Data from Literature

Data on receptor interactions of ten compounds (Fig. 2) has been collected from the literature. The four ergolines (LSD, cis-2a, RR-2b, and SS-2c) were assayed by NIMH-PDSP against forty-three receptors, transporters and ion channels [10]. Salvinorin A was assayed by NIMH-PDSP against thirty receptors and transporters [11]. EMDT and 5-MeO-TMT were assayed by NIMH-PDSP against forty receptors, transporters and ion channels [12].

Receptor data for ibogaine (Table S1), morphine (Table 1) and THC (Table 2) was collected from a variety of sources. While ibogaine has been assayed at a wide variety of receptors, morphine and THC have not, so their data should be used with caution. Although morphine is not considered to be a psychedelic, and ibogaine, THC, and salvinorin A are not considered to be “classical hallucinogens,” these four compounds are included because they provide insights into additional receptor systems (salvinorin A – κ (kappa opioid receptor), ibogaine – σ (sigma receptor) and κ, THC – CB (cannabinoid receptor), morphine – μ (mu opioid receptor)). These additional compounds could also be thought of as active controls, as compared to the three presumably inactive controls of Fig. 1.

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Table 1. Receptor affinity data for morphine.

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Table 2. Receptor affinity data for THC.

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New PDSP Binding Assays

For this study, the NIMH-PDSP (http://pdsp.med.unc.edu/) has assayed sixteen phenylalkylamines, eight tryptamines and one ergoline (twenty-two psychedelics and three controls, Fig. 1) against a panel of fifty-one receptors, transporters, and ion channels. The methodology has been described previously by Glennon et al. [12]. Each compound is initially assayed at 10 µM against each receptor, transporter or ion channel (primary assay). Those that induce >50% inhibition (“hit”) are then assayed at 1, 10, 100, 1,000, and 10,000 nM to determine K_i values (secondary assay). Each K_i value (equilibrium dissociation constant, concentration at which 50% of the hot ligand is displaced by the test ligand) is calculated from at least three replicated assays. Details of how individual assays were conducted can be found at the NIMH-PDSP web site: http://pdsp.med.unc.edu/pdspw/binding.php.

Table S2 shows raw K_i data for the current study combined with data collected from the literature for the ten additional compounds; a total of thirty-five drugs and sixty-seven receptors, transporters and ion channels which were assayed. The table has been divided into three sections.

The first section displays forty-two sites at which most compounds were assayed and at least one “hit” (K_i <10,000 nm) was found: 5ht1a (5-HT_1A, serotonin-1A receptor), 5ht1b (5-HT_1B, serotonin-1B receptor), 5ht1d (5-HT_1D, serotonin-1D receptor), 5ht1e (5-HT_1E, serotonin-1E receptor), 5ht2a (5-HT_2A, serotonin-2A receptor), 5ht2b (5-HT_2B, serotonin-2B receptor), 5ht2c (5-HT_2C, serotonin-2C receptor), 5ht5a (5-HT_5A, serotonin-5A receptor), 5ht6 (5-HT₆, serotonin-6 receptor), 5ht7 (5-HT₇, serotonin-7 receptor), D1 (D₁, dopamine-1 receptor), D2 (D₂, dopamine-2 receptor), D3 (D₃, dopamine-3 receptor), D4 (D₄, dopamine-4 receptor), D5 (D₅, dopamine-5 receptor), Alpha1A (α_1A, alpha-1A adrenergic receptor), Alpha1B (α_1B, alpha-1B adrenergic receptor), Alpha2A (α_2A, alpha-2A adrenergic receptor), Alpha2B (α_2B, alpha-2B adrenergic receptor), Alpha2C (α_2C, alpha-2C adrenergic receptor), Beta1 (β₁, beta-1 adrenergic receptor), Beta2 (β₂, beta-2 adrenergic receptor), SERT (serotonin transporter), DAT (dopamine transporter), NET (nor epinephrine transporter), Imidazoline1 (I₁, imidazoline-1 receptor), Sigma1 (σ₁, sigma-1 receptor), Sigma2 (σ₂, sigma-2 receptor), DOR (delta opioid receptor), KOR (κ, kappa opioid receptor), MOR (μ, mu opioid receptor), M1 (M₁, muscarinic-1 acetylcholine receptor), M2 (M₂, muscarinic-2 acetylcholine receptor), M3 (M₃, muscarinic-3 acetylcholine receptor), M4 (M₄, muscarinic-4 acetylcholine receptor), M5 (M₅, muscarinic-5 acetylcholine receptor), H1 (H₁, histamine-1 receptor), H2 (H₂, histamine-2 receptor), CB1 (CB₁, cannabinoid-1 receptor), CB2 (CB₂, cannabinoid-2 receptor), Ca+Channel (calcium+ ion channel), NMDA/MK801 (N-methyl D-aspartate glutamate receptor).

The second section displays seven sites at which most compounds were assayed, but at which there were no hits: 5ht3 (serotonin-3 receptor), H3 (histamine-3 receptor), H4 (histamine-4 receptor), V1 (vasopressin-1 receptor), V2 (vasopressin-2 receptor), V3 (vasopressin-3 receptor), GabaA (GABA-A receptor).

The third section displays the remaining eighteen sites, at which only a few compounds were assayed, and no hits were found: GabaB (GABA-B receptor), mGluR1a (mGluR1a metabotropic glutamate receptor), mGluR2 (mGluR2 metabotropic glutamate receptor), mGluR4 (mGluR4 metabotropic glutamate receptor), mGluR5 (mGluR5 metabotropic glutamate receptor), mGluR6 (mGluR6 metabotropic glutamate receptor), mGluR8 (mGluR8 metabotropic glutamate receptor), A2B2 (nicotinic a2/b2 acetylcholine receptor), A2B4 (nicotinic a2/b4 acetylcholine receptor), A3B2 (nicotinic a3/b2 acetylcholine receptor), A3B4 (nicotinic a3/b4 acetylcholine receptor), A4B2 (nicotinic a4/b2 acetylcholine receptor), A4B2** (nicotinic a4/b2** acetylcholine receptor), A4B4 (nicotinic a4/b4 acetylcholine receptor), BZP (a1) (GABA-BZP a1 receptor), EP3 (prostaglandin-3 receptor), MDR 1 (multidrug resistant p-Glycoprotein), PCP (PCP glutamate receptor).

Activity Assays

For the twenty-five compounds of Fig. 1, the NIMH-PDSP also performed activity assays at 5-HT_2A and 5-HT_2C. The E_max values (maximal activity) are relative to 5-HT (serotonin), measuring Ca++ mobilization. Ca++ flux assays were performed using a FLIPRTETRA. The activity assays were conducted with cell lines which have very high receptor expression levels (e.g. plenty of ‘spare receptors’). Under such conditions partial agonists will have considerable agonist activity. The data represent the mean ± variance of computer-derived estimates from single experiments done in quadruplicate. Thus, the four observations are averaged and a single estimate with error is provided (Table S3).

Sources

The following compounds (Fig. 1) were used in the study:

• 2C-B, 4-Bromo-2,5-dimethoxyphenethylamine
• 2C-B-fly, 1-(8-Bromo-2,3,6,7-tetrahydrobenzo[1,2-b;4,5-b′]difuran-4-yl)2-aminoethane
• 2C-E, 4-Ethyl-2,5-dimethoxyphenethylamine
• 2C-T-2, 4-Ethylthio-2,5-dimethoxyphenethylamine
• ALEPH-2, (±)-4-Ethylthio-2,5-dimethoxyamphetamine
• 4C-T-2, 4-Ethylthio-2,5-dimethoxyphenylbutylamine
• MEM, (±)-2,5-Dimethoxy-4-ethoxyamphetamine
• TMA-2: (±)-2,4,5-Trimethoxamphetamine
• TMA: (±)-3,4,5-Trimethoxamphetamine
• mescaline: 3,4,5-Trimethoxyphenethylamine
• DOB: (±)-2,5-Dimethoxy-4-bromoamphetamine
• DOI: (±)-2,5-Dimethoxy-4-iodoamphetamine
• DOM: (±)-2,5-Dimethoxy-4-methylamphetamine
• DOET: (±)-2,5-Dimethoxy-4-ethylamphetamine
• MDA: (±)-3,4-Methylenedioxyamphetamine
• MDMA: (±)-3,4-Methylenedioxymethamphetamine
• DMT: N,N-Dimethyltryptamine
• 5-MeO-DMT: 5-Methoxy-N,N-dimethyltryptamine
• DPT: N,N-Dipropyltryptamine
• 5-MeO-MIPT: 5-Methoxy-N-methyl-N-isopropyltryptamine
• DIPT: N,N-Diisopropyltryptamine
• 5-MeO-DIPT: 5-Methoxy-N,N-diisopropyltryptamine
• 6-fluoro-DMT: 6-Fluoro-N,N-dimethyltryptamine
• psilocin: 4-Hydroxy-N,N-dimethyltryptamine
• lisuride

5-MeO-DMT, and DOI were purchased from Sigma. DOB, DOET, mescaline, TMA, MDA, MDMA, and psilocin were provided as gifts by the National Institute on Drug Abuse Drug Supply Program. 2C-B, 2C-B-fly, MEM, 4C-T-2, 5-MeO-MIPT, 6-fluoro-DMT, TMA-2, and lisuride were provided as gifts by Dave Nichols. DMT and DOM were provided as gifts by Richard Glennon. 2C-E, 2C-T-2, Aleph-2, DIPT, 5-MeO-DIPT, and DPT were provided as gifts by Alexander Shulgin.

Normalization

The raw K_i values are distributed over several orders of magnitude, thus a log transformation is a good first step in the analysis. In addition, higher affinities produce lower K_i values, thus it is valuable to calculate: pK_i = −log₁₀(K_i). Higher affinities have higher pK_i values, and each unit of pK_i value corresponds to one order of magnitude of K_i value. Table S4 presents the raw data transformed into pK_i values. Generally, the highest K_i value generated by NIMH-PDSP is 10,000, which produces a pK_i value of −4 (although a value of 10,450 was reported for 5-MeO-TMT). For non-PDSP data gathered from the literature, some K_i values greater than 10,000 are reported (i.e. 12,500, 14,142, 22,486, 39,409 and 70,000 for ibogaine).

