinogens in a variety of animal behavioral paradigms are mediated by both 5-HT2 and non-5-HT2 receptors.”
Authors: Adam L. Halberstadt & Mark A. Geyer
Summary
Serotonergic hallucinogens such as mescaline, 2,5-dimethoxy-4-methylamphetamine (DOM), and (+)-lysergic acid diethylamide (LSD) produce profound changes in perception, mood, and cognition. They are all mediated by interactions with the 5-HT2A receptor, but also by other receptors.
- Introduction
Hallucinogens are a class of drugs that produce profound distortions of perception. They have been used by humans for thousands of years to induce states of mysticism and inebriation, and are becoming more widely available with increased access to psychoactive natural products and knowledge of their use.
- Chemical Structure of Hallucinogens
Classical hallucinogens belong to two classes of chemicals: indoleamines and phenylalkylamines. Recently, highly potent rigid analogs of hallucinogenic phenylalkylamines have been synthesized, including Bromo-Dragonfly and TCB-2. Phenylalkylamine hallucinogens are highly selective for 5-HT2 sites, while indolealkylamines are relatively non-selective for 5-HT receptors, displaying moderate to high affinity for 5-HT1 and 5-HT2 subtypes. DMT is a 1 receptor agonist with moderate affinity, but it is not clear whether this interaction contributes to the effects of DMT.
- Unitary Effects of Serotonergic Hallucinogens in Humans
Despite differences in their chemical structure, hallucinogens produce extremely similar experiences in humans. The subjective effects of hallucinogens are readily distinguished from the effects of drugs in other pharmacological classes. Indoleamine and phenylalkylamine hallucinogens have similar psychopharmacological effects and can produce cross-tolerance. The 5-HT2A receptor is the likely mechanism responsible for mediating the effects of these compounds, but the interaction of indoleamines with non-5-HT2 receptors may have psychopharmacological and behavioral consequences.
- Recent Clinical Studies of Hallucinogens
Although neglected for several decades, clinical testing of hallucinogens has resumed in recent years. Most studies have focused on psilocybin, although mescaline and DMT have also been studied.
Most studies on hallucinogens were designed to characterize their subjective and physiological effects. Some studies have also examined whether hallucinogens are effective at reducing symptoms in patients with obsessive-compulsive disorder (OCD) and anxiety in terminal cancer patients.
Vollenweider and colleagues conducted a series of studies examining the contribution of 5-HT and dopamine (DA) receptors to the subjective and behavioral effects of psilocybin in human volunteers. They found that the 5-HT2A receptor is responsible for most of the effects of psilocybin, but other receptors also contribute to the effects.
The mechanism of action of DMT has also been investigated clinically. It is likely that interactions with 5-HT1A receptors attenuate the action of DMT at the 5-HT2A receptor.
- Presynaptic Versus Postsynaptic Effects of Hallucinogens
LSD, psilocin, DMT, and 5-MeO-DMT were found to inhibit the firing of serotonergic neurons in the dorsal and median raphe nuclei of rats and cats. These effects were mediated by somatodendritic 5-HT autoreceptors.
LSD and other indoleamine hallucinogens inhibit serotonergic DRN neuronal activity by activating 5-HT1A receptors. 5-HT1A receptor-selective agonists and antagonists block the inhibition of DRN neuronal activity induced by LSD. Hallucinogenic indoleamines bind to the 5-HT1A receptor with moderate to high affinity and are potent agonists at 5-HT1A receptors negatively coupled to adenylate cyclase. LSD suppresses DRN firing in rats with an EC50 of 4.6 nM.
LSD, psilocin, DMT, and 5-MeO-DMT inhibit cells downstream from the raphe nuclei by stimulating postsynaptic 5-HT1A receptors, but leave downstream neurons relatively unaffected. This is probably due to the marked 5-HT1A receptor reserve present on the cell bodies of serotonergic raphe cells. The evidence outlined above led to the hypothesis that hallucinogens act by selectively depressing neurons in the DRN and thereby decreasing 5-HT release, thereby removing the tonic inhibition of downstream neurons mediated by 5-HT.
Trulson and coworkers observed that the behavioral effects of hallucinogens are dissociated from the inhibitory effects of those drugs. Further, DRN neurons do not develop a tolerance to the inhibitory effects of hallucinogens. Mainserin, ketanserin, and metergoline attenuate the behavioral effects of LSD, but fail to block the effect of that drug upon DRN activity. Phenylalkylamine hallucinogens have inconsistent effects upon raphe firing.