When the primary assay did not produce >50% inhibition, the K_i value is treated as >10,000. When the primary assay hit, but the secondary assay was not performed, the K_i value is also treated as >10,000. If a secondary assay produced a K_i value significantly greater than 10,000, it is usually also reported as >10,000. The lowest K_i value in the data set of this study is 0.3 (lisuride at 5-HT_1A) and the highest value is 70,000 (ibogaine at D₃), thus collectively, the data in this study cover nearly six orders of magnitude of K_i values. However, ignoring values reported as >10,000, the K_i values for a single drug in this study never exceed four orders of magnitude in range.

The goal of the normalization used in this study is to factor out potency, in order to allow easy comparison of the multi-receptor affinity profiles of different drugs. The normalization will adjust the highest pK_i value for each drug to a value of 4, and set all K_i values reported as >10,000 to a value of zero. K_i values actually measured as greater than 10,000 are not set to zero (i.e. 5-MeO-TMT and ibogaine). We will call this normalized value npK_i. Let the maximum pK_i value for each drug be called pK_iMax. For each individual drug:

• If K_i treated as >10,000, then npK_i = 0
• npK_i = 4+pK_i−pK_iMax

With this normalization:

• higher affinities have higher values
• affinities too low to be measured will be reported as zero
• for each drug, the highest affinity will be set to a value of 4
• each unit of npK_i value represents one order of magnitude of K_i value
• potency is factored out so that drugs of different potencies can be directly compared

This normalization effectively factors out the absolute potency of each drug, and allows us to focus on the relative affinities of each drug at each receptor.

Perceptibility

It will also be seen that many psychedelic drugs interact with a large number of receptors. Fig. 3 shows the ranked distributions of npK_i values for DOB and DOI, and the same data is listed below in numerical form (0.00 means K_i >10,000, ND means the data is not available):

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Figure 3. Receptor affinity profiles of DOB and DOI, ordered by decreasing affinity.

The vertical axis is normalized pK_i (npK_i). Horizontal axis is a list of forty-two receptors, arranged in order of decreasing affinity for each individual drug. Colors correspond to classes of receptors, and are the same as used in Fig. S1. The black vertical bars represent a 100-fold drop in affinity relative to the receptor with the highest affinity. As a rule of thumb, this is presumed to be the limit of perceptible receptor interaction. Receptors to the right of the black bar should be imperceptible, while receptors to the left of the black bar should be perceptible, increasingly so the further left they are.

https://doi.org/10.1371/journal.pone.0009019.g003

DOB: 4.00 5ht2b, 3.23 5ht2a, 2.97 5ht2c, 2.11 Beta2, 1.89 5ht7, 1.82 Alpha2C, 1.79 5ht1d, 1.68 D3, 1.62 5ht1b, 1.53 M3, 1.44 5ht1e, 1.41 Alpha2B, 1.39 Imidazoline1, 1.25 Sigma1, 1.21 Beta1, 1.18 5ht1a, 0.96 Alpha2A, 0.87 5ht5a, 0.85 5ht6, 0.66 SERT, 0.63 H1; 0.00: D5, D2, D4, NET, D1, Alpha1B, Sigma2, DOR, KOR, MOR, M1, M2, DAT, M4, M5, Alpha1A, H2, CB2, CB1, Ca+Channel, NMDA

DOI: 4.00 5ht2c, 3.79 Alpha2A, 3.52 Beta2, 3.44 5ht2a, 3.13 Alpha2B, 3.13 5ht2b, 3.00 5ht1d, 2.90 M4, 2.89 Beta1, 2.88 Alpha2C, 2.83 SERT, 2.66 5ht1e, 2.51 M3, 2.42 H1, 2.36 M2, 2.34 5ht6, 2.32 M5, 2.31 5ht1a, 2.23 M1, 1.90 5ht7, 1.73 Sigma1, 1.70 Sigma2, 1.67 D1; 0.00: 5ht1b, DAT, Imidazoline1, NET, 5ht5a, DOR, KOR, MOR, Alpha1B, D2, D3, D4, D5, Alpha1A, H2, CB2, CB1, NMDA; ND: Ca+Channel

For potent compounds like DOB and DOI, it is possible to measure K_i values over nearly a full four orders of magnitude range of affinity. However, not all of these affinities are able to produce perceptible mental effects. As a rule of thumb, 100-fold affinity is considered truly selective. Thus, receptors with npK_i values below about 2.0 should not have perceptible mental effects. In Fig. 3, a black vertical bar represent a 100-fold drop in affinity relative to the receptor with the highest affinity, and divides those npK_i values greater than 2.0 (on the left) from those 2.0 or less (on the right). This is presumed to be the limit of perceptible receptor interaction. Receptors to the right of the black bar should be imperceptible, while receptors to the left of the black bar should be perceptible, increasingly so the further left they are. In spite of the long tail of affinities, DOB is effectively selective for the three 5-HT₂ (serotonin-2) receptors (Beta2 falls at the approximate limit of perceptibility), while DOI by contrast has nineteen receptors in the presumed perceptible range, although they should not all be equally perceptible.

Breadth

An index of the breadth (or inverse of selectivity), B, of the binding profiles of the individual drugs or receptors can be constructed by summing the forty-two npK_i values for each drug, or the thirty-five npK_i values for each receptor. If a drug were absolutely selective, binding at only one receptor (e.g. salvinorin A), it would have the minimal B value of 4, regardless of the absolute affinity of the drug for its one receptor. If a drug bound with equal affinity to all forty-two receptors, it would have the maximum B value of 4×42 = 168, regardless of its absolute receptor affinities.

It is not clear that a simple sum of npK_i values is the best index of breadth. In this method, four receptors with K_i values of 1,000 collectively carry the same weight as one receptor with a K_i value of 1. This may not be a realistic equivalence. Thus we will include three measures of breadth:B_sq and B_exp give greater weight to higher affinity (lower K_i) values. Regression analysis of receptor affinity vs. potency in humans suggests that B_sq is the most meaningful breadth statistic. Table S5 and Table S6 present the raw K_i data converted into npK_i values, for both the individual receptors, and groups of receptors summed using the B_sq statistic.

Proportional Breadth

In addition to looking at the breadth of interaction of individual drugs with multiple receptors, it may be of value to look at an individual drug's interaction with one receptor or group of receptors, as a proportion of the drug's total interaction with all receptors.

In order to compute the proportion for and individual receptor or a group of receptors, we divide the sum of squares of npK_i values for the group of receptors, by the sum of squares of npK_i values for all receptors:For example, to compute this proportion for “5-HT” receptors, we divide the squares of the values in the “5-HT” column of Table S5 (for LSD, 11.13² = 123.9), by the squares of the values in the center column (“B_sq”) of Table 3 (for LSD, 13.12² = 172.1); 123.9/172.1 = 0.719 for LSD. We will call this proportion B_p. The proportional breadth data is displayed in Table S7 and Table S8.

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Table 3. Thirty-five drugs arranged in order of decreasing breadth, increasing selectivity.

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Truncated Receptor Profiles

The NIMH-PDSP generally does not measure K_i values greater than 10,000 nm, because at those concentrations, there is a great deal of non-specific binding which invalidates the measurement of receptor affinity. This creates a problem for drugs whose best-hit has a K_i value of greater that 100 nm (TMA, mescaline, TMA-2, DIPT, MDMA, 5-MeO-DIPT, ibogaine). For these drugs, the range of K_i values that can be measured by the NIMH-PDSP is less than the 100-fold presumed perceptible range, and therefore, the lowest measurable npK_i value is greater than the presumed limit of perceptibility at 2.00. Table 4 shows for each drug, the lowest K_i value measured (K_iMin) which is the best-hit, the best-hit receptor (K_iMinR), the theoretically lowest measurable npK_i value (npK_iLim), the lowest actually measured npK_i value (npK_iMin), and the receptor where the lowest npK_i value was actually measured (npK_iMinR). Drugs that have both a K_iMin value of greater that 100 nm and an npK_iMin value greater than 2.00 have truncated receptor affinity profiles.

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Table 4. Truncated receptor profiles for thirty-five drugs.

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Seven drugs have best-hit K_i values of greater that 100 nm: TMA, mescaline, TMA-2, DIPT, MDMA, 5-MeO-DIPT, ibogaine. For these seven drugs, the perceptible receptor profile is truncated due to the methodological limitations of the NIMH-PDSP, to the extent to which the npK_iMin value is greater than 2.00. Note that for ibogaine, whose best hit is 206 nm, the npK_iMin value is 1.47, indicating that the receptor profile is not fully truncated, because several K_i values above 10,000 nm were gathered from the literature (however, ibogaine has not received a full receptorome screening, and thus its receptor profile must be considered incomplete for other reasons).

Six drugs have both a K_iMin value of greater that 100 nm and an npK_iMin value greater than 2.00. For 5-MeO-DIPT, the npK_iMin value (2.15) is close to the presumed perceptibility limit, thus we can consider its receptor profile to be complete. For TMA-2, DIPT, and MDMA, the npK_iMin values (2.58, 2.51, 2.43 respectively) fall in the weak region of the presumed perceptibility range. Although these three receptor profiles are truncated, the missing data may be of little consequence. For TMA and mescaline, the npK_iMin values (2.98. 2.92 respectively) fall in the moderate region of the presumed perceptibility range. We must consider these two truncated receptor profiles to be truly incomplete, with potential consequences for our interpretations of the properties of these two drugs. The receptor profiles of some other drugs are incomplete due to holes in the NIMH-PDPS data set. Morphine and THC have not been broadly assayed, and must also be considered to be incomplete.

Normalized Affinity Data

Fig. S1 shows the simplest view of the normalized affinity data. The drugs in Fig. S1 are ordered to correspond roughly to similarity of structure and receptor affinity profiles. Colors correspond to classes of receptors. It can be seen at a glance that most, but not all of the drugs interact strongly with the serotonin receptors (beige), certain drugs interact strongly with the dopamine receptors (red), others with the adrenergic receptors (green), yet others with the histamine receptors (yellow), etc.

Breadth

In Table 3, the thirty-five drugs are arranged in order of decreasing breadth and increasing selectivity, based on the three breadth indices B, B_sq, and B_exp. Although the three indices provide different orderings, the orderings are quite similar at the two extremes of the table (greatest and least breadth) where most of the attention is likely to be focused. The drugs with the broadest receptor interactions (least selective) are found at the tops of the columns, and the drugs with the narrowest receptor interactions (most selective) are found at the bottoms of the columns. Regression analysis suggests that B_sq is the best statistic for combining receptors, therefore the B_sq statistic will be used in most of the breadth analyses to follow. The B, B_sq and B_exp data of Table 3 is presented graphically in Fig. 4.

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Figure 4. Thirty-five drugs arranged in order of decreasing breadth, increasing selectivity.

The thirty-five drugs are arranged in order of decreasing breadth and increasing selectivity, based on the breadth indices B, B_sq, and B_exp. Although the three indices provide different orderings, the orderings are quite similar at the two extremes of the table (greatest and least breadth) where most of the attention is likely to be focused. The drugs with the broadest receptor interactions (least selective) are found at the left of the figure, and the drugs with the narrowest receptor interactions (most selective) are found at the right of the figure.

https://doi.org/10.1371/journal.pone.0009019.g004

Profiles of Drugs

The relative breadth or selectivity of the thirty-five drugs is nicely visualized in Fig. S2, in which for each drug, the bars representing forty-two receptors are arranged in order of decreasing size. The drugs are arranged in order of decreasing breadth, based on the B_sq values of Table 3 and Fig. 4. Drugs at the top of the figure have the broadest receptor interactions (least selective), while drugs at the bottom of the figure have the narrowest receptor interactions (most selective). Colors correspond to classes of receptors, and are the same as used in Fig. S1. Scanning Fig. S2 from top to bottom shows the variation in breadth of receptor interactions between drugs. It can also be seen that some distributions are relatively convex (e.g. DMT & LSD), while others are relatively concave (e.g. DOB & 5-MeO-DMT). Convexity tends to increase breadth, while concavity tends to decrease breadth.

It is also useful to present the npK_i data of Fig. S2 in numerical format. In the listing below, the npK_i values for each drug are arranged in decreasing order. A value of 0.00 means that the K_i value was measured as >10,000 nm. “ND” indicates that the data is not available. The 5-HT_2A and 5-HT_2C receptors are also highlighted in bold font for easier location. npK_i values below about 2.0 should be imperceptible, while values above about 2.0 should be perceptible, and the higher the npK_i value, the more perceptible a receptor should be.

6-F-DMT: 4.00 5ht6, 3.93 5ht2b, 3.80 5ht7, 3.74 H1, 3.66 5ht1d, 3.25 SERT, 3.24 Alpha2C, 3.17 Alpha1A, 3.07 5ht1b, 2.99 Alpha2B, 2.81 5ht1a, 2.74 5ht1e, 2.67 D1, 2.62 D2, 2.58 5ht2c, 2.47 5ht2a, 2.47 D3, 2.45 Imidazoline1, 2.44 H2, 2.43 5ht5a, 2.25 D4, 1.61 D5, 1.57 Sigma1, 1.56 Sigma2; 0.00: DAT, Beta1, NET, Alpha2A, CB2, CB1, Ca+Channel, Beta2, M2, M3, M4, M5, M1, Alpha1B, NMDA; ND: DOR, MOR, KOR

DMT: 4.00 5ht7, 3.97 5ht1d, 3.91 5ht2b, 3.53 Alpha2B, 3.53 Alpha2C, 3.51 D1, 3.42 5ht2c, 3.28 5ht1e, 3.25 5ht6, 3.16 5ht5a, 3.13 Imidazoline1, 2.95 Alpha1B, 2.75 Alpha2A, 2.70 Alpha1A, 2.58 5ht2a, 2.37 SERT, 2.23 Sigma1; 0.00: 5ht1a, D4, D5, Beta1, D2, D3, DAT, NET, 5ht1b, Beta2, Sigma2, CB2, KOR, Ca+Channel, M1, M2, M3, M4, M5, H2, CB1; ND: H1, DOR, MOR, NMDA

DPT: 4.00 5ht1a, 3.88 5ht2b, 3.41 H1, 3.31 SERT, 3.05 5ht7, 2.97 Imidazoline1, 2.97 Alpha2B, 2.90 Sigma1, 2.86 Alpha1B, 2.84 Alpha2A, 2.79 Alpha2C, 2.71 5ht1d, 2.57 5ht1b, 2.56 Alpha1A, 2.37 D3, 2.33 DAT, 2.31 5ht2c, 2.20 D4, 2.13 5ht1e, 2.09 5ht2a, 2.04 Sigma2, 1.86 5ht5a, 1.85 5ht6, 1.54 D2; 0.00: D1, D5, NET, Beta1, DOR, KOR, MOR, Beta2, M2, M3, M4, M5, M1, H2, CB2, CB1, Ca+Channel, NMDA

DOI: 4.00 5ht2c, 3.79 Alpha2A, 3.52 Beta2, 3.44 5ht2a, 3.13 Alpha2B, 3.13 5ht2b, 3.00 5ht1d, 2.90 M4, 2.89 Beta1, 2.88 Alpha2C, 2.83 SERT, 2.66 5ht1e, 2.51 M3, 2.42 H1, 2.36 M2, 2.34 5ht6, 2.32 M5, 2.31 5ht1a, 2.23 M1, 1.90 5ht7, 1.73 Sigma1, 1.70 Sigma2, 1.67 D1; 0.00: 5ht1b, DAT, Imidazoline1, NET, 5ht5a, DOR, KOR, MOR, Alpha1B, D2, D3, D4, D5, Alpha1A, H2, CB2, CB1, NMDA; ND: Ca+Channel

LSD: 4.00 5ht1b, 3.77 5ht7, 3.75 5ht6, 3.73 5ht1a, 3.70 5ht1d, 3.64 5ht5a, 3.54 5ht2a, 3.16 D3, 3.11 5ht2b, 3.11 5ht2c, 2.93 Alpha2A, 2.62 5ht1e, 2.55 D2, 2.39 D4, 2.34 D1, 2.05 D5, 1.54 Alpha1A, 1.40 H1, 1.39 Beta1, 1.05 Beta2, 0.65 Alpha1B; 0.00: KOR, DOR, DAT, SERT, MOR, NET; ND: Sigma2, Alpha2B, Alpha2C, Imidazoline1, M1, M2, M3, M4, M5, Sigma1, H2, CB2, CB1, Ca+Channel, NMDA

lisuride: 4.00 5ht1a, 3.88 Alpha2C, 3.78 Alpha2B, 3.22 Alpha2A, 3.01 5ht2b, 2.99 5ht5a, 2.90 D4, 2.74 5ht2a, 2.65 D2, 2.64 5ht7, 2.61 5ht6, 2.56 Beta1, 2.27 5ht1b, 2.09 Alpha1A, 1.93 Beta2, 1.83 5ht1e, 1.59 D5, 1.42 H2, 1.34 D3, 1.08 Alpha1B; 0.00: 5ht1d, 5ht2c, D1, DAT, NET, Imidazoline1, M1, SERT, CB2, KOR, MOR, M3, M2, M5, M4, CB1, Ca+Channel; ND: Sigma1, H1, Sigma2, DOR, NMDA

2C-E: 4.00 5ht2b, 3.76 5ht2a, 3.54 5ht1d, 3.44 Alpha2C, 3.38 5ht2c, 3.00 5ht1b, 2.91 Alpha2B, 2.91 5ht1a, 2.77 5ht7, 2.71 Alpha2A, 2.60 5ht1e, 2.27 D3, 2.16 M5, 1.99 M3, 1.93 5ht6, 1.88 D2; 0.00: D1, Alpha1A, Alpha1B, 5ht5a, Beta1, M1, SERT, D4, NET, Imidazoline1, H1, Sigma2, DOR, KOR, MOR, NMDA, M2, DAT, M4, D5, CB2, H2, Ca+Channel, CB1; ND: Sigma1, Beta2

TMA: 4.00 5ht2b, 3.95 Sigma2, 3.95 Sigma1, 3.80 5ht7, 3.45 5ht1a, 3.36 Alpha2A, 3.22 5ht1b, 3.20 5ht1d, 3.15 5ht1e, 3.02 5ht2c, 2.98 Alpha2C; 0.00: 5ht2a, 5ht6, D4, D1, Alpha1A, D2, D3, Alpha2B, D5, Beta1, Beta2, SERT, DAT, NET, Imidazoline1, Alpha1B, 5ht5a, DOR, KOR, MOR, NMDA, M2, CB2, CB1, M5, H1, H2; ND: M3, M4, Ca+Channel, M1

2C-B: 4.00 5ht2b, 3.71 5ht1d, 3.69 5ht2a, 3.18 5ht2c, 3.12 Alpha2C, 3.11 5ht1b, 3.05 5ht1e, 2.81 5ht7, 2.75 5ht1a, 2.64 Alpha2A, 2.63 5ht6, 2.31 Alpha2B, 2.22 M3, 1.80 Imidazoline1, 1.60 D2, 1.28 D3; 0.00: D1, 5ht5a, Alpha1B, D5, NMDA, M1, SERT, D4, NET, Alpha1A, Sigma1, Sigma2, DOR, KOR, MOR, H1, M2, DAT, M4, M5, CB2, H2, CB1; ND: Beta2, Ca+Channel, Beta1

cis-2a: 4.00 5ht1a, 3.79 5ht1b, 3.46 D3, 3.30 5ht7, 3.25 5ht6, 3.15 5ht5a, 2.89 5ht2a, 2.72 5ht2b, 2.67 D2, 2.49 D4, 2.34 5ht2c, 2.07 5ht1e, 2.00 D1, 1.76 Beta1, 1.66 H1, 1.64 Alpha1A, 1.36 D5, 0.70 Beta2; 0.00: DOR, SERT, MOR, KOR, NET, DAT, Alpha1B; ND: 5ht1d, Alpha2A, Sigma2, Alpha2B, Alpha2C, Imidazoline1, M1, M2, M3, M4, M5, Sigma1, H2, CB2, CB1, Ca+Channel, NMDA

5-MeO-MIPT: 4.00 5ht1a, 3.79 5ht7, 3.74 5ht1d, 3.32 5ht2b, 2.98 5ht6, 2.85 Alpha2A, 2.61 5ht1b, 2.44 5ht2a, 2.29 Alpha2C, 2.15 Imidazoline1, 2.13 Sigma2, 2.11 5ht5a, 1.86 Alpha2B, 1.75 5ht2c, 1.70 D3, 1.55 5ht1e, 1.41 H1, 1.29 D4, 1.28 SERT; 0.00: D2, Alpha1B, D5, D1, Beta2, NET, DAT, Sigma1, Beta1, DOR, KOR, MOR, M1, M2, M3, M4, M5, Alpha1A, H2, CB2, NMDA, Ca+Channel; ND: CB1