Despite the fact that lisuride inhibits the firing of DRN neurons in rats, it is not a hallucinogenic drug in humans, and even though selective 5-HT1A receptor agonists completely suppress the firing of serotonergic neurons in the raphe nuclei, they are not hallucinogenic when administered to humans.
Evidence contradicts the hypothesis that hallucinogenic agents inhibit raphe nuclei, and suggests that postsynaptic 5-HT receptor mechanisms are likely involved in mediating the effects of this class of agents.
6.1 Drug Discrimination
The phenomenon of drug-induced stimulus control has been applied successfully to the study of hallucinogens. It has been shown that all hallucinogens evoke uniform interoceptive stimulus cues, and that hallucinogens and 5-HT1A receptor-selective agonists produce distinct interoceptive cues.
The discriminative stimulus properties of hallucinogens are blocked by a variety of non-selective 5-HT antagonists, and the stimulus effects of hallucinogens are mediated by the 5-HT2A receptor.
The 5-HT2C receptor was first proposed by Pazos and associates in 1984. It was later demonstrated that LSD binds to 5-HT2C sites with nanomolar affinity, and that phenylalkylamine and indolealkylamine hallucinogens bind to 5-HT2C receptors with moderately high-affinity.
The interaction of hallucinogens with 5-HT2C receptors confounded the hypothesis that activation of 5-HT2A receptors is the primary mechanism for the effects of serotonergic hallucinogens. However, the correlation between 5-HT2A and 5-HT2C receptor affinities may not reflect the involvement of 5-HT2C receptors in the effects of hallucinogens.
Hallucinogens act at 5-HT2C receptors, and 5-HT2C receptor occupation may play an important mechanistic role in the action of hallucinogenic drugs. However, 5-HT2A receptor-selective antagonists have been used to block the effects of hallucinogens without altering the response rate. Recent studies have demonstrated that stimulus control is blocked by the 5-HT2A antagonist M100907, and by the 5-HT2C receptor antagonist MDL 11,939, in animals trained with DOI, DOM, LSD, and 2C-T-7. Hallucinogens do not appear to involve the 5-HT2C receptor in their stimulus effects. This is supported by the fact that the selective 5-HT2C antagonist SB 242,084 does not block the psilocybin discriminative stimulus.
The interoceptive state governing hallucinogen discrimination in animals is mediated primarily by 5-HT2A receptor interactions. The phenylalkylamine cue displays greater selectivity with respect to the 5-HT2A receptor, and therefore requires higher doses of antagonists to block the LSD discriminative stimulus.
LSD evokes a compound stimulus, with the most salient component being transduced through the 5-HT2A receptor, but secondary components being mediated by 5-HT1A receptors and DA D2 receptors.
There is considerable evidence that the 5-HT1A subtype contributes to the discriminative effects of LSD. Yohimbine, a drug that is normally classified as a 2-adrenoceptor antagonist, can fully substitute for LSD in rats, indicating that there is a 5-HT1A-mediated stimulus component common to both yohimbine and LSD.
LSD binds to dopamine D1, D2, D3, D4, and D5 receptors and acts as a partial agonist at DA D1 and D2 receptors and a full agonist at DA D4 receptors. It may also act on serotonergic mechanisms, as risperidone blocks LSD discrimination with 414 times the potency of ritanserin.
Ritanserin, a 5-HT2A receptor agonist, fails to attenuate the LSD stimulus and must be administered at 40 mg/kg to completely antagonize the LSD cue. Risperidone, a DA D2 receptor agonist, is nearly identical in potency to ritanserin as an antagonist of the DOM cue.
Recent reports indicate that the dopaminergic component of the LSD discriminative stimulus is time-dependent. The delayed dopaminergic cue is not clear whether it is a direct effect of LSD or is produced by a LSD metabolite with selective DA agonist activity.
Certain indolealkylamine hallucinogens produce stimulus effects that are both DOM- and 8-OH-DPAT-like, such as 5-MeO-DPT. The 5-MeO-DMT discriminative stimulus involves 5-HT1A-and 5-HT2A-mediated components. The 5-MeO-DMT discriminative stimulus generalizes to 8-OH-DPAT and ipsapirone, and the ability of these agents to substitute for 5-MeO-DMT is correlated with their 5-HT1A, but not 5-HT2A, affinities.