Psilocin: 4.00 5ht2b, 3.40 5ht1d, 3.37 D1, 3.03 5ht1e, 2.88 5ht1a, 2.83 5ht5a, 2.82 5ht7, 2.82 5ht6, 2.67 D3, 2.52 5ht2c, 2.19 5ht1b, 2.14 5ht2a, 1.77 Imidazoline1, 1.74 SERT, 1.57 Alpha2B, 1.36 Alpha2A, 1.03 Alpha2C; 0.00: D2, Alpha1B, D5, D4, Beta2, Beta1, DAT, NET, Alpha1A, Sigma1, Sigma2, DOR, KOR, MOR, M1, M2, M3, M4, Ca+Channel, H1, H2, CB2, CB1; ND: M5, NMDA

DIPT: 4.00 5ht1a, 3.53 Imidazoline1, 3.48 5ht2b, 2.98 SERT, 2.83 Sigma1, 2.68 Alpha2C, 2.65 Sigma2, 2.62 Alpha2B, 2.56 D3, 2.55 5ht7, 2.53 H1, 2.51 5ht1d; 0.00: 5ht2a, D4, 5ht5a, D1, D2, Alpha2A, 5ht6, D5, Beta1, Beta2, 5ht2c, DAT, NET, 5ht1b, Alpha1B, 5ht1e, DOR, KOR, MOR, M1, M2, M3, M4, M5, Alpha1A, H2, CB2, CB1, Ca+Channel, NMDA

5-MeO-DIPT: 4.00 5ht1a, 3.91 5ht2b, 3.24 Imidazoline1, 3.03 5ht7, 2.89 5ht1d, 2.72 SERT, 2.66 Alpha2C, 2.64 Sigma2, 2.41 5ht1b, 2.40 Alpha2B, 2.15 Sigma1; 0.00: 5ht5a, 5ht2a, D4, D3, D1, D2, Alpha2A, 5ht6, D5, Beta1, Beta2, 5ht2c, DAT, NET, Alpha1A, Alpha1B, 5ht1e, DOR, KOR, MOR, M1, M2, M3, M4, M5, H1, H2, CB2, CB1, Ca+Channel, NMDA

RR-2b: 4.00 5ht1b, 3.59 5ht1a, 3.20 5ht5a, 3.05 5ht1d, 2.81 5ht7, 2.52 5ht6, 2.40 D3, 2.16 5ht1e, 2.08 D4, 1.88 D2, 1.81 5ht2b, 1.77 D1, 1.63 5ht2c, 1.53 D5, 1.46 5ht2a, 1.14 H1, 0.59 Alpha1A; 0.00: SERT, DOR, KOR, MOR, Alpha1B, NET, DAT; ND: Alpha2A, Imidazoline1, Beta2, Sigma2, Alpha2B, Alpha2C, Beta1, M1, M2, M3, M4, M5, Sigma1, H2, CB2, CB1, Ca+Channel, NMDA

2C-T-2: 4.00 5ht2b, 3.18 5ht2a, 3.05 5ht2c, 2.84 5ht1d, 2.56 Alpha2C, 2.20 5ht1a, 2.16 5ht1e, 1.94 M3, 1.92 Alpha2A, 1.84 5ht1b, 1.79 Alpha2B, 1.79 5ht7, 1.70 Beta2, 1.64 5ht6, 1.60 M5, 1.51 D3, 1.46 Imidazoline1, 1.33 D2, 1.19 Sigma1, 0.81 Beta1; 0.00: D1, 5ht5a, SERT, D4, NET, Alpha1A, Alpha1B, Sigma2, DOR, KOR, MOR, M1, M2, DAT, M4, D5, H1, H2, CB2, CB1, Ca+Channel, NMDA

4C-T-2: 4.00 5ht2b, 3.67 Beta2, 3.33 5ht2a, 3.09 5ht2c, 3.05 Sigma1, 2.79 Imidazoline1, 2.66 D3, 2.56 5ht5a, 2.18 5ht7, 2.04 5ht1a, 1.77 5ht1e; 0.00: 5ht6, D1, D4, D5, Alpha1A, Alpha1B, Alpha2A, Alpha2B, Alpha2C, Beta1, D2, SERT, DAT, NET, 5ht1b, 5ht1d, Sigma2, DOR, KOR, MOR, M1, M2, M3, M4, M5, H1, H2, CB2, CB1, Ca+Channel, NMDA

MDMA: 4.00 Imidazoline1, 3.64 5ht2b, 3.26 Ca+Channel, 3.21 Alpha2C, 3.09 Alpha2B, 3.07 M3, 2.94 Alpha2A, 2.54 M5, 2.43 M4; 0.00: 5ht2c, 5ht1d, D2, 5ht1e, 5ht1a, 5ht2a, Alpha1A, Alpha1B, 5ht5a, 5ht6, 5ht7, D1, Beta2, SERT, DAT, NET, 5ht1b, H1, H2, D3, KOR, Beta1, M1, M2, D5, D4, CB1, NMDA, MOR; ND: DOR, Sigma2, CB2, Sigma1

Ibogaine: 4.00 Sigma2, 3.57 SERT, 3.02 DAT, 3.01 NMDA, 2.88 KOR, 2.67 MOR, 2.55 Sigma1, 2.22 M3, 2.16 5ht2a, 1.96 M1, 1.72 M2, 1.47 D3; 0.00: DOR, 5ht1b, 5ht1d, 5ht1a, H1, 5ht2c, D2, D1, Beta1; ND: Alpha2C, D5, D4, Alpha2B, Imidazoline1, NET, Alpha2A, 5ht5a, 5ht6, 5ht7, Alpha1B, 5ht1e, 5ht2b, M4, M5, Alpha1A, H2, CB2, CB1, Ca+Channel, Beta2

DOET: 4.00 5ht1a, 3.72 5ht2a, 3.70 5ht2b, 3.13 5ht2c, 2.40 Alpha2B, 2.07 5ht7, 2.05 Alpha2A, 2.00 Alpha2C, 1.82 Beta2, 1.71 5ht1b, 1.61 5ht1e, 1.40 Beta1, 1.34 5ht1d, 1.18 Sigma2, 1.17 Sigma1; 0.00: D4, Alpha1A, D3, 5ht6, D5, D1, D2, SERT, DAT, NET, Imidazoline1, Alpha1B, 5ht5a, DOR, KOR, MOR, NMDA, M2, CB2, CB1, M5, H1, H2; ND: M3, M4, Ca+Channel, M1

5-MeO-DMT: 4.00 5ht1a, 3.69 5ht7, 3.48 5ht1d, 2.73 5ht6, 2.41 5ht1b, 2.38 D1, 1.84 5ht5a, 1.72 5ht1e, 1.58 D3, 1.57 Alpha2C, 1.55 5ht2c, 1.00 Alpha2A, 0.98 5ht2a, 0.97 SERT, 0.88 Imidazoline1, 0.86 Alpha2B, 0.82 NET, 0.78 D4, 0.73 D2, 0.69 5ht2b; 0.00: Alpha1B, Beta2, Beta1, DAT, D5, Alpha1A, Sigma1, Sigma2, CB2, KOR, Ca+Channel, M1, M2, M3, M4, M5, H2, CB1; ND: H1, DOR, MOR, NMDA

SS-2c: 4.00 5ht1a, 3.22 5ht1b, 2.82 D3, 2.45 5ht7, 2.44 5ht6, 2.32 5ht2a, 2.17 5ht5a, 2.17 5ht2b, 2.03 5ht2c, 1.74 D2, 1.72 Beta1, 1.62 D4, 1.16 5ht1e, 1.14 D1, 1.00 D5, 0.67 Alpha1A, 0.57 Beta2, 0.20 H1; 0.00: DOR, SERT, MOR, KOR, NET, DAT, Alpha1B; ND: 5ht1d, Alpha2A, Sigma2, Alpha2B, Alpha2C, Imidazoline1, M1, M2, M3, M4, M5, Sigma1, H2, CB2, CB1, Ca+Channel, NMDA

2C-B-fly: 4.00 5ht2b, 3.81 5ht1d, 2.93 5ht2c, 2.89 5ht2a, 1.91 5ht1e, 1.79 5ht1a, 1.79 Alpha2A, 1.78 5ht6, 1.69 5ht1b, 1.59 Alpha2C, 1.42 M3, 1.24 M4, 1.17 5ht7, 1.16 Alpha2B, 1.15 M1, 1.01 M5, 0.65 M2, 0.26 D1, 0.19 H1, 0.12 D2; 0.00: Beta1, Alpha1B, 5ht5a, DAT, NET, Imidazoline1, Sigma1, Sigma2, DOR, KOR, MOR, Beta2, SERT, CB2, D4, D5, Alpha1A, H2, CB1; ND: D3, Ca+Channel, NMDA

Mescaline: 4.00 Alpha2C, 3.97 5ht2b, 3.61 5ht1a, 3.44 Imidazoline1, 3.16 5ht1e, 2.92 Alpha2A; 0.00: 5ht2a, 5ht2c, 5ht6, 5ht1d, D1, D2, D3, D4, D5, Alpha1A, Alpha1B, 5ht5a, Alpha2B, 5ht7, Beta1, Beta2, SERT, DAT, NET, 5ht1b, Sigma1, Sigma2, DOR, KOR, MOR, M1, M2, M3, M4, M5, H1, H2, CB2, CB1, Ca+Channel, NMDA

DOB: 4.00 5ht2b, 3.23 5ht2a, 2.97 5ht2c, 2.11 Beta2, 1.89 5ht7, 1.82 Alpha2C, 1.79 5ht1d, 1.68 D3, 1.62 5ht1b, 1.53 M3, 1.44 5ht1e, 1.41 Alpha2B, 1.39 Imidazoline1, 1.25 Sigma1, 1.21 Beta1, 1.18 5ht1a, 0.96 Alpha2A, 0.87 5ht5a, 0.85 5ht6, 0.66 SERT, 0.63 H1; 0.00: D5, D2, D4, NET, D1, Alpha1B, Sigma2, DOR, KOR, MOR, M1, M2, DAT, M4, M5, Alpha1A, H2, CB2, CB1, Ca+Channel, NMDA

5-MeO-TMT: 4.00 5ht6, 3.62 5ht7, 3.48 5ht1a, 3.38 5ht1d, 2.52 5ht1e, 2.17 5ht2c, 1.97 NET, 1.76 5ht5a; 0.00: 5ht2a, DAT, D1, D2, D3, D4, D5, H1, H2, SERT, DOR, KOR, MOR; ND: Beta2, Alpha2A, 5ht2b, 5ht1b, Imidazoline1, Sigma1, Sigma2, Alpha2B, Alpha2C, Beta1, M1, M2, M3, M4, M5, Alpha1A, Alpha1B, CB2, CB1, Ca+Channel, NMDA

DOM: 4.00 5ht2b, 3.38 Beta2, 2.75 5ht1d, 2.36 5ht2a, 2.30 Alpha2A, 2.13 Alpha2B, 2.10 Alpha2C, 1.87 5ht7, 1.56 Alpha1A, 1.52 5ht1e, 1.51 5ht1a, 1.47 5ht2c, 1.16 5ht6; 0.00: D3, 5ht1b, D1, Alpha1B, 5ht5a, D4, D5, Beta1, D2, SERT, DAT, NET, Imidazoline1, Sigma1, Sigma2, DOR, KOR, MOR, M1, M2, CB2, CB1, M5, H1, H2, NMDA; ND: M3, Ca+Channel, M4

MDA: 4.00 5ht2b, 3.60 Alpha2C, 3.12 Alpha2B, 2.74 Alpha2A, 2.41 5ht7, 2.38 5ht1a, 2.15 5ht2c; 0.00: 5ht2a, 5ht1e, 5ht1d, D1, D2, D3, D4, 5ht1b, Alpha1A, Alpha1B, 5ht5a, 5ht6, D5, Beta1, Beta2, SERT, DAT, NET, Imidazoline1, CB2, H2, M5, KOR, M2, CB1; ND: M1, M3, Sigma1, MOR, H1, Sigma2, DOR, M4, Ca+Channel, NMDA

Aleph-2: 4.00 5ht2b, 2.79 Beta2, 2.50 5ht2c, 2.42 5ht2a, 1.83 Sigma1, 1.70 Imidazoline1, 1.41 D3, 1.08 5ht7, 1.08 SERT, 1.06 Alpha2C, 1.02 5ht1d, 0.98 5ht1a, 0.92 M3, 0.90 5ht1b, 0.74 Alpha2B, 0.72 5ht6, 0.71 5ht1e, 0.44 Alpha2A, 0.37 Beta1, 0.30 M5; 0.00: D1, D2, 5ht5a, D4, NET, Alpha1A, Alpha1B, Sigma2, DOR, KOR, MOR, M1, M2, DAT, M4, D5, H1, H2, CB2, CB1, Ca+Channel, NMDA

EMDT: 4.00 5ht6, 2.97 5ht1a, 2.74 5ht1d, 2.73 5ht7, 2.49 5ht1e, 1.95 5ht2c, 1.54 5ht5a; 0.00: 5ht2a, DAT, D5, D1, D2, D3, D4, NET, H1, H2, SERT, DOR, KOR, MOR; ND: Beta2, Alpha2A, 5ht2b, 5ht1b, Imidazoline1, Sigma1, Sigma2, Alpha2B, Alpha2C, Beta1, M1, M2, M3, M4, M5, Alpha1A, Alpha1B, CB2, CB1, Ca+Channel, NMDA

TMA-2: 4.00 5ht2b, 3.42 5ht2a, 3.04 H1, 2.58 5ht2c; 0.00: 5ht1b, 5ht1a, 5ht1e, 5ht5a, 5ht6, 5ht7, D1, D2, D3, D4, D5, 5ht1d, Alpha1B, Alpha2A, Alpha2B, Alpha2C, Beta1, Beta2, SERT, DAT, NET, M5, Alpha1A, H2, M2; ND: KOR, DOR, M1, MOR, M3, M4, Imidazoline1, Sigma1, Sigma2, CB2, CB1, Ca+Channel, NMDA

THC: 4.00 CB1, 3.78 CB2; ND: 5ht2a, 5ht2c, 5ht1b, 5ht1d, 5ht1e, 5ht2b, 5ht1a, 5ht7, D1, D2, D3, D4, D5, Alpha1A, Alpha1B, 5ht5a, 5ht6, Alpha2C, Beta1, Beta2, SERT, DAT, NET, Imidazoline1, Sigma1, Sigma2, DOR, KOR, MOR, M1, M2, M3, M4, M5, H1, H2, Alpha2A, Alpha2B, Ca+Channel, NMDA

MEM: 4.00 5ht2b, 2.21 5ht2a, 2.10 Sigma1, 1.95 5ht7; 0.00: 5ht2c, 5ht1a, 5ht1e, 5ht5a, 5ht6, 5ht1b, D1, D2, D3, D4, D5, Alpha1A, Alpha1B, Alpha2A, Alpha2B, Alpha2C, Beta1, Beta2, SERT, DAT, NET, Imidazoline1, 5ht1d, Sigma2, DOR, KOR, MOR, M1, M2, M3, M4, M5, H1, H2, CB2, CB1, Ca+Channel, NMDA

Morphine: 4.00 MOR, 2.21 KOR, 0.72 DOR; ND: 5ht2c, 5ht2a, 5ht1d, 5ht1e, 5ht2b, 5ht1a, 5ht1b, D1, D2, D3, D4, D5, Alpha1A, Alpha1B, Alpha2A, Alpha2B, Alpha2C, Beta1, Beta2, SERT, DAT, NET, Imidazoline1, Sigma1, Sigma2, 5ht5a, 5ht6, 5ht7, M1, M2, M3, M4, M5, H1, H2, CB2, CB1, Ca+Channel, NMDA

Salvinorin A: 4.00 KOR; 0.00: 5ht2a, 5ht2b, 5ht2c, 5ht1b, 5ht1d, 5ht1e, 5ht5a, 5ht1a, 5ht7, D1, D2, D3, D4, D5, Alpha1A, Alpha1B, SERT, DOR, 5ht6, Beta1, Beta2, M2, DAT, M4, M5, H1, M1, M3, MOR; ND: Alpha2A, Alpha2C, Sigma2, Alpha2B, NET, Imidazoline1, Sigma1, H2, CB2, CB1, Ca+Channel, NMDA

Groups of Related Receptors

In addition to looking at breadth at the full complement of forty-two receptors with which the drugs interact, we can use the B_sq statistic to look at the participation of selected groups of receptors (Table S5). 5-HT₆ and 5-HT₇ are grouped because they share a common G-protein, G_s [13]. The same data is also presented in Table S6, which also includes interactions with individual receptors. Tables S5 and S6 allow us to easily identify drugs with the greatest or least interaction with an individual receptor or any group of related receptors.

For example, among drugs with measurable affinity at a 5-HT₂ receptor, 5-MeO-DMT has the weakest interaction with both the three 5-HT₂ receptors and the two paradigmatic 5-HT₂ receptors (5-HT_2A/C). This can be seen in that 5-MeO-DMT has the lowest non-zero value in all four of the columns: “5-HT₂,” “5-HT₂max,” “5-HT_2A, 5-HT_2C,” and “5-HT_2A/Cmax.” Meanwhile, the drugs 2C-E and DOI rise to the top of the same four columns, indicating that they have the strongest interactions with the 5-HT₂ receptors (fourteen drugs tie for the top value in the 5-HT₂max column because thirteen drugs have 5-HT_2B as their best hit and one has 5-HT_2C as its best hit). LSD has the strongest interaction collectively with the five dopamine receptors (D₁, D₂, D₃, D₄, D₅), the ten assayed 5-HT receptors, and the four assayed 5-HT₁ (serotonin-1) receptors. DMT has the strongest interaction with any single dopamine receptor (Dmax), and is the only drug to have its best hit at the 5-HT₇ receptor (Table S6). Mescaline is the only drug to have its best hit at an adrenergic receptor (α_2C, Table S6). Ibogaine is the only drug to have its best hit at a sigma receptor. MDMA is the only drug to have its best hit at an imidazoline receptor (Table S6). These observations likely provide clues to the qualitative diversity of these drugs.

Proportional Breadth

There is yet another way to look at the participation of the sub-sets of receptors. It may be relevant to consider the participation of a sub-set of receptors in proportion to the participation of all receptors (Table S7). For this we use the proportional breadth statistic (B_p) described in the methods section. The same data is also displayed in Table S8.

The proportional breadth statistic, B_p, is strongly influenced by the degree of overall breadth of the drug (B_sq²), as this determines the denominator in calculating the proportion. Therefore, we find MEM at the top of the 5-HT column because it is almost completely selective for a single receptor, 5-HT_2B. Similarly, TMA-2 is at the top of the 5-HT₂ columns because it is highly selective for the 5-HT₂ receptors, and EMDT is at the top of the “5-HT₆, 5-HT₇” column because it is highly selective for the 5-HT₆ receptor. Due to their high degree of selectivity, MEM, TMA-2, and EMDT all have small denominators in calculating the B_p statistic.

More interesting cases involve less selective drugs. For example, DMT is a very promiscuous drug, yet it falls at the top of the “α_1A, α_1B” column. MDA falls at the top of the “Adrenergic” and “α_2A, α_2B, α_2C” columns. 5-MeO-DMT appears third from the top of the “5-HT₆, 5-HT₇” column and second from the top of the “5-HT₇” column (Table S8). Ibogaine appears at the top of the “σ₁, σ₂” column. Although fairly selective, TMA-2's position at the top of the “H₁, H₂” column represents an important aspect of its pharmacology, likewise for DOM's position at the top of the “β₁, β₂” column.

Profiles of Receptors

The B statistics can also be used to look at the relative role played by the various receptors in the pharmacology of the entire set of drugs of this study. In this case, for each receptor, we sum the npK_i values at each receptor across each of the thirty-five drugs. In Table 5 we can see the rankings from the three B statistics. The data in Table 5 can also be represented graphically (Fig. 5). The three B statistics provide a very consistent ranking for the top seven receptors. In descending order of importance: 5-HT_2B, 5-HT_1A, 5-HT₇, 5-HT_1D, 5-HT_2A, 5-HT_2C, α_2C (with some play between the sixth and seventh positions). This set of top receptors would be a good place to look for receptors other than 5-HT_2A and 5-HT_2C, which play an important role in the actions of psychedelic drugs.

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Figure 5. Forty-two receptors arranged in order of decreasing interaction with the full set of thirty-five drugs.