Pirenperone, ketanserin, and ritanserin are less effective antagonists of 8-OH-DPAT than 5-MeO-DMT, and 5-MeO-DMT induces behavioral disruption in 8-OH-DPAT-trained animals but not in ipsapirone-trained animals. This suggests that 5-MeO-DMT may disrupt 5-HT1A-mediated stimulus control.
The hallucinogen DPT produces a compound stimulus involving both 5-HT1A receptor- and 5-HT2A receptor-mediated components, and the ability of DPT to evoke partial generalization in animals trained with psilocybin appears to involve interactions with both 5-HT1A and 5-HT2A receptors.
6.2 5-HT Behavioral Syndrome
8-OH-DPAT induces a 5-HT behavioral syndrome in rats that includes flat body posture, reciprocal forepaw treading, hindlimb abduction, and lateral head weaving. This behavioral syndrome is likely mediated by 5-HT1A receptors, and is induced by relatively high doses of indoleamine hallucinogens.
Although 5-HT1A receptors are present in the DRN but not in postsynaptic regions, partial agonists block the ability of 8-OH-DPAT and 5-MeO-DMT to induce the behavioral syndrome.
Lower lip retraction (LLR) is induced by 5-HT1A receptor activation, and 5-MeO-DMT and DPT attenuate LLR induced by 5-HT1A receptor activation, indicating that 5-HT2A and/or 5-HT2C receptors function to attenuate LLR induced by 5-HT1A receptor activation.
6.3 Exploratory and Investigatory Behavior
Studies examining the effects of hallucinogens on locomotor activity produce inconsistent results because they do not assess whether changes in sensitivity to environmental stimuli contribute to the behavioral effect. The Behavioral Pattern Monitor (BPM) is a combination of activity and holeboard chambers that can be used to measure unconditioned locomotor and investigatory activity in rats and to assess for changes in the response of animals to environmental stimuli.
Hallucinogens reduce locomotor activity, diminish the frequency of investigatory behaviors, and increase avoidance of the center of the BPM chamber in rats. These effects are not observed in rats tested in a familiar environment, likely reflecting potentiation of the neophobia displayed by rats in a novel environment. Hallucinogens produce different effects on the BPM than other drug classes such as lisuride, 5-HT releasers, 5-HT1 agonists, psychostimulants, and NMDA antagonists.
Ritanserin and ketanserin block the effects of DOI, DOM, and mescaline in the BPM, but not by the selective 5-HT2C/2B antagonist SER-082. LSD and 5-MeO-DMT both induce behavioral effects in the BPM, and these effects are mediated by 5-HT1A and 5-HT2A receptors, with 5-MeO-DMT producing delayed hyperactivity that is blocked by 5-HT2A-selective antagonist MDL 11,939.
Hallucinogens decrease exploratory and investigatory behavior in mice and increase locomotor activity, with low and moderate doses increasing activity and higher doses decreasing activity. The effects are mediated by 5-HT2A receptors and 5-HT2C receptors.
Phenylalkylamine hallucinogens, psilocin, DMT, 5-MeO-DMT, and LSD decrease locomotor activity, investigatory behavior, and time spent in the center of the mouse BPM chambers, whereas indoleamines produce disparate effects on exploratory and investigatory behavior in mice.
6.4 Prepulse Inhibition of Startle
LSD, DOI, DOB, mescaline, and 5-MeO-DMT disrupt PPI in rats, and this effect is blocked by the highly selective 5-HT2A antagonists M100907 and MDL 11,939, but not by the 5-HT2C antagonist SB 242,084, the 5-HT2C/2B antagonist SER-082, or the 5-HT1A antagonist (+)WAY-100135. Lisuride, a nonhallucinogenic LSD congener, disrupts PPI in rats via distinct mechanisms from LSD, and its effect is blocked by raclopride but not by MDL 11,939 pretreatment.
DOI disrupts PPI in rats by activating 5-HT2A receptors in the ventral pallidum, but it is not clear whether dopamine receptors in the ventral pallidum or in other brain regions play a downstream role in the PPI-disruptive effects of DOI.
Activation of 5-HT1A receptors has opposing effects on sensorimotor gating in rats and mice. 5-MeO-DMT and psilocin increase PPI in 129/SV and Balb/c mice, and this effect is partially attenuated by pretreatment with WAY-100,635.
Clinical studies have demonstrated that psilocybin can alter prepulse inhibition in human volunteers. However, the effects are dependent on the testing parameters and the receptor mechanism(s) responsible for the effects have not yet been investigated.