The forty-two receptors are arranged in order of decreasing interaction with the full set of thirty-five drugs, based on the breadth statistics, B, B_sq. and B_exp. The receptors with the greatest interactions are found at the left of the figures, and the receptors with the least interactions are found at the right of the figures. The black vertical bars represent a 100-fold drop in affinity relative to the receptor with the highest affinity at each drug. As a rule of thumb, this is presumed to be the limit of perceptible receptor interaction. Drugs to the right of the black bar should have imperceptible interactions with the receptor, while drugs to the left of the black bar should have perceptible interactions with the receptor, increasingly so the further left they are.

https://doi.org/10.1371/journal.pone.0009019.g005

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Table 5. Forty-two receptors arranged in order of decreasing interaction with the full set of thirty-five drugs.

https://doi.org/10.1371/journal.pone.0009019.t005

Fig. S3 is a more detailed graphical view of data presented in Table 5. The receptors are presented in order of decreasing breadth (B_sq). The figures for each individual receptor provide information on the relative importance of each receptor at each drug, similar to that in Table S5 and Table S6. Receptors at the top of the figure have the broadest interactions with the thirty-five drugs, while receptors at the bottom of the figure have the narrowest interactions with the thirty-five drugs. The black vertical bars represent a 100-fold drop in affinity relative to the receptor with the highest affinity at each drug. As a rule of thumb, this is presumed to be the limit of perceptible receptor interaction. Drugs to the right of the black bar should have imperceptible interactions with the receptor, while drugs to the left of the black bar should have perceptible interactions with the receptor, increasingly so the further left they are. It is also useful to present the npK_i data of Fig. S3 in numerical format. npK_i values below about 2.0 should be imperceptible, while values above about 2.0 should be perceptible, and the higher the npK_i value, the more perceptible a receptor should be at a particular drug.

5ht2b: 4.00 DOB, 4.00 MDA, 4.00 Aleph-2, 4.00 2C-B-fly, 4.00 2C-B, 4.00 TMA, 4.00 psilocin, 4.00 TMA-2, 4.00 2C-E, 4.00 2C-T-2, 4.00 4C-T-2, 4.00 MEM, 4.00 DOM, 3.97 mescaline, 3.93 6-F-DMT, 3.91 5-MeO-DIPT, 3.91 DMT, 3.88 DPT, 3.70 DOET, 3.64 MDMA, 3.48 DIPT, 3.32 5-MeO-MIPT, 3.13 DOI, 3.11 LSD, 3.01 lisuride, 2.72 cis-2a, 2.17 SS-2c, 1.81 RR-2b, 0.69 5-MeO-DMT; 0.00 salvinorin A; ND: 5-MeO-TMT, ibogaine, EMDT, morphine, THC

5ht1a: 4.00 5-MeO-MIPT, 4.00 lisuride, 4.00 DOET, 4.00 SS-2c, 4.00 5-MeO-DIPT, 4.00 DIPT, 4.00 5-MeO-DMT, 4.00 cis-2a, 4.00 DPT, 3.73 LSD, 3.61 mescaline, 3.59 RR-2b, 3.48 5-MeO-TMT, 3.45 TMA, 2.97 EMDT, 2.91 2C-E, 2.88 psilocin, 2.81 6-F-DMT, 2.75 2C-B, 2.38 MDA, 2.31 DOI, 2.20 2C-T-2, 2.04 4C-T-2, 1.79 2C-B-fly, 1.51 DOM, 1.18 DOB, 0.98 Aleph-2; 0.00: TMA-2, MEM, MDMA, DMT, ibogaine, salvinorin A; ND: morphine, THC

5ht7: 4.00 DMT, 3.80 6-F-DMT, 3.80 TMA, 3.79 5-MeO-MIPT, 3.77 LSD, 3.69 5-MeO-DMT, 3.62 5-MeO-TMT, 3.30 cis-2a, 3.05 DPT, 3.03 5-MeO-DIPT, 2.82 psilocin, 2.81 2C-B, 2.81 RR-2b, 2.77 2C-E, 2.73 EMDT, 2.64 lisuride, 2.55 DIPT, 2.45 SS-2c, 2.41 MDA, 2.18 4C-T-2, 2.07 DOET, 1.95 MEM, 1.90 DOI, 1.89 DOB, 1.87 DOM, 1.79 2C-T-2, 1.17 2C-B-fly, 1.08 Aleph-2; 0.00: TMA-2, MDMA, mescaline, salvinorin A; ND: ibogaine, morphine, THC

5ht1d: 3.97 DMT, 3.81 2C-B-fly, 3.74 5-MeO-MIPT, 3.71 2C-B, 3.70 LSD, 3.66 6-F-DMT, 3.54 2C-E, 3.48 5-MeO-DMT, 3.40 psilocin, 3.38 5-MeO-TMT, 3.20 TMA, 3.05 RR-2b, 3.00 DOI, 2.89 5-MeO-DIPT, 2.84 2C-T-2, 2.75 DOM, 2.74 EMDT, 2.71 DPT, 2.51 DIPT, 1.79 DOB, 1.34 DOET, 1.02 Aleph-2; 0.00: 4C-T-2, mescaline, TMA-2, MEM, lisuride, MDMA, salvinorin A, MDA, ibogaine; ND: cis-2a, SS-2c, morphine, THC

5ht2a: 3.76 2C-E, 3.72 DOET, 3.69 2C-B, 3.54 LSD, 3.44 DOI, 3.42 TMA-2, 3.33 4C-T-2, 3.23 DOB, 3.18 2C-T-2, 2.89 2C-B-fly, 2.89 cis-2a, 2.74 lisuride, 2.58 DMT, 2.47 6-F-DMT, 2.44 5-MeO-MIPT, 2.42 Aleph-2, 2.36 DOM, 2.32 SS-2c, 2.21 MEM, 2.16 ibogaine, 2.14 psilocin, 2.09 DPT, 1.46 RR-2b, 0.98 5-MeO-DMT; 0.00: TMA, DIPT, MDA, MDMA, mescaline, 5-MeO-TMT, EMDT, 5-MeO-DIPT, salvinorin A; ND: morphine, THC

5ht2c: 4.00 DOI, 3.42 DMT, 3.38 2C-E, 3.18 2C-B, 3.13 DOET, 3.11 LSD, 3.09 4C-T-2, 3.05 2C-T-2, 3.02 TMA, 2.97 DOB, 2.93 2C-B-fly, 2.58 TMA-2, 2.58 6-F-DMT, 2.52 psilocin, 2.50 Aleph-2, 2.34 cis-2a, 2.31 DPT, 2.17 5-MeO-TMT, 2.15 MDA, 2.03 SS-2c, 1.95 EMDT, 1.75 5-MeO-MIPT, 1.63 RR-2b, 1.55 5-MeO-DMT, 1.47 DOM; 0.00: 5-MeO-DIPT, mescaline, lisuride, MEM, MDMA, DIPT, ibogaine, salvinorin A; ND: morphine, THC

Alpha2C: 4.00 mescaline, 3.88 lisuride, 3.60 MDA, 3.53 DMT, 3.44 2C-E, 3.24 6-F-DMT, 3.21 MDMA, 3.12 2C-B, 2.98 TMA, 2.88 DOI, 2.79 DPT, 2.68 DIPT, 2.66 5-MeO-DIPT, 2.56 2C-T-2, 2.29 5-MeO-MIPT, 2.10 DOM, 2.00 DOET, 1.82 DOB, 1.59 2C-B-fly, 1.57 5-MeO-DMT, 1.06 Aleph-2, 1.03 psilocin; 0.00: 4C-T-2, MEM, TMA-2; ND: LSD, cis-2a, RR-2b, SS-2c, 5-MeO-TMT, EMDT, ibogaine, salvinorin A, morphine, THC

5ht6: 4.00 6-F-DMT, 4.00 EMDT, 4.00 5-MeO-TMT, 3.75 LSD, 3.25 cis-2a, 3.25 DMT, 2.98 5-MeO-MIPT, 2.82 psilocin, 2.73 5-MeO-DMT, 2.63 2C-B, 2.61 lisuride, 2.52 RR-2b, 2.44 SS-2c, 2.34 DOI, 1.93 2C-E, 1.85 DPT, 1.78 2C-B-fly, 1.64 2C-T-2, 1.16 DOM, 0.85 DOB, 0.72 Aleph-2; 0.00: 4C-T-2, 5-MeO-DIPT, mescaline, TMA, TMA-2, MDA, DOET, MEM, MDMA, DIPT, salvinorin A; ND: ibogaine, morphine, THC

5ht1b: 4.00 LSD, 4.00 RR-2b, 3.79 cis-2a, 3.22 SS-2c, 3.22 TMA, 3.11 2C-B, 3.07 6-F-DMT, 3.00 2C-E, 2.61 5-MeO-MIPT, 2.57 DPT, 2.41 5-MeO-DIPT, 2.41 5-MeO-DMT, 2.27 lisuride, 2.19 psilocin, 1.84 2C-T-2, 1.71 DOET, 1.69 2C-B-fly, 1.62 DOB, 0.90 Aleph-2; 0.00: 4C-T-2, MDMA, mescaline, DMT, DIPT, TMA-2, DOM, MDA, DOI, MEM, ibogaine, salvinorin A; ND: 5-MeO-TMT, EMDT, morphine, THC

5ht1e: 3.28 DMT, 3.16 mescaline, 3.15 TMA, 3.05 2C-B, 3.03 psilocin, 2.74 6-F-DMT, 2.66 DOI, 2.62 LSD, 2.60 2C-E, 2.52 5-MeO-TMT, 2.49 EMDT, 2.16 2C-T-2, 2.16 RR-2b, 2.13 DPT, 2.07 cis-2a, 1.91 2C-B-fly, 1.83 lisuride, 1.77 4C-T-2, 1.72 5-MeO-DMT, 1.61 DOET, 1.55 5-MeO-MIPT, 1.52 DOM, 1.44 DOB, 1.16 SS-2c, 0.71 Aleph-2; 0.00: 5-MeO-DIPT, TMA-2, MDA, MEM, MDMA, DIPT, salvinorin A; ND: ibogaine, morphine, THC

Alpha2A: 3.79 DOI, 3.36 TMA, 3.22 lisuride, 2.94 MDMA, 2.93 LSD, 2.92 mescaline, 2.85 5-MeO-MIPT, 2.84 DPT, 2.75 DMT, 2.74 MDA, 2.71 2C-E, 2.64 2C-B, 2.30 DOM, 2.05 DOET, 1.92 2C-T-2, 1.79 2C-B-fly, 1.36 psilocin, 1.00 5-MeO-DMT, 0.96 DOB, 0.44 Aleph-2; 0.00: 4C-T-2, DIPT, 5-MeO-DIPT, MEM, TMA-2, 6-F-DMT; ND: cis-2a, RR-2b, SS-2c, 5-MeO-TMT, EMDT, ibogaine, salvinorin A, morphine, THC

Alpha2B: 3.78 lisuride, 3.53 DMT, 3.13 DOI, 3.12 MDA, 3.09 MDMA, 2.99 6-F-DMT, 2.97 DPT, 2.91 2C-E, 2.62 DIPT, 2.40 DOET, 2.40 5-MeO-DIPT, 2.31 2C-B, 2.13 DOM, 1.86 5-MeO-MIPT, 1.79 2C-T-2, 1.57 psilocin, 1.41 DOB, 1.16 2C-B-fly, 0.86 5-MeO-DMT, 0.74 Aleph-2; 0.00: 4C-T-2, mescaline, TMA, MEM, TMA-2; ND: LSD, cis-2a, RR-2b, SS-2c, 5-MeO-TMT, EMDT, ibogaine, salvinorin A, morphine, THC

Imidazoline1: 4.00 MDMA, 3.53 DIPT, 3.44 mescaline, 3.24 5-MeO-DIPT, 3.13 DMT, 2.97 DPT, 2.79 4C-T-2, 2.45 6-F-DMT, 2.15 5-MeO-MIPT, 1.80 2C-B, 1.77 psilocin, 1.70 Aleph-2, 1.46 2C-T-2, 1.39 DOB, 0.88 5-MeO-DMT; 0.00: MEM, 2C-E, MDA, lisuride, DOI, 2C-B-fly, DOM, TMA, DOET; ND: TMA-2, LSD, cis-2a, RR-2b, SS-2c, 5-MeO-TMT, EMDT, ibogaine, salvinorin A, morphine, THC

5ht5a: 3.64 LSD, 3.20 RR-2b, 3.16 DMT, 3.15 cis-2a, 2.99 lisuride, 2.83 psilocin, 2.56 4C-T-2, 2.43 6-F-DMT, 2.17 SS-2c, 2.11 5-MeO-MIPT, 1.86 DPT, 1.84 5-MeO-DMT, 1.76 5-MeO-TMT, 1.54 EMDT, 0.87 DOB; 0.00: MDMA, 5-MeO-DIPT, 2C-B, MDA, mescaline, 2C-B-fly, DOI, TMA, DOET, TMA-2, 2C-E, 2C-T-2, Aleph-2, MEM, DOM, DIPT, salvinorin A; ND: ibogaine, morphine, THC

D3: 3.46 cis-2a, 3.16 LSD, 2.82 SS-2c, 2.67 psilocin, 2.66 4C-T-2, 2.56 DIPT, 2.47 6-F-DMT, 2.40 RR-2b, 2.37 DPT, 2.27 2C-E, 1.70 5-MeO-MIPT, 1.68 DOB, 1.58 5-MeO-DMT, 1.51 2C-T-2, 1.47 ibogaine, 1.41 Aleph-2, 1.34 lisuride, 1.28 2C-B; 0.00: MDMA, mescaline, MEM, DMT, TMA, DOET, TMA-2, DOM, MDA, DOI, salvinorin A, 5-MeO-TMT, EMDT, 5-MeO-DIPT; ND: 2C-B-fly, morphine, THC

Sigma1: 3.95 TMA, 3.05 4C-T-2, 2.90 DPT, 2.83 DIPT, 2.55 ibogaine, 2.23 DMT, 2.15 5-MeO-DIPT, 2.10 MEM, 1.83 Aleph-2, 1.73 DOI, 1.57 6-F-DMT, 1.25 DOB, 1.19 2C-T-2, 1.17 DOET; 0.00: 2C-B, mescaline, 5-MeO-MIPT, DOM, 2C-B-fly, 5-MeO-DMT, psilocin; ND: 2C-E, lisuride, MDA, TMA-2, LSD, cis-2a, MDMA, SS-2c, 5-MeO-TMT, EMDT, RR-2b, salvinorin A, morphine, THC

SERT: 3.57 ibogaine, 3.31 DPT, 3.25 6-F-DMT, 2.98 DIPT, 2.83 DOI, 2.72 5-MeO-DIPT, 2.37 DMT, 1.74 psilocin, 1.28 5-MeO-MIPT, 1.08 Aleph-2, 0.97 5-MeO-DMT, 0.66 DOB; 0.00: 2C-E, MDA, 2C-B, mescaline, 4C-T-2, 2C-T-2, lisuride, MEM, 2C-B-fly, DOM, TMA, MDMA, TMA-2, LSD, cis-2a, RR-2b, SS-2c, 5-MeO-TMT, EMDT, DOET, salvinorin A; ND: morphine, THC

Beta2: 3.67 4C-T-2, 3.52 DOI, 3.38 DOM, 2.79 Aleph-2, 2.11 DOB, 1.93 lisuride, 1.82 DOET, 1.70 2C-T-2, 1.05 LSD, 0.70 cis-2a, 0.57 SS-2c; 0.00: 5-MeO-DMT, DMT, mescaline, DIPT, DPT, 5-MeO-MIPT, 6-F-DMT, 5-MeO-DIPT, MDMA, 2C-B-fly, psilocin, TMA, TMA-2, MDA, MEM, salvinorin A; ND: 2C-B, 2C-E, RR-2b, 5-MeO-TMT, ibogaine, EMDT, morphine, THC

Sigma2: 4.00 ibogaine, 3.95 TMA, 2.65 DIPT, 2.64 5-MeO-DIPT, 2.13 5-MeO-MIPT, 2.04 DPT, 1.70 DOI, 1.56 6-F-DMT, 1.18 DOET; 0.00: 2C-T-2, 2C-E, mescaline, 2C-B, DOB, Aleph-2, MEM, 4C-T-2, DOM, DMT, 5-MeO-DMT, 2C-B-fly, psilocin; ND: lisuride, MDA, TMA-2, LSD, cis-2a, MDMA, SS-2c, 5-MeO-TMT, EMDT, RR-2b, salvinorin A, morphine, THC

H1: 3.74 6-F-DMT, 3.41 DPT, 3.04 TMA-2, 2.53 DIPT, 2.42 DOI, 1.66 cis-2a, 1.41 5-MeO-MIPT, 1.40 LSD, 1.14 RR-2b, 0.63 DOB, 0.20 SS-2c, 0.19 2C-B-fly; 0.00: psilocin, 2C-B, 5-MeO-DIPT, TMA, 4C-T-2, 2C-E, 2C-T-2, MDMA, mescaline, DOM, EMDT, DOET, salvinorin A, 5-MeO-TMT, MEM, Aleph-2, ibogaine; ND: lisuride, DMT, MDA, 5-MeO-DMT, morphine, THC

D1: 3.51 DMT, 3.37 psilocin, 2.67 6-F-DMT, 2.38 5-MeO-DMT, 2.34 LSD, 2.00 cis-2a, 1.77 RR-2b, 1.67 DOI, 1.14 SS-2c, 0.26 2C-B-fly; 0.00: 2C-B, MDA, 5-MeO-MIPT, DIPT, 5-MeO-DIPT, DPT, 4C-T-2, DOB, lisuride, MDMA, mescaline, DOM, TMA, DOET, TMA-2, 2C-E, 2C-T-2, Aleph-2, MEM, 5-MeO-TMT, EMDT, ibogaine, salvinorin A; ND: morphine, THC

D2: 2.67 cis-2a, 2.65 lisuride, 2.62 6-F-DMT, 2.55 LSD, 1.88 RR-2b, 1.88 2C-E, 1.74 SS-2c, 1.60 2C-B, 1.54 DPT, 1.33 2C-T-2, 0.73 5-MeO-DMT, 0.12 2C-B-fly; 0.00: psilocin, 5-MeO-MIPT, 5-MeO-DIPT, DMT, 4C-T-2, DIPT, MDMA, DOI, mescaline, DOM, TMA, DOET, TMA-2, DOB, MDA, Aleph-2, MEM, 5-MeO-TMT, EMDT, ibogaine, salvinorin A; ND: morphine, THC

D4: 2.90 lisuride, 2.49 cis-2a, 2.39 LSD, 2.25 6-F-DMT, 2.20 DPT, 2.08 RR-2b, 1.62 SS-2c, 1.29 5-MeO-MIPT, 0.78 5-MeO-DMT; 0.00: psilocin, MDMA, DMT, 2C-B, DIPT, 5-MeO-DIPT, mescaline, 4C-T-2, DOB, MDA, DOI, 2C-B-fly, DOM, TMA, DOET, TMA-2, 2C-E, 2C-T-2, Aleph-2, MEM, 5-MeO-TMT, EMDT, salvinorin A; ND: ibogaine, morphine, THC

M3: 3.07 MDMA, 2.51 DOI, 2.22 2C-B, 2.22 ibogaine, 1.99 2C-E, 1.94 2C-T-2, 1.53 DOB, 1.42 2C-B-fly, 0.92 Aleph-2; 0.00: DMT, lisuride, 5-MeO-DMT, 5-MeO-MIPT, DIPT, psilocin, DPT, 4C-T-2, 6-F-DMT, mescaline, MEM, salvinorin A, 5-MeO-DIPT; ND: MDA, DOM, TMA, LSD, cis-2a, RR-2b, SS-2c, 5-MeO-TMT, EMDT, DOET, TMA-2, morphine, THC

Alpha1A: 3.17 6-F-DMT, 2.70 DMT, 2.56 DPT, 2.09 lisuride, 1.64 cis-2a, 1.56 DOM, 1.54 LSD, 0.67 SS-2c, 0.59 RR-2b; 0.00: psilocin, MDMA, mescaline, 5-MeO-MIPT, DIPT, 5-MeO-DIPT, 5-MeO-DMT, 4C-T-2, DOB, MDA, DOI, 2C-B-fly, 2C-B, TMA, DOET, TMA-2, 2C-E, 2C-T-2, Aleph-2, MEM, salvinorin A; ND: 5-MeO-TMT, ibogaine, EMDT, morphine, THC