6.5 Head Twitch Response
In 1967 Corne and Pickering reported that a variety of hallucinogens induce a head twitch response (HTR) in mice. This behavior had previously been observed in rats after systemic administration of the 5-HT precursor 5-hydroxytryptophan.
The HTR was linked to the 5-HT2A receptor almost immediately after 5-HT2A binding sites were first detected by radioligand binding studies. The HTR was also linked to the 5-HT2A receptor in mice, and was restored by genetic restoration of the 5-HT2A receptor to the cortex.
The expression of 5-HT2A receptor-induced HTR can be modified by activity at a variety of receptors, including 5-HT1A. 5-MeO-DMT can also reduce DOI-induced HTR.
Indoleamines may attenuate their ability to induce the HTR, but LSD is not altered by deletion of the 5-HT1A receptor gene, and 5-MeO-DMT has a potent 5-HT1A agonist effect, but WAY-100,635 can antagonize DPT-induced HTR in mice.
There is evidence that the 5-HT2C receptor can regulate the HTR induced by 5-HT2A receptor activation. The 5-HT2C receptor also inhibits the HTR induced by DOI in mice. Fantegrossi and colleagues reported that the HTR induced by DOI, 2C-T-7, DPT, and 5-MeO-DIPT follows an inverted U-shaped dose-response function, but Canal et al. (2010) reported that 5-HT2C knockout mice display a significant reduction in DOI-induced HTR. Strain differences in 5-HT2C receptor mRNA editing could alter how 5-HT2A and 5-HT2C receptors interact in different strains of mice.
6.6 Ear Scratch Response
The ear-scratch response (ESR) is induced by mescaline, DOM, DOI, DOET, and the 4-ethoxy analog of mescaline (escaline), and is mediated by 5-HT2A receptors. The ESR is not induced by indoleamine hallucinogens, such as LSD and 5-MeO-DMT.
- Conclusions
Despite structural differences, indoleamine and phenylalkylamine hallucinogens evoke a nearly identical spectrum of behavioral effects in rats and provoke similar mental and subjective states in humans. The 5-HT2A receptor plays a primary mechanistic role in mediating the behavioral effects of these serotonergic hallucinogens.
It is currently accepted that phenylisopropylamine hallucinogens such as DOB and DOI are highly selective for 5-HT2 sites, whereas indoleamine hallucinogens bind to a much larger set of monoamine receptors and produce similar effects.
Evidence indicates that both 5-HT1A and 5-HT2A receptors are responsible for the behavioral effects of indoleamine hallucinogens, and that 5-HT1 receptor activation by indoleamines acts to suppress expression of HTR, ESR, and other 5-HT2A-mediated behavioral effects.
LSD appears to have a secondary temporal phase that involves ideas of reference or paranoid ideation, which may be related to the delayed dopaminergic discriminative stimulus effects of LSD and the delayed hyperactivity produced by LSD in the rat BPM.
LSD and other hallucinogens can produce biphasic behavioral effects, and DOM and mescaline can also produce biphasic effects. Further studies are needed to determine whether pharmacokinetic or pharmacodynamic factors are responsible for the biphasic behavioral profiles displayed by certain hallucinogens.
Hallucinogens are agonists at the 5-HT2C receptor, but it is now believed that these agents do not act via a 5-HT2A-dependent mechanism. In addition, it is believed that activity at the 5-HT2C receptor actually serves to attenuate many of the behavioral effects of hallucinogens.
Evidence has emerged that the effects of serotonergic and dopaminergic drugs on behaviors in rats and mice are different, and that these differences may actually be more predictive of effects of hallucinogens on PPI in humans.
Indoleamine hallucinogens such as psilocin and 5-MeO-DMT produce distinct effects on exploratory and investigatory behavior in mice.
Indoleamine hallucinogens can induce distinct behavioral profiles in mice, which may be useful in probing the contribution of 5-HT1A receptors to indoleamine-induced behavioral effects. Additional studies are necessary to determine the significance of these behavioral differences and to explore whether there are subtle behavioral differences in the human psychopharmacology of these compounds.
Figure 2.
The relationship between binding affinity at [3H]DOB-labeled 5-HT2A receptors in rat frontal cortex and ED50 values for stimulus generalization is 0.90.
Figure 3.
Psilocin affects locomotor activity, time spent in the center region of the BPM chamber, number of holepokes and rearings in rats.
Figure 5.
The effects of 5-MeO-DMT and psilocin on prepulse inhibition of startle were investigated in 129/SvEv mice.