KOR: 4.00 salvinorin A, 2.88 ibogaine, 2.21 morphine; 0.00: MDA, 2C-B, DMT, MDMA, mescaline, DOB, 2C-T-2, Aleph-2, MEM, 5-MeO-MIPT, DIPT, psilocin, 5-MeO-DMT, 2C-E, LSD, lisuride, DOI, 2C-B-fly, DOM, TMA, DOET, DPT, 4C-T-2, cis-2a, RR-2b, SS-2c, 5-MeO-TMT, EMDT, 5-MeO-DIPT; ND: TMA-2, 6-F-DMT, THC

Beta1: 2.89 DOI, 2.56 lisuride, 1.76 cis-2a, 1.72 SS-2c, 1.40 DOET, 1.39 LSD, 1.21 DOB, 0.81 2C-T-2, 0.37 Aleph-2; 0.00: 5-MeO-DMT, DMT, mescaline, DOM, DIPT, 5-MeO-MIPT, DPT, 4C-T-2, 6-F-DMT, 5-MeO-DIPT, MDMA, 2C-B-fly, 2C-E, TMA, psilocin, TMA-2, ibogaine, MDA, MEM, salvinorin A; ND: 2C-B, 5-MeO-TMT, RR-2b, EMDT, morphine, THC

MOR: 4.00 morphine, 2.67 ibogaine; 0.00: lisuride, mescaline, 2C-B, TMA, MDMA, DPT, DOB, 2C-T-2, Aleph-2, MEM, 5-MeO-MIPT, DIPT, psilocin, DOET, 2C-E, LSD, cis-2a, DOI, 2C-B-fly, DOM, EMDT, 5-MeO-DIPT, salvinorin A, 4C-T-2, SS-2c, RR-2b, 5-MeO-TMT; ND: MDA, DMT, 5-MeO-DMT, TMA-2, 6-F-DMT, THC

M5: 2.54 MDMA, 2.32 DOI, 2.16 2C-E, 1.60 2C-T-2, 1.01 2C-B-fly, 0.30 Aleph-2; 0.00: 2C-B, DMT, DOB, MDA, DOET, 5-MeO-DMT, 5-MeO-MIPT, DIPT, 5-MeO-DIPT, DPT, 4C-T-2, 6-F-DMT, lisuride, MEM, mescaline, DOM, TMA, TMA-2, salvinorin A; ND: psilocin, LSD, RR-2b, cis-2a, 5-MeO-TMT, EMDT, ibogaine, SS-2c, morphine, THC

Alpha1B: 2.95 DMT, 2.86 DPT, 1.08 lisuride, 0.65 LSD; 0.00: MDMA, 2C-B, psilocin, mescaline, DOB, 2C-T-2, Aleph-2, MEM, 5-MeO-MIPT, DIPT, 5-MeO-DIPT, 5-MeO-DMT, 4C-T-2, 6-F-DMT, MDA, DOI, 2C-B-fly, DOM, TMA, DOET, TMA-2, 2C-E, cis-2a, RR-2b, SS-2c, salvinorin A; ND: 5-MeO-TMT, ibogaine, EMDT, morphine, THC

CB1: 4.00 THC; 0.00: MDA, MDMA, mescaline, 2C-B, DMT, psilocin, 5-MeO-DMT, 2C-E, 2C-T-2, Aleph-2, MEM, 2C-B-fly, DIPT, 5-MeO-DIPT, DPT, 4C-T-2, DOB, lisuride, DOI, TMA, DOM, 6-F-DMT, DOET; ND: 5-MeO-MIPT, LSD, TMA-2, RR-2b, SS-2c, 5-MeO-TMT, EMDT, ibogaine, salvinorin A, morphine, cis-2a

M4: 2.90 DOI, 2.43 MDMA, 1.24 2C-B-fly; 0.00: DOB, 2C-B, lisuride, psilocin, DMT, 2C-E, 2C-T-2, Aleph-2, 5-MeO-DMT, 5-MeO-MIPT, DIPT, 5-MeO-DIPT, DPT, 4C-T-2, 6-F-DMT, mescaline, MEM, salvinorin A; ND: DOM, MDA, DOET, TMA, LSD, cis-2a, RR-2b, SS-2c, 5-MeO-TMT, EMDT, ibogaine, TMA-2, morphine, THC

DAT: 3.02 ibogaine, 2.33 DPT; 0.00: DOB, MDA, 2C-B, DMT, MDMA, mescaline, 2C-E, 2C-T-2, Aleph-2, MEM, 5-MeO-MIPT, DIPT, psilocin, 5-MeO-DMT, 4C-T-2, 6-F-DMT, lisuride, DOI, 2C-B-fly, DOM, TMA, DOET, TMA-2, LSD, cis-2a, RR-2b, SS-2c, 5-MeO-TMT, EMDT, 5-MeO-DIPT, salvinorin A; ND: morphine, THC

D5: 2.05 LSD, 1.61 6-F-DMT, 1.59 lisuride, 1.53 RR-2b, 1.36 cis-2a, 1.00 SS-2c; 0.00: psilocin, 5-MeO-DMT, 2C-B, DMT, MDMA, mescaline, 5-MeO-MIPT, DIPT, 5-MeO-DIPT, DPT, 4C-T-2, DOB, MDA, DOI, 2C-B-fly, DOM, TMA, DOET, TMA-2, 2C-E, 2C-T-2, Aleph-2, MEM, 5-MeO-TMT, EMDT, salvinorin A; ND: ibogaine, morphine, THC

CB2: 3.78 THC; 0.00: MDA, DOI, mescaline, 2C-B, DMT, psilocin, 5-MeO-DMT, 2C-E, 2C-T-2, Aleph-2, MEM, 5-MeO-MIPT, DIPT, 5-MeO-DIPT, DPT, 4C-T-2, DOB, lisuride, DOET, 2C-B-fly, DOM, TMA, 6-F-DMT; ND: MDMA, LSD, TMA-2, RR-2b, SS-2c, 5-MeO-TMT, EMDT, ibogaine, salvinorin A, morphine, cis-2a

Ca+Channel: 3.26 MDMA; 0.00: lisuride, DOB, mescaline, 5-MeO-MIPT, DMT, psilocin, 5-MeO-DMT, 2C-E, 2C-T-2, Aleph-2, MEM, 4C-T-2, DIPT, 5-MeO-DIPT, DPT, 6-F-DMT; ND: 2C-B, MDA, DOI, 2C-B-fly, DOM, TMA, DOET, TMA-2, LSD, cis-2a, RR-2b, SS-2c, 5-MeO-TMT, EMDT, ibogaine, salvinorin A, morphine, THC

M1: 2.23 DOI, 1.96 ibogaine, 1.15 2C-B-fly; 0.00: lisuride, DOB, DMT, 2C-B, 5-MeO-DMT, 2C-E, 2C-T-2, Aleph-2, MEM, 5-MeO-MIPT, DIPT, psilocin, DPT, 4C-T-2, 6-F-DMT, mescaline, MDMA, salvinorin A, DOM, 5-MeO-DIPT; ND: MDA, TMA, LSD, cis-2a, RR-2b, SS-2c, 5-MeO-TMT, EMDT, DOET, TMA-2, morphine, THC

NMDA: 3.01 ibogaine; 0.00: 2C-T-2, DOB, mescaline, 2C-B, TMA, MDMA, DPT, 2C-E, 6-F-DMT, Aleph-2, MEM, 5-MeO-MIPT, DIPT, DOET, 5-MeO-DIPT, 4C-T-2, DOM, DOI; ND: lisuride, 2C-B-fly, MDA, DMT, 5-MeO-DMT, TMA-2, LSD, cis-2a, RR-2b, SS-2c, 5-MeO-TMT, EMDT, psilocin, salvinorin A, morphine, THC

M2: 2.36 DOI, 1.72 ibogaine, 0.65 2C-B-fly; 0.00: MDA, DOB, DMT, 2C-B, 5-MeO-DMT, 2C-E, 2C-T-2, Aleph-2, MEM, 5-MeO-MIPT, DIPT, psilocin, DPT, 4C-T-2, 6-F-DMT, lisuride, MDMA, mescaline, DOM, TMA, DOET, TMA-2, 5-MeO-DIPT, salvinorin A; ND: LSD, cis-2a, 5-MeO-TMT, EMDT, RR-2b, SS-2c, morphine, THC

H2: 2.44 6-F-DMT, 1.42 lisuride; 0.00: MDMA, mescaline, 2C-B, DMT, psilocin, 5-MeO-DMT, 2C-E, 2C-T-2, Aleph-2, MEM, 5-MeO-MIPT, DIPT, 5-MeO-DIPT, DPT, 4C-T-2, DOB, MDA, DOI, 2C-B-fly, DOM, TMA, DOET, TMA-2, 5-MeO-TMT, EMDT; ND: RR-2b, SS-2c, LSD, cis-2a, ibogaine, salvinorin A, morphine, THC

NET: 1.97 5-MeO-TMT, 0.82 5-MeO-DMT; 0.00: MDMA, MDA, DOB, DMT, psilocin, mescaline, 2C-E, 2C-T-2, Aleph-2, MEM, 2C-B, DIPT, 5-MeO-DIPT, DPT, 4C-T-2, 6-F-DMT, lisuride, DOI, 2C-B-fly, DOM, TMA, DOET, TMA-2, LSD, cis-2a, RR-2b, SS-2c, 5-MeO-MIPT, EMDT; ND: ibogaine, salvinorin A, morphine, THC

DOR: 0.72 morphine; 0.00: 2C-T-2, DOI, mescaline, 2C-B, TMA, psilocin, DPT, DOB, LSD, Aleph-2, MEM, 5-MeO-MIPT, DIPT, 5-MeO-DIPT, DOET, 2C-E, 4C-T-2, cis-2a, RR-2b, 2C-B-fly, DOM, EMDT, ibogaine, salvinorin A, 5-MeO-TMT, SS-2c; ND: MDMA, lisuride, MDA, DMT, 5-MeO-DMT, TMA-2, 6-F-DMT, THC

Activity Data

The NIMH-PDSP provided activity data for the twenty-five drugs of Fig. 1, for 5-HT_2A and 5-HT_2C (Table S3). While most compounds appear to be full agonists at the two receptors, there are a few exceptions. Lower values of activity were reported for psilocin, MDMA, DOM and the three control drugs: 4C-T-2, 6-fluoro-DMT, and lisuride.